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Hereditary Neuropathy v0.149 CNTNAP1 Sangavi Sivagnanasundram reviewed gene: CNTNAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29511323, 27881385; Phenotypes: Hypomyelinating neuropathy, congenital, 3 (MONDO:0017049, MIM#618186); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary Neuropathy v0.149 BAG3 Sangavi Sivagnanasundram reviewed gene: BAG3: Rating: AMBER; Mode of pathogenicity: None; Publications: 19085932; Phenotypes: Myopathy, myofibrillar, 6 (MIM#612954, MONDO:0013061); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cerebral Palsy v1.36 COL4A1 Luisa Weiss reviewed gene: COL4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33528536, 34531397; Phenotypes: Brain small vessel disease MIM#614483; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary Neuropathy v0.149 B4GALNT1 Sangavi Sivagnanasundram edited their review of gene: B4GALNT1: Changed rating: AMBER
Cerebral Palsy v1.36 CLTC Luisa Weiss gene: CLTC was added
gene: CLTC was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: CLTC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLTC were set to 33528536; 31776469
Phenotypes for gene: CLTC were set to Intellectual developmental disorder MIM#617854
Review for gene: CLTC was set to GREEN
Added comment: One large CP cohort study with one patient reported.

One more publication with 13 cases of syndromic ID due to heterozygous CLTC mutations. Cerebral palsy affecting gait recurrently seen in these individuals.
Sources: Literature
Hereditary Neuropathy v0.149 B4GALNT1 Sangavi Sivagnanasundram changed review comment from: Variable age of onset (typically during juvenile aged). Mutations in B4GALNT1 are known to be a rarer and more complicated form of SPG compared to other genes. (PMID: 20301682)

PMID: 23746551
5 unrelated families with gait abnormalities due to lower limb spasticity, hyperreflexia, extensor plantar responses, muscle weakness and atrophy, and mild to moderate intellectual disability.
All affected individuals in the families had homozygous mutations in B4GALNT1; to: Neuropathy is not a prominent feature in individuals

Variable age of onset (typically during juvenile aged). Mutations in B4GALNT1 are known to be a rarer and more complicated form of SPG compared to other genes. (PMID: 20301682)

PMID: 23746551
5 unrelated families with gait abnormalities due to lower limb spasticity, hyperreflexia, extensor plantar responses, muscle weakness and atrophy, and mild to moderate intellectual disability.
All affected individuals in the families had homozygous mutations in B4GALNT1
Hereditary Neuropathy v0.149 B4GALNT1 Sangavi Sivagnanasundram edited their review of gene: B4GALNT1: Changed rating: RED
Cerebral Palsy v1.36 CLCN4 Luisa Weiss gene: CLCN4 was added
gene: CLCN4 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: CLCN4 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: CLCN4 were set to 34788679
Phenotypes for gene: CLCN4 were set to Raynaud-Claes syndrome MIM#300114
Review for gene: CLCN4 was set to AMBER
Added comment: One female patient presented in a large cohort study with phenotypic overlap to Raynaud-Claes syndrome (ID, epilepsy and language deficits). The mutation is a heterozygous missense mutation previously reported to cause Raynaud-Claes syndrome.
Sources: Literature
Hereditary Neuropathy v0.149 B4GALNT1 Sangavi Sivagnanasundram reviewed gene: B4GALNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301682, 23746551; Phenotypes: Spastic paraplegia 26, autosomal recessive (MIM#609195, MONDO:0012213); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebral Palsy v1.36 ATP7B Luisa Weiss gene: ATP7B was added
gene: ATP7B was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: ATP7B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP7B were set to 34788679
Phenotypes for gene: ATP7B were set to Wilson disease MIM#277900
Review for gene: ATP7B was set to RED
Added comment: One reported case in a large CP cohort study with two mutations in ATP7B, however bi-parental inheritance was not confirmed. Low evidence for causality.
Sources: Literature
Cerebral Palsy v1.36 CHD8 Luisa Weiss gene: CHD8 was added
gene: CHD8 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: CHD8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD8 were set to 33528536
Phenotypes for gene: CHD8 were set to Intellectual developmental disorder with autism and macrocephaly #615032
Review for gene: CHD8 was set to GREEN
Added comment: 3 individual cases in one large cohort study, two de novo missense mutations and one frameshift mutation with unknown inheritance.
Sources: Literature
Cerebral Palsy v1.36 CDKL5 Luisa Weiss gene: CDKL5 was added
gene: CDKL5 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: CDKL5 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: CDKL5 were set to 33528536; 34788679
Review for gene: CDKL5 was set to AMBER
Added comment: 2 individual cases in two independent large cohort studies. One mutation reported as a mosaic nonsense mutation, the other one reported as a de novo hemizygous frameshift mutation. No phenotype information given.
Sources: Literature
Cerebral Palsy v1.36 CASK Luisa Weiss gene: CASK was added
gene: CASK was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: CASK was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: CASK were set to 33528536
Phenotypes for gene: CASK were set to Intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia MIM#300749
Review for gene: CASK was set to GREEN
Added comment: 4 individual cases in one large CP cohort study. 3 of them confirmed de novo nonsense mutations, one in-frame five AA deletion with unknown inheritance. All reported to be heterozygous in an X-linked gene and thus affecting females as known for the allelic disease ID with pontine and cerebellar hypoplasia.
Sources: Literature
Cerebral Palsy v1.36 CACNA1A Luisa Weiss reviewed gene: CACNA1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 29761117, 33528536, 34364746, 34531397, 34788679; Phenotypes: Developmental and epileptic encephalopathy MIM#617106, Episodic ataxia MIM#108500, familial hemiplegic Migraine MIM#141500 and MIM#141500, Spinocerebellar ataxia MIM#183086; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cerebral Palsy v1.36 BRAT1 Luisa Weiss gene: BRAT1 was added
gene: BRAT1 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: BRAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BRAT1 were set to 29997391
Phenotypes for gene: BRAT1 were set to Neurodevelopmental disorder with cerebellar atrophy and with or without seizures MIM#618056; neonatal lethal rigidity and multifocal seizure syndrome MIM#614498
Review for gene: BRAT1 was set to AMBER
Added comment: Biallelic BRAT1 mutations cause a neurodevelopmental phenotype with evidence of marked genotype–phenotype correlation: homozygous null variants result in a severe phenotype, whereas compound heterozygosity for null/hypomorphic variants is associated with a milder phenotype. In one study one patient with homozygous hypomorphic variants was diagnosed as a congenital cerebral palsy due to spastic paraplegia.
Sources: Literature
Cerebral Palsy v1.36 BCL11A Luisa Weiss reviewed gene: BCL11A: Rating: GREEN; Mode of pathogenicity: None; Publications: 35856171, 33528536, 34077496; Phenotypes: Dias-Logan syndrome, MIM#617101; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Repeat Disorders v0.153 SCA27B Bryony Thompson Marked STR: SCA27B as ready
Repeat Disorders v0.153 SCA27B Bryony Thompson Str: sca27b has been classified as Green List (High Evidence).
Repeat Disorders v0.153 SCA27B Bryony Thompson Classified STR: SCA27B as Green List (high evidence)
Repeat Disorders v0.153 SCA27B Bryony Thompson Str: sca27b has been classified as Green List (High Evidence).
Repeat Disorders v0.152 SCA27B Bryony Thompson STR: SCA27B was added
STR: SCA27B was added to Repeat Disorders. Sources: Literature
Mode of inheritance for STR: SCA27B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA27B were set to 37165652; 36516086; 36493768
Phenotypes for STR: SCA27B were set to Spinocerebellar ataxia type 27B MONDO:0012247; Spinocerebellar ataxia 50; late-onset cerebellar ataxias (LOCAs)
Review for STR: SCA27B was set to GREEN
STR: SCA27B was marked as clinically relevant
Added comment: NM_175929.3(FGF14):c.208+239747CTT[X]
Expansions of 250 or more GAA repeat units were associated with late-onset cerebellar ataxia in a French-Canadian (OR: 105.60 [95% CI=31.09-334.20], p<0.001) and a German (OR: 8.76 [95% CI=3.45-20.84], p<0.001) case-control series. Additionally, expanded alleles greater than (GAA)332 are pathogenic and fully penetrant in a combined Australian and German dataset (p = 6.0 × 10−8, OR = 72 [95% CI = 4.3–1,227]). Whereas, alleles in the range of (GAA)250-334 are likely to be pathogenic with reduced penetrance (p = 0.0015, OR = 3.6 [95% CI = 1.6–7.9]).
250-300 repeats in the incompletely penetrant range
>300 is fully penetrant for ataxia
Sources: Literature
Cerebral Palsy v1.36 ATP8A2 Luisa Weiss gene: ATP8A2 was added
gene: ATP8A2 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: ATP8A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP8A2 were set to 35321980; 30542205; 34077496
Phenotypes for gene: ATP8A2 were set to Cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome, MIM#615268
Review for gene: ATP8A2 was set to GREEN
Added comment: 4 individuals from 3 families with biallelic mutations in ATP8A2 and CP. 3/4 patients presented with intellectual disability.

PMID 35321980: Two sibling reported with a non-progressive dyskinetic cerebral palsy resembling cerebellar ataxia (athetotic movements, ptosis, ophthalmoplegia, hypotonia, delayed development)

PMID 30542205: One patient with atypical CP (atypical due to intellectual disability)because intell dis and typical neurologic pattern (hypertonia, ataxia or transient episodic exacerbations of neurologic symptoms)

PMID 34077496: One patient with CP and microcephaly likely due to simultaneously present biallelic CIT mutations
Sources: Literature
Cerebral Palsy v1.36 ATP7A Luisa Weiss gene: ATP7A was added
gene: ATP7A was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: ATP7A was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: ATP7A were set to 35322241; 33528536; 34788679
Phenotypes for gene: ATP7A were set to Menkes disease MIM#3094009
Review for gene: ATP7A was set to GREEN
Added comment: 3 individuals from 3 different publications with CP. Two patients were male with de novo splice affecting mutations. One patient was female with a heterozygous de novo frameshift mutation in ATP7B causative for the disease as described before for Menkes disease.
Sources: Literature
Cerebral Palsy v1.36 ATM Luisa Weiss gene: ATM was added
gene: ATM was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: ATM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATM were set to 34364746; 26380989; 34114234
Phenotypes for gene: ATM were set to Ataxia-telangiectasia, MIM#208900
Review for gene: ATM was set to GREEN
Added comment: 3 individuals presenting with CP and harboring biallelic compound heterozygous mutations in ATM. At least one the individual had an overlapping phenotype of CP with Ataxia Teleangiectasia
Sources: Literature
Cerebral Palsy v1.36 ARID2 Luisa Weiss gene: ARID2 was added
gene: ARID2 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: ARID2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARID2 were set to 33528536
Phenotypes for gene: ARID2 were set to Coffin-Siris syndrome, MIM#617808
Review for gene: ARID2 was set to GREEN
Added comment: Large cohort study with three individual cases with CP and de novo ARID2 mutations (2 nonsense and 1 frameshift mutation)
Sources: Literature
Cerebral Palsy v1.36 ARG1 Luisa Weiss gene: ARG1 was added
gene: ARG1 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: ARG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARG1 were set to 35505270; 34788679
Phenotypes for gene: ARG1 were set to Argininemia MIM#207800
Review for gene: ARG1 was set to GREEN
Added comment: Literature review: Three independent cases have been published with biallelic mutations in ARG1 and presenting with cerebral palsy. Two patients harbored a recurrent splice site mutation, one patient presented with compound heterozygous missense mutations.
Sources: Literature
Mendeliome v1.891 SCN4A Zornitza Stark Phenotypes for gene: SCN4A were changed from Hyperkalemic periodic paralysis, type 2, MIM# 170500; Hypokalemic periodic paralysis, type 2, MIM# 613345; Myasthenic syndrome, congenital, 16, MIM# 614198; Myotonia congenita, atypical, acetazolamide-responsive , MIM#608390; Paramyotonia congenita , MIM#168300 to Congenital myopathy 22A, classic, MIM# 620351; Congenital myopathy 22B, severe fetal, MIM# 620369; Hyperkalemic periodic paralysis, type 2, MIM# 170500; Hypokalemic periodic paralysis, type 2, MIM# 613345; Myasthenic syndrome, congenital, 16, MIM# 614198; Myotonia congenita, atypical, acetazolamide-responsive , MIM#608390; Paramyotonia congenita , MIM#168300
Mendeliome v1.890 SCN4A Zornitza Stark edited their review of gene: SCN4A: Changed phenotypes: Congenital myopathy 22A, classic, MIM# 620351, Congenital myopathy 22B, severe fetal, MIM# 620369, Hyperkalemic periodic paralysis, type 2, MIM# 170500, Hypokalemic periodic paralysis, type 2, MIM# 613345, Myasthenic syndrome, congenital, 16, MIM# 614198, Myotonia congenita, atypical, acetazolamide-responsive , MIM#608390, Paramyotonia congenita , MIM#168300
Fetal anomalies v1.108 SCN4A Zornitza Stark Phenotypes for gene: SCN4A were changed from Congenital myopathy; Myasthenic syndrome, congenital, 16 MIM#614198 to Congenital myopathy 22B, severe fetal, MIM# 620369; Myasthenic syndrome, congenital, 16 MIM#614198
Fetal anomalies v1.107 SCN4A Zornitza Stark reviewed gene: SCN4A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital myopathy 22B, severe fetal, MIM# 620369; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Renal Tubulopathies and related disorders v1.9 OXGR1 Zornitza Stark Phenotypes for gene: OXGR1 were changed from Nephrolithiasis/nephrocalcinosis, MONDO:0008171, OXGR1-related to Nephrolithiasis, calcium oxalate, 2, with nephrocalcinosis, MIM# 620374
Renal Tubulopathies and related disorders v1.8 OXGR1 Zornitza Stark reviewed gene: OXGR1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Nephrolithiasis, calcium oxalate, 2, with nephrocalcinosis, MIM# 620374; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.890 OXGR1 Zornitza Stark Phenotypes for gene: OXGR1 were changed from Nephrolithiasis/nephrocalcinosis MONDO:0008171, OXGR1-related to Nephrolithiasis, calcium oxalate, 2, with nephrocalcinosis, MIM# 620374
Mendeliome v1.889 OXGR1 Zornitza Stark reviewed gene: OXGR1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Nephrolithiasis, calcium oxalate, 2, with nephrocalcinosis, MIM# 620374; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cerebral Palsy v1.36 AKT3 Luisa Weiss gene: AKT3 was added
gene: AKT3 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: AKT3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AKT3 were set to 34354878; 30542205; 32989326
Review for gene: AKT3 was set to AMBER
Added comment: Two individual patients with CP and an AKT3 mutation have been published. In one of them (PMID 34354878) CP might be caused by birth asphyxia and is not be related to the AKT3 mutation. Additionally, there is functional data supporting the hypothesis that AKT3 might be a causative gene (PMID 32989326).

PMID 34354878: One patient described as presenting with MPPH and having a mutation in AKT3, while the mutation itself is not named (unknown whether LoF or missense, de novo or inherited). CP is listed as a coexisting feature in this patient which was caused by birth asphyxia due to umbilical cord strangulation around his neck.

30542205: One additional case with atypical CP (atypical due to major brain malformations and progressive neurologic disease) and a de novo missense mutation
Sources: Literature
Disorders of immune dysregulation v0.174 LYN Zornitza Stark Marked gene: LYN as ready
Disorders of immune dysregulation v0.174 LYN Zornitza Stark Gene: lyn has been classified as Green List (High Evidence).
Disorders of immune dysregulation v0.174 LYN Zornitza Stark Classified gene: LYN as Green List (high evidence)
Disorders of immune dysregulation v0.174 LYN Zornitza Stark Gene: lyn has been classified as Green List (High Evidence).
Disorders of immune dysregulation v0.173 LYN Zornitza Stark gene: LYN was added
gene: LYN was added to Disorders of immune dysregulation. Sources: Literature
Mode of inheritance for gene: LYN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LYN were set to 36932076; 36122175
Phenotypes for gene: LYN were set to Autoinflammatory disease, systemic, with vasculitis, MIM# 620376
Review for gene: LYN was set to GREEN
Added comment: Three unrelated individuals from described with three distinct de novo variants in LYN, p.Y508*, p.Q507* and a missense variant, p.Y508F. The PTC variants do not cause NMD, and all three variants have been shown to result in constitutively active LYN kinase by preventing inhibitory phosphorylation of the Y508 regulatory tyrosine. Extensive functional data to confirm gain-of-function effect was presented. Patient presented perinatally with immunological symptoms, including diffuse purpuric skin lesions, fever, and increased C-reactive protein (CRP). mild anemia, mild leukocytosis, moderate to severe thrombocytopenia. The patients with PTC were more severe, developing liver fibrosis and signs of cirrhosis. All three patients responded to various degrees to treatment with src kinase inhibitors, dasatinib, etanercept and/or colchicine. Authors named the condition Lyn kinase-associated vasculopathy and liver fibrosis (LAVLI). A fourth patient with a Tyr508His has also been described and presented with since birth with recurrent fever, chronic urticaria, atopic dermatitis, arthralgia, increased inflammatory biomarkers, and elevated plasma cytokine levels. Other features not consistent with LYN disease were attributed to prematurity (following maternal HELLP syndrome) and potentially other genetic factors.
Sources: Literature
Mendeliome v1.889 LYN Zornitza Stark Phenotypes for gene: LYN were changed from Vasculitis, MONDO:0018882, LYN-related to Autoinflammatory disease, systemic, with vasculitis, MIM# 620376
Mendeliome v1.888 LYN Zornitza Stark edited their review of gene: LYN: Changed phenotypes: Autoinflammatory disease, systemic, with vasculitis, MIM# 620376
Cerebral Palsy v1.36 AHDC1 Luisa Weiss gene: AHDC1 was added
gene: AHDC1 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: AHDC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AHDC1 were set to 33528536
Phenotypes for gene: AHDC1 were set to Xia-Gibbs syndrome, MIM#615829
Review for gene: AHDC1 was set to GREEN
Added comment: 3 individuals in CP cohort with mono-allelic de novo variants (2 frameshift, 1 6-AA-deletion).

Other ADHC1 frameshift mutations have been known to cause an early onset neurological disorder with absent or poor expressive language, obstructive sleep apnea and brain abnormalities.
Sources: Literature
Cerebral Palsy v1.36 ADNP Luisa Weiss gene: ADNP was added
gene: ADNP was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: ADNP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ADNP were set to 33528536
Phenotypes for gene: ADNP were set to Helsmoortel-van der Aa syndrome MIM#615873
Review for gene: ADNP was set to AMBER
Added comment: Large cohort study of cerebral palsy cases identified two variants in two individual patients with CP. One mutation was a recurrent Helsmoortel-van der Aa-syndrome nonsense mutation, the other was a de novo frameshift mutation. No further information about the patient's phenotype was given.
Sources: Literature
Cerebral Palsy v1.36 ACADM Luisa Weiss gene: ACADM was added
gene: ACADM was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: ACADM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACADM were set to 11263545; 35076175
Phenotypes for gene: ACADM were set to Acyl-CoA dehydrogenase, medium chain, deficiency of, MIM# 201450
Review for gene: ACADM was set to AMBER
Added comment: Currently unclear if variants in this gene can cause CP. If so, CP is likely to happen as a secondary effect of the brain damage happening if Acyl-CoA dehydrogenase deficiency is not treated correctly or early enough.
According to one study, CP can be present in 9% of cases with biallelic mutations in ACADM, probably secondary to the underlying disease and associated with early-onset seizures (PMID 11263545).
In a second publication one other case of CP associated with biallelic mutations in ACADM was presented, but this patient's phenotype was likely caused by biallelic mutations in PDHX which were present simultaneously.
Sources: Literature
Hereditary Neuropathy v0.149 APTX Sangavi Sivagnanasundram reviewed gene: APTX: Rating: GREEN; Mode of pathogenicity: None; Publications: 11586299; Phenotypes: Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (MIM#208920); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.888 NDUFA13 Zornitza Stark Classified gene: NDUFA13 as Green List (high evidence)
Mendeliome v1.888 NDUFA13 Zornitza Stark Gene: ndufa13 has been classified as Green List (High Evidence).
Mitochondrial disease v0.874 NDUFA13 Zornitza Stark Classified gene: NDUFA13 as Green List (high evidence)
Mitochondrial disease v0.874 NDUFA13 Zornitza Stark Gene: ndufa13 has been classified as Green List (High Evidence).
Motor Neurone Disease v0.156 SLC52A3 Zornitza Stark Marked gene: SLC52A3 as ready
Motor Neurone Disease v0.156 SLC52A3 Zornitza Stark Gene: slc52a3 has been classified as Green List (High Evidence).
Motor Neurone Disease v0.156 SLC52A3 Zornitza Stark Phenotypes for gene: SLC52A3 were changed from to Amytrophic Lateral Sclerosis (ALS); Brown-Vialetto-van Laere syndrome 1 (MIM# 211530)
Motor Neurone Disease v0.155 SLC52A3 Zornitza Stark Publications for gene: SLC52A3 were set to
Motor Neurone Disease v0.154 SLC52A3 Zornitza Stark Mode of inheritance for gene: SLC52A3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Motor Neurone Disease v0.153 TARDBP Zornitza Stark Marked gene: TARDBP as ready
Motor Neurone Disease v0.153 TARDBP Zornitza Stark Gene: tardbp has been classified as Green List (High Evidence).
Motor Neurone Disease v0.153 TARDBP Zornitza Stark Phenotypes for gene: TARDBP were changed from to Amyotrophic lateral sclerosis 10, with or without FTD; Frontotemporal lobar degeneration, TARDBP-related (MIM#612069; MONDO: 0012790)
Motor Neurone Disease v0.152 TARDBP Zornitza Stark Publications for gene: TARDBP were set to
Motor Neurone Disease v0.151 TARDBP Zornitza Stark Mode of inheritance for gene: TARDBP was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Motor Neurone Disease v0.150 TBK1 Zornitza Stark Marked gene: TBK1 as ready
Motor Neurone Disease v0.150 TBK1 Zornitza Stark Gene: tbk1 has been classified as Green List (High Evidence).
Motor Neurone Disease v0.150 TBK1 Zornitza Stark Phenotypes for gene: TBK1 were changed from to Amyotrophic lateral sclerosis 4 (MIM#616439; MONDO:0011223)
Motor Neurone Disease v0.149 TBK1 Zornitza Stark Publications for gene: TBK1 were set to
Motor Neurone Disease v0.148 TBK1 Zornitza Stark Mode of inheritance for gene: TBK1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Motor Neurone Disease v0.147 UBQLN2 Zornitza Stark Marked gene: UBQLN2 as ready
Motor Neurone Disease v0.147 UBQLN2 Zornitza Stark Gene: ubqln2 has been classified as Green List (High Evidence).
Motor Neurone Disease v0.147 UBQLN2 Zornitza Stark Phenotypes for gene: UBQLN2 were changed from to Amyotrophic lateral sclerosis type 15 (MONDO:0010459; MIM#300857)
Motor Neurone Disease v0.146 UBQLN2 Zornitza Stark Publications for gene: UBQLN2 were set to
Motor Neurone Disease v0.145 UBQLN2 Zornitza Stark Mode of inheritance for gene: UBQLN2 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Motor Neurone Disease v0.144 VAPB Zornitza Stark Marked gene: VAPB as ready
Motor Neurone Disease v0.144 VAPB Zornitza Stark Gene: vapb has been classified as Green List (High Evidence).
Motor Neurone Disease v0.144 VAPB Zornitza Stark Phenotypes for gene: VAPB were changed from to Spinal muscular atrophy, late-onset, Finkel type (MIM# 182980); Amyotrophic lateral sclerosis 8
Motor Neurone Disease v0.143 VAPB Zornitza Stark Publications for gene: VAPB were set to
Motor Neurone Disease v0.142 VAPB Zornitza Stark Mode of inheritance for gene: VAPB was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Motor Neurone Disease v0.141 VAPB Zornitza Stark Tag founder tag was added to gene: VAPB.
Motor Neurone Disease v0.141 VCP Zornitza Stark Marked gene: VCP as ready
Motor Neurone Disease v0.141 VCP Zornitza Stark Gene: vcp has been classified as Green List (High Evidence).
Motor Neurone Disease v0.141 VCP Zornitza Stark Phenotypes for gene: VCP were changed from to Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (ALS) (MIM#613954)
Motor Neurone Disease v0.140 VCP Zornitza Stark Publications for gene: VCP were set to
Motor Neurone Disease v0.139 VCP Zornitza Stark Mode of inheritance for gene: VCP was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary Neuropathy v0.149 ABCD1 Zornitza Stark Marked gene: ABCD1 as ready
Hereditary Neuropathy v0.149 ABCD1 Zornitza Stark Gene: abcd1 has been classified as Green List (High Evidence).
Hereditary Neuropathy v0.149 ABCD1 Zornitza Stark Phenotypes for gene: ABCD1 were changed from Adrenomyeloneuropathy, spastic paraparesis, adrenal insufficiency, axonal sensory-motor neuropathy, sphincter disturbance to Adrenomyeloneuropathy, adult (MIM#300100); Adrenomyeloneuropathy, spastic paraparesis, adrenal insufficiency, axonal sensory-motor neuropathy, sphincter disturbance
Hereditary Neuropathy v0.148 ABCD1 Zornitza Stark Publications for gene: ABCD1 were set to
Hereditary Neuropathy v0.147 AFG3L2 Zornitza Stark Marked gene: AFG3L2 as ready
Hereditary Neuropathy v0.147 AFG3L2 Zornitza Stark Gene: afg3l2 has been classified as Green List (High Evidence).
Hereditary Neuropathy v0.147 AFG3L2 Zornitza Stark Phenotypes for gene: AFG3L2 were changed from Early-onset spastic paraplegia, later myoclonic epilepsy, sensory-motor axonal neuropathy, ataxia, dystonia to Spastic ataxia 5, autosomal recessive, MIM# 614487, MONDO:0013776; Early-onset spastic paraplegia, later myoclonic epilepsy, sensory-motor axonal neuropathy, ataxia, dystonia
Hereditary Neuropathy v0.146 AFG3L2 Zornitza Stark Publications for gene: AFG3L2 were set to
Hereditary Neuropathy v0.145 AFG3L2 Zornitza Stark Mode of inheritance for gene: AFG3L2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Hereditary Neuropathy v0.144 AFG3L2 Zornitza Stark reviewed gene: AFG3L2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic ataxia 5, autosomal recessive, MIM# 614487; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary Neuropathy v0.144 AMACR Zornitza Stark Marked gene: AMACR as ready
Hereditary Neuropathy v0.144 AMACR Zornitza Stark Gene: amacr has been classified as Green List (High Evidence).
Hereditary Neuropathy v0.144 AMACR Zornitza Stark Phenotypes for gene: AMACR were changed from Retinopathy, myelopathy, axonal or SNCV neuropathy, elevated phytanic and pristanic acids to Alpha-methylacyl-CoA racemase deficiency (MIM#614307); Retinopathy, myelopathy, axonal or SNCV neuropathy, elevated phytanic and pristanic acids
Hereditary Neuropathy v0.143 AMACR Zornitza Stark Publications for gene: AMACR were set to
Miscellaneous Metabolic Disorders v1.27 Bryony Thompson removed gene:PINK1 from the panel
Mitochondrial disease v0.873 PINK1 Bryony Thompson Marked gene: PINK1 as ready
Mitochondrial disease v0.873 PINK1 Bryony Thompson Gene: pink1 has been classified as Green List (High Evidence).
Mitochondrial disease v0.873 PINK1 Bryony Thompson Phenotypes for gene: PINK1 were changed from to Parkinson disease 6, early onset, MIM# 605909
Mitochondrial disease v0.872 PINK1 Bryony Thompson Publications for gene: PINK1 were set to
Mitochondrial disease v0.871 PINK1 Bryony Thompson Classified gene: PINK1 as Green List (high evidence)
Mitochondrial disease v0.871 PINK1 Bryony Thompson Added comment: Comment on list classification: ICIMD Nosology Group
Disorders of mitochondrial protein quality control
Mitochondrial disease v0.871 PINK1 Bryony Thompson Gene: pink1 has been classified as Green List (High Evidence).
Mitochondrial disease v0.869 PINK1 Bryony Thompson gene: PINK1 was added
gene: PINK1 was added to Mitochondrial disease. Sources: Expert list
Mode of inheritance for gene: PINK1 was set to BIALLELIC, autosomal or pseudoautosomal
Macular Dystrophy/Stargardt Disease v0.43 CDHR1 Bryony Thompson Marked gene: CDHR1 as ready
Macular Dystrophy/Stargardt Disease v0.43 CDHR1 Bryony Thompson Gene: cdhr1 has been classified as Green List (High Evidence).
Macular Dystrophy/Stargardt Disease v0.43 CDHR1 Bryony Thompson Classified gene: CDHR1 as Green List (high evidence)
Macular Dystrophy/Stargardt Disease v0.43 CDHR1 Bryony Thompson Gene: cdhr1 has been classified as Green List (High Evidence).
Macular Dystrophy/Stargardt Disease v0.42 CDHR1 Bryony Thompson gene: CDHR1 was added
gene: CDHR1 was added to Macular Dystrophy/Stargardt Disease. Sources: Expert list
Mode of inheritance for gene: CDHR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDHR1 were set to 32681094; 31387115; 35627310
Phenotypes for gene: CDHR1 were set to Genetic macular dystrophy MONDO:0020242
Review for gene: CDHR1 was set to GREEN
gene: CDHR1 was marked as current diagnostic
Added comment: >10 individuals with late-onset macular dystrophy reported, mainly with c.783G>A (synonymous variant leading to in-frame skipping of exon 8) in the homozygous state or compound heterozygous with a second pathogenic variant in CDHR1
Sources: Expert list
Hereditary Neuropathy v0.142 AMACR Sangavi Sivagnanasundram reviewed gene: AMACR: Rating: GREEN; Mode of pathogenicity: None; Publications: 36108118, 10655068, 20821052, 18032455; Phenotypes: Alpha-methylacyl-CoA racemase deficiency (MIM#614307); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary Neuropathy v0.142 AFG3L2 Sangavi Sivagnanasundram reviewed gene: AFG3L2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 22022284, 25401298; Phenotypes: Spastic Ataxia 5 (MIM#614487, MONDO:0013776); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.240 GIGYF2 Bryony Thompson Publications for gene: GIGYF2 were set to 18358451; 33239198; 25279164; 20060621; 19250854; 26152800; 19449032
Early-onset Parkinson disease v0.239 GIGYF2 Bryony Thompson Publications for gene: GIGYF2 were set to PMID: 18358451, 19449032
Early-onset Parkinson disease v0.238 GIGYF2 Bryony Thompson Classified gene: GIGYF2 as Red List (low evidence)
Early-onset Parkinson disease v0.238 GIGYF2 Bryony Thompson Gene: gigyf2 has been classified as Red List (Low Evidence).
Early-onset Parkinson disease v0.237 GIGYF2 Bryony Thompson reviewed gene: GIGYF2: Rating: RED; Mode of pathogenicity: None; Publications: 18358451, 33239198, 25279164, 20060621, 19250854, 26152800; Phenotypes: {Parkinson disease 11} , OMIM # 607688; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.887 GIGYF2 Bryony Thompson Publications for gene: GIGYF2 were set to PMID: 18358451, 19449032
Mendeliome v1.886 GIGYF2 Bryony Thompson Classified gene: GIGYF2 as Red List (low evidence)
Mendeliome v1.886 GIGYF2 Bryony Thompson Gene: gigyf2 has been classified as Red List (Low Evidence).
Mendeliome v1.885 GIGYF2 Bryony Thompson reviewed gene: GIGYF2: Rating: RED; Mode of pathogenicity: None; Publications: 18358451, 33239198, 25279164, 20060621, 19250854, 26152800; Phenotypes: {Parkinson disease 11} , OMIM # 607688; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary Neuropathy v0.142 ABCD1 Sangavi Sivagnanasundram reviewed gene: ABCD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301491; Phenotypes: Adrenomyeloneuropathy, adult (MIM#300100); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Motor Neurone Disease v0.138 VCP Sangavi Sivagnanasundram reviewed gene: VCP: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301649, 20301623, 21145000; Phenotypes: Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (ALS) (MIM#613954); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Motor Neurone Disease v0.138 VAPB Sangavi Sivagnanasundram reviewed gene: VAPB: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301623, 15372378; Phenotypes: Spinal muscular atrophy, late-onset, Finkel type (MIM# 182980), Amyotrophic lateral sclerosis 8; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Craniosynostosis v1.66 CDC45 Zornitza Stark Publications for gene: CDC45 were set to 27374770
Craniosynostosis v1.65 MAN2B1 Zornitza Stark Marked gene: MAN2B1 as ready
Craniosynostosis v1.65 MAN2B1 Zornitza Stark Gene: man2b1 has been classified as Green List (High Evidence).
Craniosynostosis v1.65 MAN2B1 Zornitza Stark Classified gene: MAN2B1 as Green List (high evidence)
Craniosynostosis v1.65 MAN2B1 Zornitza Stark Gene: man2b1 has been classified as Green List (High Evidence).
Craniosynostosis v1.64 IL6ST Zornitza Stark Marked gene: IL6ST as ready
Craniosynostosis v1.64 IL6ST Zornitza Stark Gene: il6st has been classified as Amber List (Moderate Evidence).
Craniosynostosis v1.64 IL6ST Zornitza Stark Classified gene: IL6ST as Amber List (moderate evidence)
Craniosynostosis v1.64 IL6ST Zornitza Stark Gene: il6st has been classified as Amber List (Moderate Evidence).
Craniosynostosis v1.63 FBXO11 Zornitza Stark Marked gene: FBXO11 as ready
Craniosynostosis v1.63 FBXO11 Zornitza Stark Gene: fbxo11 has been classified as Green List (High Evidence).
Craniosynostosis v1.63 FBXO11 Zornitza Stark Classified gene: FBXO11 as Green List (high evidence)
Craniosynostosis v1.63 FBXO11 Zornitza Stark Gene: fbxo11 has been classified as Green List (High Evidence).
Craniosynostosis v1.62 KAT6B Zornitza Stark Marked gene: KAT6B as ready
Craniosynostosis v1.62 KAT6B Zornitza Stark Gene: kat6b has been classified as Green List (High Evidence).
Craniosynostosis v1.62 KAT6B Zornitza Stark Classified gene: KAT6B as Green List (high evidence)
Craniosynostosis v1.62 KAT6B Zornitza Stark Gene: kat6b has been classified as Green List (High Evidence).
Motor Neurone Disease v0.138 UBQLN2 Sangavi Sivagnanasundram reviewed gene: UBQLN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301623, 21857683; Phenotypes: Amyotrophic lateral sclerosis type 15 (MONDO:0010459, MIM#300857); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Incidentalome v0.230 UBQLN2 Sangavi Sivagnanasundram edited their review of gene: UBQLN2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Incidentalome v0.230 UBQLN2 Sangavi Sivagnanasundram changed review comment from: Established gene identified in many individuals with ALS and/or dementia however there is conflicting evidence on the mode of pathogenicity.

PMID: 21857683 – 3 unrelated individuals with missense mutations (P497S, P509S, P525S) causative of UBQLN2- related ALS and ALS/Dementia.

PMID: 31319884 Reports on multiple articles conducting functional studies with evidence supporting that mutations in UBQLN2 impair the UPS pathway.

PMID: 26152284 – In vivo mouse model that showed that UBQLN2 mutants cause neurodegeneration and aggregate formation however the gene-disease association link wasn’t identified.

PMID: 25388785 – transgenic knockout rat model showed that mutant UBQLN2 cells lead to aggregation formation. Cresyl violet staining in the rats showed a reduction in neuron density which led to neurodegeneration. Neural impairment in the rats were confirmed by Golgi staining and was shown to have a distorted structure of cortex.; to: Established gene identified in many individuals with ALS and/or dementia however there is conflicting evidence on the mode of pathogenicity.

PMID: 21857683 – 3 unrelated individuals with missense mutations (P497S, P509S, P525S) causative of UBQLN2- related ALS and ALS/Dementia.

PMID: 31319884 Reports on multiple articles conducting functional studies with evidence supporting that mutations in UBQLN2 impair the UPS pathway.

PMID: 26152284 – In vivo mouse model that showed that UBQLN2 mutants cause neurodegeneration and aggregate formation however the gene-disease association link wasn’t identified.

PMID: 25388785 – transgenic knockout rat model showed that mutant UBQLN2 cells lead to aggregation formation. Cresyl violet staining in the rats showed a reduction in neuron density which led to neurodegeneration. Neural impairment in the rats were confirmed by Golgi staining and was shown to have a distorted structure of cortex.
Motor Neurone Disease v0.138 TBK1 Sangavi Sivagnanasundram reviewed gene: TBK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301623, 25803835; Phenotypes: Amyotrophic lateral sclerosis 4 (MIM#616439, mMONDO:0011223); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Motor Neurone Disease v0.138 TARDBP Sangavi Sivagnanasundram reviewed gene: TARDBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301761, 18309045, 19609911; Phenotypes: Amyotrophic lateral sclerosis 10, with or without FTD, Frontotemporal lobar degeneration, TARDBP-related (MIM#612069, MONDO: 0012790); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Motor Neurone Disease v0.138 SLC52A3 Sangavi Sivagnanasundram reviewed gene: SLC52A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26072523; Phenotypes: Amytrophic Lateral Sclerosis (ALS), Brown-Vialetto-van Laere syndrome 1 (MIM# 211530); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Motor Neurone Disease v0.138 SLC52A2 Sangavi Sivagnanasundram changed review comment from: Well established gene causative of ALS - Phenotypic features typically seen with an early age of onset (within the first few years of life)

PMID: 22864630
HEK293 in vitro functional assay was conducted that showed the reduced transporter activity compared to the wildtype in the presence of a SLC52A2 mutation.; to: Well established gene with overlapping phenotypic features consistent with ALS - Phenotypic features typically seen with an early age of onset (within the first few years of life)

PMID: 22864630
HEK293 in vitro functional assay was conducted that showed the reduced transporter activity compared to the wildtype in the presence of a SLC52A2 mutation.
Motor Neurone Disease v0.138 SLC52A2 Sangavi Sivagnanasundram reviewed gene: SLC52A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26072523, 22864630, 22740598, 20206331, 21110228; Phenotypes: Amyotrophic lateral sclerosis (ALS), Brown-Vialetto-van Laere syndrome 2 (MIM#614707) (BVVLS2); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Motor Neurone Disease v0.138 SIGMAR1 Sangavi Sivagnanasundram reviewed gene: SIGMAR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26078401; Phenotypes: ?Spinal muscular atrophy, distal, autosomal recessive, 2 (MIM#605726); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Motor Neurone Disease v0.138 SETX Sangavi Sivagnanasundram reviewed gene: SETX: Rating: GREEN; Mode of pathogenicity: None; Publications: 15106121, 9497266; Phenotypes: Amyotrophic Lateral Sclerosis 4, juvenile (MIM#602433); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Motor Neurone Disease v0.138 OPTN Sangavi Sivagnanasundram reviewed gene: OPTN: Rating: GREEN; Mode of pathogenicity: None; Publications: 20428114, 31838784, 27493188; Phenotypes: Amyotrophic lateral sclerosis 12 with or without frontotemporal dementia (MONDO: 0013264, MIM#613435); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Motor Neurone Disease v0.138 FUS Sangavi Sivagnanasundram reviewed gene: FUS: Rating: GREEN; Mode of pathogenicity: None; Publications: 19251628, 19251627; Phenotypes: Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia (MIM#608030); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Motor Neurone Disease v0.138 ASCC1 Sangavi Sivagnanasundram reviewed gene: ASCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26924529, 28218388; Phenotypes: spinal muscular atrophy with congenital bone fractures 2 (MONDO:0014807, MIM#616867); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.885 NDUFA13 Lucy Spencer reviewed gene: NDUFA13: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex I deficiency, nuclear type 28, MIM# 618249; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mitochondrial disease v0.868 NDUFA13 Lucy Spencer reviewed gene: NDUFA13: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial complex I deficiency, nuclear type 28, MIM# 618249; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1851 UNC13A Ain Roesley Marked gene: UNC13A as ready
Genetic Epilepsy v0.1851 UNC13A Ain Roesley Gene: unc13a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1851 UNC13A Ain Roesley Classified gene: UNC13A as Green List (high evidence)
Genetic Epilepsy v0.1851 UNC13A Ain Roesley Gene: unc13a has been classified as Green List (High Evidence).
Autism v0.188 UNC13A Ain Roesley commented on gene: UNC13A
Genetic Epilepsy v0.1850 UNC13A Ain Roesley gene: UNC13A was added
gene: UNC13A was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: UNC13A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UNC13A were set to 28192369
Phenotypes for gene: UNC13A were set to neurodevelopmental disorder MONDO#0700092, UNC13A-related
Penetrance for gene: UNC13A were set to Complete
Review for gene: UNC13A was set to GREEN
gene: UNC13A was marked as current diagnostic
Added comment: Total of 3 probands with de novo Pro814Leu

Clinvar (believed to be a different proband reported in Lipstein 2017 in whom regression was never observed) :
Delayed speech and language development, Cerebellar ataxia, Tremor, Febrile seizure (within the age range of 3 months to 6 years), Developmental regression

VCGS internal cohort:
GDD, speech apraxia, febrile seizures, tremor, aortic root aneurysm, dilatation of the renal pelvis and Arnold-Chiari type I malformation

Lipstein 2017:
abnormal movements, developmental delay and autism
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5229 UNC13A Ain Roesley Phenotypes for gene: UNC13A were changed from Congenital myasthenia; dyskinesia; autism; developmental delay to Congenital myasthenia; dyskinesia; autism; developmental delay; neurodevelopmental disorder MONDO#0700092, UNC13A-related
Intellectual disability syndromic and non-syndromic v0.5229 UNC13A Ain Roesley Classified gene: UNC13A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5229 UNC13A Ain Roesley Gene: unc13a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5228 UNC13A Ain Roesley reviewed gene: UNC13A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder MONDO#0700092, UNC13A-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.885 UNC13A Ain Roesley Phenotypes for gene: UNC13A were changed from Congenital myasthenia; dyskinesia; autism; developmental delay to Congenital myasthenia; dyskinesia; autism; developmental delay; neurodevelopmental disorder MONDO#0700092, UNC13A-related
Mendeliome v1.884 UNC13A Ain Roesley Classified gene: UNC13A as Green List (high evidence)
Mendeliome v1.884 UNC13A Ain Roesley Gene: unc13a has been classified as Green List (High Evidence).
Mendeliome v1.883 UNC13A Ain Roesley reviewed gene: UNC13A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder MONDO#0700092, UNC13A-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.883 RANBP2 Bryony Thompson Phenotypes for gene: RANBP2 were changed from to familial acute necrotizing encephalopathy MONDO:0011953
Mendeliome v1.882 RANBP2 Bryony Thompson Mode of inheritance for gene: RANBP2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.881 RANBP2 Bryony Thompson Publications for gene: RANBP2 were set to
Craniosynostosis v1.61 CDC45 Yetong Chen reviewed gene: CDC45: Rating: GREEN; Mode of pathogenicity: None; Publications: 33639314, 27884935; Phenotypes: Meier-Gorlin syndrome 7, MIM#617063; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Craniosynostosis v1.61 MAN2B1 Yetong Chen gene: MAN2B1 was added
gene: MAN2B1 was added to Craniosynostosis. Sources: Expert Review
Mode of inheritance for gene: MAN2B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2B1 were set to 34429528; 33288889; 35242565
Phenotypes for gene: MAN2B1 were set to Mannosidosis, alpha-, types I and II, MIM# 248500
Review for gene: MAN2B1 was set to GREEN
Added comment: A total of 3 unrelated individuals are reported.
PMID 34429528 reports a patient (case 1) with compound heterozygous MAN2B1 variants (c.1830+1G>C and c.2248C>T) who had craniosynostosis.
PMID 33288889 reports a patient with recessive MAN2B1 variants (c.1055 T > C,p.Leu352Pro) who presented craniosynostosis.
PMID 35242565 reports a patient (patient 3) with compound heterozygous MAN2B1 variants (c.2245C > T, p.Arg749Trp and c.2355G > A, p.Thr785*) who had craniosynostosis.
Sources: Expert Review
Craniosynostosis v1.61 IL6ST Yetong Chen gene: IL6ST was added
gene: IL6ST was added to Craniosynostosis. Sources: Expert Review
Mode of inheritance for gene: IL6ST was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL6ST were set to 32566365; 28747427
Phenotypes for gene: IL6ST were set to Hyper-IgE recurrent infection syndrome 4B, autosomal recessive, MIM# 618523
Review for gene: IL6ST was set to AMBER
Added comment: PMID 32566365 describes a patient with homozygous IL6ST variants (p.R281Q) who had craniosynostosis. Abnormalities in nasofrontal sutures and reduced interdigitation of premaxillary sutures were seen in mouse models with homozygous R281Q variants in the IL6ST gene.
PMID 28747427 report a patient with homozygous IL6ST variants (p.N404Y) who had craniosynostosis.
Sources: Expert Review
Craniosynostosis v1.61 FBXO11 Yetong Chen gene: FBXO11 was added
gene: FBXO11 was added to Craniosynostosis. Sources: Expert Review
Mode of inheritance for gene: FBXO11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBXO11 were set to 34429528; 30057029
Phenotypes for gene: FBXO11 were set to intellectual developmental disorder with dysmorphic facies and behavioral abnormalities, MIM# 618089
Review for gene: FBXO11 was set to GREEN
Added comment: A total of 3 unrelated individuals are reported.
PMID 34429528 reports a patient with a de novo FBXO11 variant (c.2731_2732insGACA, p.Thr911Argfs*5) who had craniosynostosis.
PMID 30057029 reports 2 patients (patients 5 and 11) with monoallelic FBXO11 variants (c.2518T>C, p.Ser840Pro and c.1042−1G>C with unknown p.) who had sagittal and metopic craniosynostosis, respectively.
Sources: Expert Review
Motor Neurone Disease v0.138 FIG4 Sangavi Sivagnanasundram reviewed gene: FIG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 19118816, 20301623; Phenotypes: Amyotrophic Lateral Sclerosis Type 11 (MONDO: 0012945, MIM#612577); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Motor Neurone Disease v0.138 DCTN1 Sangavi Sivagnanasundram reviewed gene: DCTN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15326253, 12062019; Phenotypes: {Amyotrophic lateral sclerosis, susceptibility to} - MIM# 105400; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.880 GATAD2A Bryony Thompson Publications for gene: GATAD2A were set to https://doi.org/10.1016/j.xhgg.2023.100198; 17565372
Mendeliome v1.879 GATAD2A Bryony Thompson changed review comment from: https://doi.org/10.1016/j.xhgg.2023.100198 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5
PMID: 17565372 - null mouse model is embryonic lethal.
Sources: Literature; to: PMID: 37181331 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5
PMID: 17565372 - null mouse model is embryonic lethal.
Sources: Literature
Mendeliome v1.879 GATAD2A Bryony Thompson edited their review of gene: GATAD2A: Changed publications: 37181331, 17565372
Motor Neurone Disease v0.138 ANG Sangavi Sivagnanasundram reviewed gene: ANG: Rating: GREEN; Mode of pathogenicity: None; Publications: 17886298, 16501576, 18087731, 20301623; Phenotypes: Amyotrophic Lateral Sclerosis 9 (MONDO: 0012753, MIM#611895); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Motor Neurone Disease v0.138 ALS2 Sangavi Sivagnanasundram reviewed gene: ALS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24562058, 11586298; Phenotypes: Amyotrophic lateral sclerosis 2, juvenile (MIM# 205100, MONDO: MONDO:0008780); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Craniosynostosis v1.61 KAT6B Yetong Chen gene: KAT6B was added
gene: KAT6B was added to Craniosynostosis. Sources: Expert Review
Mode of inheritance for gene: KAT6B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KAT6B were set to 33288889; 28696035
Phenotypes for gene: KAT6B were set to SBBYSS syndrome, MIM# 603736
Review for gene: KAT6B was set to GREEN
Added comment: Three unrelated patients are reported.
PMID 33288889 reports a patient with a KAT6B variant (c.3769_3772del, p.Lys1258Glyfs*13) who was diagnosed with craniosynostosis.
PMID 28696035 reports 2 patients with different monoallelic KAT6B variants (c.4572dupT, p.Thr1525Tyrfs*16 and c.4205_4206delCT, p.Ser1402Cysfs*5, respectively) who had sagittal craniosynostosis.
Sources: Expert Review
Craniosynostosis v1.61 KAT6A Yetong Chen Deleted their review
Craniosynostosis v1.61 CDK13 Zornitza Stark Marked gene: CDK13 as ready
Craniosynostosis v1.61 CDK13 Zornitza Stark Gene: cdk13 has been classified as Green List (High Evidence).
Craniosynostosis v1.61 CDK13 Zornitza Stark Classified gene: CDK13 as Green List (high evidence)
Craniosynostosis v1.61 CDK13 Zornitza Stark Gene: cdk13 has been classified as Green List (High Evidence).
Craniosynostosis v1.60 ARID1B Zornitza Stark Marked gene: ARID1B as ready
Craniosynostosis v1.60 ARID1B Zornitza Stark Gene: arid1b has been classified as Green List (High Evidence).
Craniosynostosis v1.60 ARID1B Zornitza Stark Classified gene: ARID1B as Green List (high evidence)
Craniosynostosis v1.60 ARID1B Zornitza Stark Gene: arid1b has been classified as Green List (High Evidence).
Craniosynostosis v1.59 NFIX Zornitza Stark Marked gene: NFIX as ready
Craniosynostosis v1.59 NFIX Zornitza Stark Gene: nfix has been classified as Green List (High Evidence).
Craniosynostosis v1.59 NFIX Zornitza Stark Classified gene: NFIX as Green List (high evidence)
Craniosynostosis v1.59 NFIX Zornitza Stark Gene: nfix has been classified as Green List (High Evidence).
Craniosynostosis v1.58 KAT6A Zornitza Stark Publications for gene: KAT6A were set to 30245513; 25728777
Craniosynostosis v1.57 AHDC1 Zornitza Stark Marked gene: AHDC1 as ready
Craniosynostosis v1.57 AHDC1 Zornitza Stark Gene: ahdc1 has been classified as Green List (High Evidence).
Craniosynostosis v1.57 AHDC1 Zornitza Stark Classified gene: AHDC1 as Green List (high evidence)
Craniosynostosis v1.57 AHDC1 Zornitza Stark Gene: ahdc1 has been classified as Green List (High Evidence).
Cerebral Palsy v1.36 ACTB Luisa Weiss changed review comment from: Three independent cases in one cohort study.
Sources: Literature; to: Three independent cases in one cohort study.
Sources: Literature
Cerebral Palsy v1.36 ACTB Luisa Weiss gene: ACTB was added
gene: ACTB was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: ACTB was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ACTB were set to 33528536
Phenotypes for gene: ACTB were set to Baraitser-Winter syndrome 1 MIM#243310
Review for gene: ACTB was set to GREEN
Added comment: Three independent cases in one cohort study.
Sources: Literature
Cerebral Palsy v1.36 ADCY5 Luisa Mackenroth gene: ADCY5 was added
gene: ADCY5 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: ADCY5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ADCY5 were set to 33528536; 33098801
Phenotypes for gene: ADCY5 were set to Dyskinesia with orofacial involvement MIM#606703
Mode of pathogenicity for gene: ADCY5 was set to Other
Review for gene: ADCY5 was set to GREEN
Added comment: Multiple individuals reported in two different cohort studies analyzing children diagnosed with CP. Clinical overlap with childhood onset dystonia likely. Reported mutations in CP patients indicate gain-of-function mechanism, but loss-of-function mechanism has been described for allelic mutations.
Sources: Literature
Craniosynostosis v1.56 CDK13 Yetong Chen changed review comment from: A total of 4 unrelated individuals are reported.
PMID 34429528 reports a patient with a monoallelic CDK13 variant (c.2563G>C, p.Asp855His) who had metopic synostosis.
PMID 28807008 mentioned 2 patients with craniosynostosis were identified from 9 individuals with CDK13 variants. However, detailed information about the 2 patients is not provided.
PMID 33288889 reported a patient with a CDK13 variant (c.2524 A > G, p.Asn842Asp) who presented with craniosynostosis.
Sources: Expert Review; to: A total of 4 unrelated individuals are reported.
PMID 34429528 reports a patient with a monoallelic CDK13 variant (c.2563G>C, p.Asp855His) who had metopic synostosis.
PMID 28807008 mentions 2 patients with craniosynostosis were identified from 9 individuals with CDK13 variants. However, detailed information about the 2 patients is not provided.
PMID 33288889 reports a patient with a CDK13 variant (c.2524 A > G, p.Asn842Asp) who presented with craniosynostosis.
Sources: Expert Review
Craniosynostosis v1.56 CDK13 Yetong Chen gene: CDK13 was added
gene: CDK13 was added to Craniosynostosis. Sources: Expert Review
Mode of inheritance for gene: CDK13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDK13 were set to 34429528; 28807008; 33288889
Phenotypes for gene: CDK13 were set to Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder, MIM# 617360
Review for gene: CDK13 was set to GREEN
Added comment: A total of 4 unrelated individuals are reported.
PMID 34429528 reports a patient with a monoallelic CDK13 variant (c.2563G>C, p.Asp855His) who had metopic synostosis.
PMID 28807008 mentioned 2 patients with craniosynostosis were identified from 9 individuals with CDK13 variants. However, detailed information about the 2 patients is not provided.
PMID 33288889 reported a patient with a CDK13 variant (c.2524 A > G, p.Asn842Asp) who presented with craniosynostosis.
Sources: Expert Review
Craniosynostosis v1.56 ARID1B Yetong Chen gene: ARID1B was added
gene: ARID1B was added to Craniosynostosis. Sources: Expert Review
Mode of inheritance for gene: ARID1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARID1B were set to 36118902; 34429528; 27474218; 32530565
Phenotypes for gene: ARID1B were set to Coffin-Siris syndrome 1, MIM# 135900
Review for gene: ARID1B was set to GREEN
Added comment: A total of 4 unrelated individuals are reported.
PMID 36118902 reports a patient with an ARID1B variant (chr6:g.157431670_157431676 delCCAGTCA) who presented with sagittal craniosynostosis.
PMID 34429528 identifies a patient (case 16) with an ARID1B variant (c.3594delinsCCCCCA) by screening 127 families classified with craniosynostosis.
PMID 27474218 reported a patient (patient 10) with an ARID1B variant (c.1468_1472delTGGGC) who presented with craniosynostosis.
PMID 32530565 listed a patient (OKI-047-1 M) harbouring an ARID1B variant (c.2277delC) who had trigonocephaly.
Sources: Expert Review
Craniosynostosis v1.56 NFIX Yetong Chen gene: NFIX was added
gene: NFIX was added to Craniosynostosis. Sources: Expert Review
Mode of inheritance for gene: NFIX was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NFIX were set to 33288889; 35997807
Phenotypes for gene: NFIX were set to Malan syndrome, MIM# 614753
Review for gene: NFIX was set to GREEN
Added comment: PMID 33288889 reports a patient with an NFIX variant (c.143 T > A, p.Met48Lys) who presented craniosynostosis.
PMID 35997807: Of 25 patients with lambdoid craniosynostosis, 4 unrelated patients carried NFIX variants. The patient with the c.143 T > A (p.Met48Lys) variant of the NFIX gene has been reported by PMID 33288889.
Sources: Expert Review
Craniosynostosis v1.56 KAT6A Yetong Chen reviewed gene: KAT6A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33288889, 28696035; Phenotypes: SBBYSS syndrome, MIM# 603736; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mosaic skin disorders v1.10 Bryony Thompson Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease; Tasmanian Clinical Genetics Service
Pulmonary Fibrosis_Interstitial Lung Disease v0.54 NAF1 Zornitza Stark Phenotypes for gene: NAF1 were changed from Pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148 to Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, MIM# 620365
Pulmonary Fibrosis_Interstitial Lung Disease v0.53 NAF1 Zornitza Stark reviewed gene: NAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, MIM# 620365; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.879 NAF1 Zornitza Stark Phenotypes for gene: NAF1 were changed from Pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148 to Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, MIM# 620365
Mendeliome v1.878 NAF1 Zornitza Stark reviewed gene: NAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, MIM# 620365; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bone Marrow Failure v1.41 NAF1 Zornitza Stark Phenotypes for gene: NAF1 were changed from Pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148 to Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, MIM# 620365
Bone Marrow Failure v1.40 NAF1 Zornitza Stark reviewed gene: NAF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, MIM# 620365; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Muscular dystrophy and myopathy_Paediatric v0.146 RYR1 Bryony Thompson Classified gene: RYR1 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v0.146 RYR1 Bryony Thompson Gene: ryr1 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.145 RYR1 Bryony Thompson edited their review of gene: RYR1: Added comment: Congenital myopathy is reported in both dominant and recessive forms. Loss of function is the disease mechanism for recessive RYR1-related myopathy, whereas gain-of-function is typically the mechanism for dominant disease.; Changed publications: 22473935, 30611313, 8220422, 12112081; Changed phenotypes: RYR1-related myopathy MONDO:0100150; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.878 ZNF292 Michelle Torres reviewed gene: ZNF292: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 64, MIM#619188; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5228 ZNF292 Michelle Torres reviewed gene: ZNF292: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 64, MIM#619188; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.107 ESAM Zornitza Stark Phenotypes for gene: ESAM were changed from Neurodevelopmental disorder (MONDO#0700092), ESAM-related to Neurodevelopmental disorder with intracranial haemorrhage, seizures, and spasticity, MIM# 620371
Fetal anomalies v1.106 ESAM Zornitza Stark reviewed gene: ESAM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with intracranial haemorrhage, seizures, and spasticity, MIM# 620371; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5228 ESAM Zornitza Stark Phenotypes for gene: ESAM were changed from Neurodevelopmental disorder (MONDO#0700092), ESAM-related to Neurodevelopmental disorder with intracranial haemorrhage, seizures, and spasticity, MIM# 620371
Intellectual disability syndromic and non-syndromic v0.5227 ESAM Zornitza Stark reviewed gene: ESAM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with intracranial haemorrhage, seizures, and spasticity, MIM# 620371; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1849 ESAM Zornitza Stark Phenotypes for gene: ESAM were changed from Neurodevelopmental disorder (MONDO#0700092), ESAM-related to Neurodevelopmental disorder with intracranial haemorrhage, seizures, and spasticity, MIM# 620371
Genetic Epilepsy v0.1848 ESAM Zornitza Stark reviewed gene: ESAM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with intracranial haemorrhage, seizures, and spasticity, MIM# 620371; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.878 ESAM Zornitza Stark Phenotypes for gene: ESAM were changed from Neurodevelopmental disorder (MONDO#0700092), ESAM-related to Neurodevelopmental disorder with intracranial haemorrhage, seizures, and spasticity, MIM# 620371
Mendeliome v1.877 ESAM Zornitza Stark reviewed gene: ESAM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with intracranial haemorrhage, seizures, and spasticity, MIM# 620371; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.91 ESAM Zornitza Stark Phenotypes for gene: ESAM were changed from Neurodevelopmental disorder (MONDO#0700092), ESAM-related to Neurodevelopmental disorder with intracranial haemorrhage, seizures, and spasticity, MIM# 620371
Brain Calcification v1.90 ESAM Zornitza Stark reviewed gene: ESAM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with intracranial haemorrhage, seizures, and spasticity, MIM# 620371; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Craniosynostosis v1.56 AHDC1 Yetong Chen gene: AHDC1 was added
gene: AHDC1 was added to Craniosynostosis. Sources: Expert Review
Mode of inheritance for gene: AHDC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AHDC1 were set to 27884935; 30858058; 30152016; 27148574; 33288889
Phenotypes for gene: AHDC1 were set to Xia-Gibbs syndrome, MIM# 615829
Review for gene: AHDC1 was set to GREEN
Added comment: More than 3 unrelated individuals are reported.
PMID 27884935 scanned craniosynostosis patients and identified an AHDC1 variant (c.2373_2374delTG, p.C791fs*57) from a patient with craniosynostosis.
PMID 30858058 reports a patient with a heterozygous AHDC1 variant (c.4370 A>G, p.Asp1457Gly) who had craniosynostosis.
PMID 30152016 reports a patient (patient 1) with a heterozygous AHDC1 variant (c.2473C>T; p.Q825*) who had craniosynostosis.
PMID 27148574 reports a patient (patient 3) with an AHDC1 variant (c.1881delG
p.Q627Hfs*105) who had sagittal craniosynostosis.
PMID 33288889: Of 94 individuals with syndromic craniosynostosis, 2 individuals carried AHDC1 variants (c.3185_3186del p.(Thr1062Serfs*63) and c.2772del p.(Arg925Glufs*7), respectively).
Sources: Expert Review
Brain Calcification v1.90 ZBTB20 Zornitza Stark Marked gene: ZBTB20 as ready
Brain Calcification v1.90 ZBTB20 Zornitza Stark Gene: zbtb20 has been classified as Green List (High Evidence).
Brain Calcification v1.90 ZBTB20 Zornitza Stark Classified gene: ZBTB20 as Green List (high evidence)
Brain Calcification v1.90 ZBTB20 Zornitza Stark Gene: zbtb20 has been classified as Green List (High Evidence).
Brain Calcification v1.89 ZBTB20 Yetong Chen gene: ZBTB20 was added
gene: ZBTB20 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: ZBTB20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZBTB20 were set to 32734340; 25017102
Phenotypes for gene: ZBTB20 were set to Primrose syndrome, MIM# 259050
Review for gene: ZBTB20 was set to GREEN
Added comment: PMID 32266967 reports 4 patients (1, 2, 22 and 24) with different ZBTB20 variants (p.Gln209Arg, p.Cys580Tyr, p.His624Pro, and p.Met625Val) who had brain calcifications.
PMID reports 3 patients (11D5135, 12D6966 and PRS_02) with different ZBTB20 variants (p.T601I, p.G602A and p.V626M) who had intracranial calcification.
Sources: Expert list
Microcephaly v1.204 HPDL Lucy Spencer gene: HPDL was added
gene: HPDL was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HPDL were set to 33188300
Phenotypes for gene: HPDL were set to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (MIM#619026)
Review for gene: HPDL was set to GREEN
Added comment: PMID: 33188300 cohort of infantile neurodegenerative condition, all have biallelic HPDL variants. 7 of 14 individuals have microcephaly, however its noted that head circumference was not remarkable at birth but smaller head circumference/microcephaly was seen by 5 years old.
Sources: Literature
Muscular dystrophy and myopathy_Paediatric v0.145 CHST14 Bryony Thompson Marked gene: CHST14 as ready
Muscular dystrophy and myopathy_Paediatric v0.145 CHST14 Bryony Thompson Gene: chst14 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.145 CHST14 Bryony Thompson Classified gene: CHST14 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v0.145 CHST14 Bryony Thompson Gene: chst14 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.144 CHST14 Bryony Thompson gene: CHST14 was added
gene: CHST14 was added to Muscular dystrophy_Paediatric. Sources: Expert list
Mode of inheritance for gene: CHST14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHST14 were set to 26373698; 20842734; 36833362
Phenotypes for gene: CHST14 were set to Ehlers-Danlos syndrome, musculocontractural type 1 MIM# 601776
Review for gene: CHST14 was set to GREEN
gene: CHST14 was marked as current diagnostic
Added comment: Well-established gene-disease association. MC-EDS represents a differential diagnosis within the congenital myopathy spectrum of disease. Myopathy also present in the null mouse model.
Sources: Expert list
Muscular dystrophy and myopathy_Paediatric v0.143 CACNA1S Bryony Thompson Marked gene: CACNA1S as ready
Muscular dystrophy and myopathy_Paediatric v0.143 CACNA1S Bryony Thompson Gene: cacna1s has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.143 CACNA1S Bryony Thompson Classified gene: CACNA1S as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v0.143 CACNA1S Bryony Thompson Gene: cacna1s has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.142 CACNA1S Bryony Thompson gene: CACNA1S was added
gene: CACNA1S was added to Muscular dystrophy_Paediatric. Sources: Expert list
Mode of inheritance for gene: CACNA1S was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CACNA1S were set to 28012042; 31227654; 33060286
Phenotypes for gene: CACNA1S were set to Congenital myopathy MONDO:0019952
Review for gene: CACNA1S was set to GREEN
gene: CACNA1S was marked as current diagnostic
Added comment: At least 5 families with biallelic variants and 3 families with monoallelic missense variants (mainly de novo) with congenital myopathy. A decrease in protein level and a major impairment of Ca2+ release induced by depolarization in cultured myotubes was identified in both the dominant and recessive families. Thus, loss of function is the mechanism of disease for CACNA1S-related congenital myopathy.
Sources: Expert list
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.145 UNC45B Sangavi Sivagnanasundram gene: UNC45B was added
gene: UNC45B was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Other
Mode of inheritance for gene: UNC45B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNC45B were set to 33217308; 31852522
Phenotypes for gene: UNC45B were set to Myofibrillar myopathy 11 (MIM#619178)
Review for gene: UNC45B was set to GREEN
Added comment: Onset is within the first decade of life typically indicated by slow progression of proximal muscle weakness.

PMID: 33217308; 31852522
11 individuals from 9 unrelated families with symptoms of progressive proximal muscle weakness.

PMID: 31852522
Muscle biopsy was conducted on one individual which showed myopathic changes with core-like structures
Sources: Other
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.145 SVIL Sangavi Sivagnanasundram gene: SVIL was added
gene: SVIL was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Other
Mode of inheritance for gene: SVIL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SVIL were set to 32779703
Phenotypes for gene: SVIL were set to Myofibrillar myopathy 10 (MIM#619040)
Review for gene: SVIL was set to AMBER
Added comment: Onset is typically within the first or second decade of life while some individuals of onset in early childhood.
Typical features at onset is muscle pain, cramping, and exercise fatigue.

PMID: 32779703
2 affected individuals from 2 unrelated consanguineous families with hypertrophic muscles and muscle rigidity
Sources: Other
Mendeliome v1.877 ARFGEF3 Ain Roesley reviewed gene: ARFGEF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Dystonia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Muscular dystrophy and myopathy_Paediatric v0.141 CFL2 Bryony Thompson Marked gene: CFL2 as ready
Muscular dystrophy and myopathy_Paediatric v0.141 CFL2 Bryony Thompson Gene: cfl2 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.141 CFL2 Bryony Thompson Classified gene: CFL2 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v0.141 CFL2 Bryony Thompson Gene: cfl2 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.140 CFL2 Bryony Thompson Publications for gene: CFL2 were set to PMID: 17160903; 22560515
Muscular dystrophy and myopathy_Paediatric v0.139 CCDC78 Bryony Thompson Marked gene: CCDC78 as ready
Muscular dystrophy and myopathy_Paediatric v0.139 CCDC78 Bryony Thompson Gene: ccdc78 has been classified as Amber List (Moderate Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.145 MYL2 Sangavi Sivagnanasundram gene: MYL2 was added
gene: MYL2 was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Other
Mode of inheritance for gene: MYL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYL2 were set to 23365102; 9673982
Phenotypes for gene: MYL2 were set to Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy (MIM#619424)
Review for gene: MYL2 was set to GREEN
Added comment: Onset is in the first few weeks of life.
Typical features include hypotrophy of skeletal and cardiac muscle

PMID: 23365102; 9673982
13 affected individuals from 6 unrelated family with progressive muscle weakness and cardiomyopathy
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.139 CCDC78 Bryony Thompson Classified gene: CCDC78 as Amber List (moderate evidence)
Muscular dystrophy and myopathy_Paediatric v0.139 CCDC78 Bryony Thompson Gene: ccdc78 has been classified as Amber List (Moderate Evidence).
Muscular dystrophy and myopathy_Paediatric v0.138 BIN1 Bryony Thompson Marked gene: BIN1 as ready
Muscular dystrophy and myopathy_Paediatric v0.138 BIN1 Bryony Thompson Gene: bin1 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.138 BIN1 Bryony Thompson Publications for gene: BIN1 were set to 17676042; 29950440
Muscular dystrophy and myopathy_Paediatric v0.137 BIN1 Bryony Thompson Classified gene: BIN1 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v0.137 BIN1 Bryony Thompson Added comment: Comment on list classification: ClinGen Definititive for semidominant centronuclear myopathy by the Congenital myopathy GCEP - Classification - 27/04/2020
Muscular dystrophy and myopathy_Paediatric v0.137 BIN1 Bryony Thompson Gene: bin1 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.136 ASCC3 Bryony Thompson Marked gene: ASCC3 as ready
Muscular dystrophy and myopathy_Paediatric v0.136 ASCC3 Bryony Thompson Gene: ascc3 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.136 ASCC3 Bryony Thompson Classified gene: ASCC3 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v0.136 ASCC3 Bryony Thompson Gene: ascc3 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.135 ASCC1 Bryony Thompson Marked gene: ASCC1 as ready
Muscular dystrophy and myopathy_Paediatric v0.135 ASCC1 Bryony Thompson Gene: ascc1 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.135 ASCC1 Bryony Thompson Classified gene: ASCC1 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v0.135 ASCC1 Bryony Thompson Gene: ascc1 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.134 DNAJB4 Bryony Thompson Marked gene: DNAJB4 as ready
Muscular dystrophy and myopathy_Paediatric v0.134 DNAJB4 Bryony Thompson Gene: dnajb4 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.134 DNAJB4 Bryony Thompson Classified gene: DNAJB4 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v0.134 DNAJB4 Bryony Thompson Gene: dnajb4 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.133 DNAJB4 Bryony Thompson reviewed gene: DNAJB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 36264506; Phenotypes: Myopathy, MONDO:0005336, DNAJB4-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Muscular dystrophy and myopathy_Paediatric v0.133 ADSSL1 Bryony Thompson Marked gene: ADSSL1 as ready
Muscular dystrophy and myopathy_Paediatric v0.133 ADSSL1 Bryony Thompson Gene: adssl1 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.133 ADSSL1 Bryony Thompson Phenotypes for gene: ADSSL1 were changed from Myopathy Distal 5 (MONDO:0014877; MIM#617030) to Nemaline myopathy MONDO:0018958
Muscular dystrophy and myopathy_Paediatric v0.132 ADSSL1 Bryony Thompson Publications for gene: ADSSL1 were set to 32646962
Muscular dystrophy and myopathy_Paediatric v0.131 ADSSL1 Bryony Thompson Publications for gene: ADSSL1 were set to PMID: 3650622; 28268051; 32646962
Muscular dystrophy and myopathy_Paediatric v0.131 ADSSL1 Bryony Thompson Classified gene: ADSSL1 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v0.131 ADSSL1 Bryony Thompson Gene: adssl1 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.130 ADSSL1 Bryony Thompson reviewed gene: ADSSL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32646962; Phenotypes: Nemaline myopathy MONDO:0018958; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Muscular dystrophy and myopathy_Paediatric v0.130 ACTN2 Bryony Thompson Classified gene: ACTN2 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v0.130 ACTN2 Bryony Thompson Gene: actn2 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.129 ACTN2 Bryony Thompson Classified gene: ACTN2 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v0.129 ACTN2 Bryony Thompson Gene: actn2 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.128 ACTN2 Bryony Thompson Marked gene: ACTN2 as ready
Muscular dystrophy and myopathy_Paediatric v0.128 ACTN2 Bryony Thompson Gene: actn2 has been removed from the panel.
Muscular dystrophy and myopathy_Paediatric v0.128 ACTN2 Bryony Thompson reviewed gene: ACTN2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 30701273; Phenotypes: Myopathy, congenital with structured cores and Z-line abnormalities MIM#618654; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.145 KY Sangavi Sivagnanasundram gene: KY was added
gene: KY was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Other
Mode of inheritance for gene: KY was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KY were set to 27484770; 27485408; 30591934; 11136708
Phenotypes for gene: KY were set to Myopathy, myofibrillar, 7 (MIM#617114)
Review for gene: KY was set to GREEN
Added comment: Onset is early childhood with slow progression of muscle weakness

PMID: 27484770; 27485408; 30591934
4 individuals from 3 unrelated consanguineous families with slowly progressive myopathy.
Muscle biopsy showed myopathic changes (increased variability in fibre size) and all individuals had a homozygous mutation present in the KY gene.

PMID: 11136708
A mouse model showed myopathy degeneration in the presence of a mutation in KY.
Histopathology on the mutant mouse confirmed the importance of KY protein in muscle growth and function.
Sources: Other
Rhabdomyolysis and Metabolic Myopathy v0.168 GFER Sangavi Sivagnanasundram gene: GFER was added
gene: GFER was added to Rhabdomyolysis and Metabolic Myopathy. Sources: Other
Mode of inheritance for gene: GFER was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GFER were set to 28155230; 19409522; 26018198
Phenotypes for gene: GFER were set to Myopathy, mitochondrial progressive, with congenital cataract and developmental delay (MIM#613076)
Review for gene: GFER was set to GREEN
Added comment: Onset - at birth and/or during infancy

8 individuals from 4 unrelated families with clinical symptoms of hypotonia and elevated plasma lactate levels.
Sources: Other
Rhabdomyolysis and Metabolic Myopathy v0.168 FASTKD2 Sangavi Sivagnanasundram gene: FASTKD2 was added
gene: FASTKD2 was added to Rhabdomyolysis and Metabolic Myopathy. Sources: Other
Mode of inheritance for gene: FASTKD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FASTKD2 were set to 31944455; 18771761
Phenotypes for gene: FASTKD2 were set to Combined oxidative phosphorylation deficiency 44 (MIM#618855)
Review for gene: FASTKD2 was set to GREEN
Added comment: - Onset in infancy or early childhood
- Features typically include global developmental delay, hypotonia, and abnormal movements.

5 individuals from 4 unrelated families with features of with hypotonia, increased serum lactate and phenotypes relating to hypertrophic cardiomyopathy

PMID: 31944455
Functional study using HEK293 cells showed the depletion in FASTKD2 protein resulting in defective mitochondrial RNA translation.
Sources: Other
Rhabdomyolysis and Metabolic Myopathy v0.168 AIFM1 Sangavi Sivagnanasundram gene: AIFM1 was added
gene: AIFM1 was added to Rhabdomyolysis and Metabolic Myopathy. Sources: Other
Mode of inheritance for gene: AIFM1 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: AIFM1 were set to 20362274; 22019070; 26173962
Phenotypes for gene: AIFM1 were set to Combined oxidative phosphorylation deficiency 6 (COXPD6) (MIM#300816); Encephalamyopathy, Mitochondrial, X-Linked
Review for gene: AIFM1 was set to GREEN
Added comment: - Onset is in utero or in infancy
- Affected individuals typically present with hypotonia, impaired psychomotoro development with decreased enzymatic activity, specifically in skeletal muscle or fibroblasts

6 individuals from 3 unrelated families presented with hypotonia with muscle weakness and increased plasma lactate and a hemizygous mutation in AIFM1 causative of Combined oxidative phosphorylation deficiency 6 (COXPD6).

PMID: 20362274
2 individuals (first cousins) from one family with Hypotonia and hypo-areflexia and increased lactate in plasma and both individuals carried a hemizygous deletion
In vitro studies showed that in the presence of the deletion, the inner mitochondrial membrane is destabilised causing damage to the respiratory chain structure and activities.

PMID: 22019070
2 brothers (one deceased) with hyptonia and symptoms of hypertrophic cardiomyopathy (HCM) and complete cytochrome C oxidase deficiency on a histochemistry staining.

PMID: 26173962
2 individuals from one family (cousins) with hemizyggous mutation in AIFM1
Both presented with hypotonia with muscle weakness and increased plasma lactate
Segregation study showed unaffected mother was a carrier for the hemizygous mutation
Sources: Other
Brain Calcification v1.89 XPR1 Zornitza Stark Publications for gene: XPR1 were set to 25938945
Brain Calcification v1.88 WDR45 Zornitza Stark Classified gene: WDR45 as Amber List (moderate evidence)
Brain Calcification v1.88 WDR45 Zornitza Stark Gene: wdr45 has been classified as Amber List (Moderate Evidence).
Brain Calcification v1.87 VARS2 Zornitza Stark Marked gene: VARS2 as ready
Brain Calcification v1.87 VARS2 Zornitza Stark Gene: vars2 has been classified as Red List (Low Evidence).
Brain Calcification v1.87 VARS2 Zornitza Stark Classified gene: VARS2 as Red List (low evidence)
Brain Calcification v1.87 VARS2 Zornitza Stark Gene: vars2 has been classified as Red List (Low Evidence).
Brain Calcification v1.86 TYROBP Zornitza Stark Publications for gene: TYROBP were set to 30242731
Brain Calcification v1.85 TSC2 Zornitza Stark Publications for gene: TSC2 were set to
Brain Calcification v1.84 TBCE Zornitza Stark Marked gene: TBCE as ready
Brain Calcification v1.84 TBCE Zornitza Stark Gene: tbce has been classified as Green List (High Evidence).
Brain Calcification v1.84 TBCE Zornitza Stark Classified gene: TBCE as Green List (high evidence)
Brain Calcification v1.84 TBCE Zornitza Stark Gene: tbce has been classified as Green List (High Evidence).
Brain Calcification v1.83 TBCE Zornitza Stark reviewed gene: TBCE: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypoparathyroidism-retardation-dysmorphism syndrome, MIM# 241410; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.83 XPR1 Yetong Chen reviewed gene: XPR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27230854, 29955172, 33433330; Phenotypes: Basal ganglia calcification, idiopathic, 6, MIM# 616413; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rhabdomyolysis and Metabolic Myopathy v0.168 AGK Sangavi Sivagnanasundram gene: AGK was added
gene: AGK was added to Rhabdomyolysis and Metabolic Myopathy. Sources: Other
Mode of inheritance for gene: AGK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGK were set to 22284826
Phenotypes for gene: AGK were set to Sengers Syndrome (MIM#212350; MONDO:0008922)
Review for gene: AGK was set to GREEN
Added comment: Mitochondrial disorder with typical features such as hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis

PMID: 22284826
Predicted LoF variants in 10 individuals from unrelated families
> 5 individuals with confirmed combined respiratory-chain-complex deficiency in muscle tissue as well as lactic acidosis.
Sources: Other
Rhabdomyolysis and Metabolic Myopathy v0.168 AARS2 Sangavi Sivagnanasundram gene: AARS2 was added
gene: AARS2 was added to Rhabdomyolysis and Metabolic Myopathy. Sources: Other
Mode of inheritance for gene: AARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AARS2 were set to 21549344; 25058219
Phenotypes for gene: AARS2 were set to Combined oxidative phosphorylation deficiency 8 MIM#614096
Review for gene: AARS2 was set to GREEN
Added comment: PMID: 21549344
2 Individuals with infantile mitochondrial HCM and lactic acidosis as well as a severe COX deficiency

PMID: 25058219
5 individuals from unrelated families with a mutation in AARS and phenotypic features of cardiomyopathy but only 3 individuals presented with lactic acidosis.
Sources: Other
Cardiomyopathy_Paediatric v0.160 RRAGC Zornitza Stark Phenotypes for gene: RRAGC were changed from Pediatric Dilated Cardiomyopathy to Dilated cardiomyopathy (MONDO:0005021), RRAGC-related
Cardiomyopathy_Paediatric v0.159 RRAGC Zornitza Stark Publications for gene: RRAGC were set to PMID: 29367541; 27234373
Cardiomyopathy_Paediatric v0.158 RRAGC Zornitza Stark Classified gene: RRAGC as Green List (high evidence)
Cardiomyopathy_Paediatric v0.158 RRAGC Zornitza Stark Gene: rragc has been classified as Green List (High Evidence).
Mendeliome v1.877 RRAGC Zornitza Stark Phenotypes for gene: RRAGC were changed from Dilated cardiomyopathy; cataract to Dilated cardiomyopathy (MONDO:0005021), RRAGC-related
Mendeliome v1.876 RRAGC Zornitza Stark Classified gene: RRAGC as Green List (high evidence)
Mendeliome v1.876 RRAGC Zornitza Stark Gene: rragc has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.128 TPM3 Sangavi Sivagnanasundram edited their review of gene: TPM3: Changed mode of pathogenicity: Other
Muscular dystrophy and myopathy_Paediatric v0.128 TRIP4 Sangavi Sivagnanasundram gene: TRIP4 was added
gene: TRIP4 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: TRIP4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIP4 were set to 27008887; 31794073
Phenotypes for gene: TRIP4 were set to ?Muscular dystrophy, congenital, Davignon-Chauveau type (MIM#617066)
Review for gene: TRIP4 was set to GREEN
Added comment: PMID: 27008887
4 individuals from a consanguineous French family with congenital muscular dystrophy

PMID: 31794073
5 individuals from unrelated families with phenotypic onset in childhood or at birth consistent with congenital muscular dystrophy.
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 TPM3 Sangavi Sivagnanasundram gene: TPM3 was added
gene: TPM3 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: TPM3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TPM3 were set to 26418456; 18300303; 10619715; 12196661; 18382475
Phenotypes for gene: TPM3 were set to Congenital myopathy 4A, autosomal dominant (MIM#255310); Congenital myopathy 4B, autosomal recessive (MIM#609284)
Review for gene: TPM3 was set to GREEN
Added comment: Variable age of onset due to the variability of phenotypes. Mutations in TPM3 cause a diverse group of congenital myopathies all characterised by muscle weakness/hypotonia.

AD Congenital Myopathy:
PMID: 26418456
Quantitative in vitro motility assay show that gain of function is mechanism of disease - mutations in the TPM3 gene led to an increased function in the myofibres/muscle cells.
2 unrelated individuals with ΔE218 and ΔE224 de novo deletions in TPM3 with muscle stiffness. Both muscle biopsies showed features of mild myopathy.

PMID: 18300303
4 individuals with phenotypic features of congenital myopathy and mutation present in TPM3

AR Congenital myopathy:
PMID: 10619715
Individual from consanguineous parents with severe symptoms of congenital myopathy

PMID: 12196661
Individual who is a compound heterozygote for nemaline myopathy

PMID: 18382475
Affected individuals from two turkish families with myopathy phenotypes.
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 TPM2 Sangavi Sivagnanasundram gene: TPM2 was added
gene: TPM2 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: TPM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TPM2 were set to 17846275; 23378224
Phenotypes for gene: TPM2 were set to Nemaline myopathy 4, autosomal dominant (MIM#609285)
Review for gene: TPM2 was set to GREEN
Added comment: - Variable age of onset
- Phenotypic symptoms overlap with CAP syndrome

PMID: 17846275
2 individuals identified with mutations in TPM2 however only one had clinical features and a muscle biopsy (with an accumulation of nemaline rods), concordant with nemaline myopathy.

PMID: 23378224
8 individuals from 5 unrelated families
Presence of congenital contractures in early childhood and all had the presence of rods in their muscle biopsies
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 TNNC2 Sangavi Sivagnanasundram gene: TNNC2 was added
gene: TNNC2 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: TNNC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TNNC2 were set to 33755597
Phenotypes for gene: TNNC2 were set to Congenital Myopathy 15 (MIM#62016)
Review for gene: TNNC2 was set to AMBER
Added comment: Age of onset is soon after birth

PMID: 33755597
2 individuals from unrelated families
Muscle biopsies showed hypertrophy or slow-twitch myofibres.
Sources: Other
Brain Calcification v1.83 WDR45 Yetong Chen gene: WDR45 was added
gene: WDR45 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: WDR45 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: WDR45 were set to 26859818; 25301227
Phenotypes for gene: WDR45 were set to Neurodegeneration with brain iron accumulation 5, MIM# 300894
Review for gene: WDR45 was set to AMBER
Added comment: PMID 26859818 reports a patient with a heterozygous WDR45 variant (c.400G > A) who had symmetrical calcification of the medial globus pallidi.
PMID 25301227 reports a patient with a heterozygous WDR45 variant (c.488del C p.Pro163Argfs*34) who had bilateral dense calcification of the globus pallidus.
Sources: Expert list
Muscular dystrophy and myopathy_Paediatric v0.128 STAC3 Sangavi Sivagnanasundram gene: STAC3 was added
gene: STAC3 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: STAC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STAC3 were set to 28411587; 28777491
Phenotypes for gene: STAC3 were set to Congenital myopathy 13 (MIM#255995)
Review for gene: STAC3 was set to GREEN
Added comment: Also known as Bailey-Bloch congenital myopathy and Native American myopathy (NAM)

PMID: 28411587
An individual with congenital muscle weakness and contracture and clinical phenotypes consistent with myopathy.

PMID: 28777491
3 individuals from 2 unrelated consanguineous families with clinical symptoms of myopathy.

(Note: Individuals with a mutation in STAC3 are shown to have MH susceptibility in the presence of anesthesia.)
Sources: Other
Brain Calcification v1.83 VARS2 Yetong Chen gene: VARS2 was added
gene: VARS2 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: VARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VARS2 were set to 29314548
Phenotypes for gene: VARS2 were set to Combined oxidative phosphorylation deficiency 20, MIM# 615917
Review for gene: VARS2 was set to RED
Added comment: Limited evidence supports the causal role of the VARS2 gene in brain calcification.
PMID 29314548 reports a patient (Patient 5) with compound heterozygous VARS2 variants (c.1135G > A, p.Ala379Thr and c.1877C > A, p.Ala626Asp) who had symmetrical bilateral basal ganglia calcification.
Sources: Expert list
Brain Calcification v1.83 TYROBP Yetong Chen reviewed gene: TYROBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 11402114; Phenotypes: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1, MIM# 221770; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Muscular dystrophy and myopathy_Paediatric v0.128 SPEG Sangavi Sivagnanasundram gene: SPEG was added
gene: SPEG was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: SPEG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPEG were set to 25087613; 30412272
Phenotypes for gene: SPEG were set to Centronuclear myopathy 5, MIM# 615959
Review for gene: SPEG was set to GREEN
Added comment: Variable age of onset (typically seen from birth to early childhood)

PMID: 25087613
3 unrelated individuals with myopathic changes in their biopsy findings (increased centralize nuclei) and decreased amounts of SPEG protein.

Mouse model showed the increase in centralised nuclei in muscle biopsies concordant with a clinical diagnosis of centronuclear myopathy.

PMID: 30412272
2 individuals from unrelated families with hypotonia at birth as well as other phenotypes concordant with a clinical diagnosis of centronuclear myopathy.
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 PAX7 Sangavi Sivagnanasundram gene: PAX7 was added
gene: PAX7 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: PAX7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAX7 were set to 31092906
Phenotypes for gene: PAX7 were set to Congenital myopathy 19 (MIM#618578)
Review for gene: PAX7 was set to GREEN
Added comment: Infantile onset of progressive muscle weakness and atrophy

PMID: 31092906
5 individuals from 4 unrelated families with consanguineous parents - all having clinical signs of myopathy from birth.
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 MYOD1 Sangavi Sivagnanasundram gene: MYOD1 was added
gene: MYOD1 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: MYOD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYOD1 were set to 26733463; 31260566; 30403323
Phenotypes for gene: MYOD1 were set to Congenital Myopathy 17 (MIM#618975)
Review for gene: MYOD1 was set to GREEN
Added comment: Onset of condition is typically at birth.

PMID: 26733463
3 siblings from a first degree consanguineous family with myopathy phenotype.

PMID: 31260566
Two siblings from a fourth degree consansanguineous family with poor weight gain and motor delay and muscle biopsy suggestive of myopathy.

PMID: 30403323
Patient with motor delay, hypotonia identified with a homozygous variant in MYOD1 causative of congenital myopathy. The variant was shown to segregate in the family.
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 MYL1 Sangavi Sivagnanasundram gene: MYL1 was added
gene: MYL1 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: MYL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYL1 were set to 30275711
Phenotypes for gene: MYL1 were set to Congenital Myopathy 14 (MIM#618414)
Review for gene: MYL1 was set to AMBER
Added comment: Phenotypic onset is seen typically at birth or in utero during pregnancy.
Skeletal muscle biopsy typically show a variation in fibre size with specific atrophy of the fast-twitch type II fibres.

PMID: 30275711
2 individuals from unrelated consanguineous families.
Zebrafish model showed a reduced muscle development resulting in the aberrant phenotypes.
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 MYBPC1 Sangavi Sivagnanasundram gene: MYBPC1 was added
gene: MYBPC1 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: MYBPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYBPC1 were set to 31264822; 31025394
Phenotypes for gene: MYBPC1 were set to Congenital Myopathy 16 (MIM#618524)
Review for gene: MYBPC1 was set to GREEN
Added comment: age of onset is seen to be typically during infancy

PMID: 31264822
4 individuals from 3 unrelated families with myopathy related phenotypes

PMID: 31025394
2 individuals from unrelated families with myopathy
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 MTMR14 Sangavi Sivagnanasundram gene: MTMR14 was added
gene: MTMR14 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: MTMR14 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MTMR14 were set to 20400459; 20817957; 19465920; 17008356
Phenotypes for gene: MTMR14 were set to {Centronuclear myopathy, autosomal, modifier of} (MIM#160150)
Review for gene: MTMR14 was set to AMBER
Added comment: Functional assays show the effect of the protein on the gene function that related to the phenotypes expected, however the gene has only been reported and confirmed to cause myopathy in one case.

PMID: 20400459; 20817957; 19465920
Mouse and Zebrafish models show the effect of loss of function of MTMR14 protein due to mutations in MTMR14 which resulted in phenotypic features of myopathy

PMID: 17008356
Reported in two families with myopathy however the second individual had an alternate diagnosis.
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 MAP3K20 Sangavi Sivagnanasundram gene: MAP3K20 was added
gene: MAP3K20 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: MAP3K20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAP3K20 were set to 27816943
Phenotypes for gene: MAP3K20 were set to Centronuclear myopathy 6 with fiber-type disproportion (MIM#617760; MONDO:0054695)
Review for gene: MAP3K20 was set to GREEN
Added comment: Age of onset - Infancy or early childhood

Phenotype and muscle biopsy abnormalities are variable - centralized nuclei and fibre type disproportion seem to be a common finding

PMID: 27816943
6 individuals from 3 unrelated consanguineous families with myopathy
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 LMOD3 Sangavi Sivagnanasundram gene: LMOD3 was added
gene: LMOD3 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: LMOD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LMOD3 were set to 25250574; 28815944; 30291184
Phenotypes for gene: LMOD3 were set to Nemaline myopathy 10 (MIM# 616165; MONDO:0014513)
Review for gene: LMOD3 was set to GREEN
Added comment: Age of onset is typically during pregnancy (antenatal) however severity of the condition is variable.
Typical phenotypes include: severe generalized hypotonia and weakness at birth, respiratory insufficiency, feeding difficulties, and bulbar weakness

PMID: 25250574
Multiple individuals from unrelated families (21 individuals from 14 patients).
Segregation analysis was consistent of an AR inheritance
Zebrafish model showed the complete loss of function in myotubes resulting in abnormal motor function.
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 KLHL41 Sangavi Sivagnanasundram gene: KLHL41 was added
gene: KLHL41 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: KLHL41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KLHL41 were set to 24268659
Phenotypes for gene: KLHL41 were set to Nemaline Myopathy 9 (MIM#615731; MONDO:0014326)
Review for gene: KLHL41 was set to GREEN
Added comment: Age of onset is not definitive - condition has high phenotypic variability

PMID: 24268659
Zebrafish functional study model showed the loss of function of KLHL41 resulting in highly diminished motor function.

5 unrelated children with nemaline myopathy 9. Muscle biopsies in individuals showed the presence of sarcoplamisc rods in myofibers.
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 KLHL40 Sangavi Sivagnanasundram gene: KLHL40 was added
gene: KLHL40 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: KLHL40 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KLHL40 were set to 23746549
Phenotypes for gene: KLHL40 were set to Nemaline myopathy 8, autosomal recessive, MIM# 615348
Review for gene: KLHL40 was set to GREEN
Added comment: PMID: 23746549
Multiple individuals from unrelated families identified with NEM (both severe and milder forms)
Study showed that KLHL40 mutations are more likely to cause severe NEM

Identified founder mutation, c.1582G>A, in Japanese population. Was also found in Kurdish and Turkish population.
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 KBTBD13 Sangavi Sivagnanasundram gene: KBTBD13 was added
gene: KBTBD13 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: KBTBD13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KBTBD13 were set to 21104864; 11731279; 21109227
Phenotypes for gene: KBTBD13 were set to Nemaline myopathy 6, autosomal dominant (MIM# 609273; MONDO:0012237)
Review for gene: KBTBD13 was set to GREEN
Added comment: PMID: 21104864; 11731279; 21109227
4 individuals from unrelated families with clinical features consistent with nemaline myopathy

(articles reference the gene NEM6 - previous name)
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 HRAS Sangavi Sivagnanasundram gene: HRAS was added
gene: HRAS was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: HRAS was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HRAS were set to 17412879
Phenotypes for gene: HRAS were set to Congenital myopathy with excess of muscle spindles (MIM#218040)
Review for gene: HRAS was set to AMBER
Added comment: A variant of Costello Syndrome which is typically characterised by diffuse hypotonia, short stature, developmental delay etc.

Age of onset - birth to early childhood

Most of the mutations related to CMEMS are inherited in an Autosomal Dominant manner, some can be caused by Somatic mutations as well.

PMID: 17412879
4 unrelated individuals identified with a mutation in HRAS and clinical features causative of congenital myopathy with excess of muscle spindles (CMEMS). No functional evidence or animal model study conducted yet
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 HACD1 Sangavi Sivagnanasundram gene: HACD1 was added
gene: HACD1 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: HACD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HACD1 were set to 32426512; 27939133; 33354762; 23933735
Phenotypes for gene: HACD1 were set to Congenital myopathy 11 (MIM#619967; MONDO:0019952)
Review for gene: HACD1 was set to GREEN
Added comment: Age of onset - from birth to early childhood (typically) but is not progressive

PMID: 32426512; 27939133
Individual from consanguineous parents present with a LINE insertation mutation in HACD1 known to cause a form of centronuclear myopathy in dogs.
Developed myopathy features from the age of 4

PMID: 33354762
3 individuals from unrelated families with a homozygous mutation causative of congenital myopathy. Age of onset of symptoms varied between birth to early childhood in these patients. The symptoms showed that the disorder is not progressive and muscle weakness improves in late childhood.

PMID: 23933735
Large consanguineous family with 4 carrying a homozygous mutation in HACD1 causative of congenital myopathy.
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 FXR1 Sangavi Sivagnanasundram gene: FXR1 was added
gene: FXR1 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: FXR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FXR1 were set to 30770808; 35393337
Phenotypes for gene: FXR1 were set to Congenital myopathy 9B, proximal, with minicore lesions (MIM#618823; MONDO:0032937)
Review for gene: FXR1 was set to GREEN
Added comment: Variable age of onset - typically early to late childhood

PMID: 30770808
4 individuals from 2 unrelated families (3 individuals reported from the same family) present with phenotypic features of myopathy such as hypotonia.

PMID: 35393337
8 individuals from 4 unrelated families identified with bi-allelic variants with myopathy phenotypes
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 EPG5 Sangavi Sivagnanasundram gene: EPG5 was added
gene: EPG5 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: EPG5 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: EPG5 were set to 23222957
Phenotypes for gene: EPG5 were set to Vici Syndrome (MONDO: 0009452; MIM#242840)
Review for gene: EPG5 was set to GREEN
Added comment: Rare congenital disorder (that is reported in multiple individuals) - individuals typically present with profound psychomotor retardation and hypotonia due to myopathy.

Age of onset is typically early childhood.

PMID: 23222957
>6 individuals from unrelated families identified with mutations in EPG5 and phenotypic features related to Vici Syndrome
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 DYNC1H1 Sangavi Sivagnanasundram gene: DYNC1H1 was added
gene: DYNC1H1 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: DYNC1H1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DYNC1H1 were set to PMID: 2245967; 25609763
Phenotypes for gene: DYNC1H1 were set to Spinal muscular atrophy, lower extremity-predominant 1, (MIM#158600; MONDO:0008026)
Review for gene: DYNC1H1 was set to GREEN
Added comment: Phenotypes can resemble those similar to congenital myopathy
Age of onset ranges from birth to early childhood

PMID: 22459677
Phenotypes included early childood onset of proximal leg weakness with muscle atropy and significant motor delay

PMID: 25609763
>10 individuals with SMA phenotypic features similar to congenital myopathy
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 DHX16 Sangavi Sivagnanasundram gene: DHX16 was added
gene: DHX16 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: DHX16 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DHX16 were set to 36211162
Phenotypes for gene: DHX16 were set to Neuromuscular disease and ocular or auditory anomalies with or without seizures (MIM#618733; MONDO:0032890)
Review for gene: DHX16 was set to RED
Added comment: Gene not related to congenital myopathies but has phenotype overlap

PMID: 36211162
One individual presents with severe hypotonia as well as sensorineural deafness and a mixed axonal sensory with developmental delay.
Identified a de novo vairant present causative of Neuromuscular disease and ocular or auditory anomalies with or without seizures.
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 CNTN1 Sangavi Sivagnanasundram gene: CNTN1 was added
gene: CNTN1 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: CNTN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNTN1 were set to 10926398
Phenotypes for gene: CNTN1 were set to Congenital Myopathy 12, Compton-North myopathy (MONDO:0012929; MIM#612540)
Review for gene: CNTN1 was set to AMBER
Added comment: PMID: 10926398
single family reported with clinical features consistent with severe lethal myopathy
(age of onset is unknown as only one family has been reported)
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 CFL2 Sangavi Sivagnanasundram gene: CFL2 was added
gene: CFL2 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: CFL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFL2 were set to PMID: 17160903; 22560515
Phenotypes for gene: CFL2 were set to Nemaline myopathy 7 (MONDO:0012538; MIM#610687)
Review for gene: CFL2 was set to GREEN
Added comment: PMID: 17160903; 22560515
Age of onset - from birth to early childhood (typically around the ages of expected childhood milestones)
- 4 individuals from 2 unrelated consangineous families with clinical phenotypes consistent with congenital myopathy
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 CCDC78 Sangavi Sivagnanasundram gene: CCDC78 was added
gene: CCDC78 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: CCDC78 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCDC78 were set to 22818856
Phenotypes for gene: CCDC78 were set to Centronuclear Myopathy (MIM#614807; MONDO: 0018947)
Review for gene: CCDC78 was set to AMBER
Added comment: PMID: 22818856
5 individuals in the same family with features of myopathy
(Hypotonia, excessive fatigue, prominent myalgias)
Mutations in this gene are not common for congenital myopathy.
Sources: Other
Brain Calcification v1.83 TSC2 Yetong Chen reviewed gene: TSC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21175459, 30628968, 19258292, 28786492; Phenotypes: Tuberous sclerosis-2, MIM# 613254; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Muscular dystrophy and myopathy_Paediatric v0.128 ASCC3 Sangavi Sivagnanasundram gene: ASCC3 was added
gene: ASCC3 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: ASCC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASCC3 were set to 35047834
Phenotypes for gene: ASCC3 were set to Congenital Myopathy (MONDO:0019952); Neuromuscular Symptoms
Review for gene: ASCC3 was set to GREEN
Added comment: PMID: 35047834
11 individuals from 7 unrelated families present with clinical phenotypes consistent with ASCC3-related myopathy.
All individuals reported developmental delay and muscle weakness but age of onset is unknown
Sources: Other
Muscular dystrophy and myopathy_Paediatric v0.128 ASCC1 Sangavi Sivagnanasundram gene: ASCC1 was added
gene: ASCC1 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: ASCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASCC1 were set to (PMID: 30327447; 35838082; 26924529)
Phenotypes for gene: ASCC1 were set to Congenital Myopathy - MONDO:0019952
Review for gene: ASCC1 was set to GREEN
Added comment: PMID: 30327447; 35838082
>3 individuals from unrelated families with clinical features consistent with congenital myopathy

PMID: 35838082
Individual with congenital myopathy phenotype and a mutation in ASCC1.

PMID: 26924529
Animal study showed the effect on ASCC1 protein function in muscle cells.
Sources: Other
Brain Calcification v1.83 TBCE Yetong Chen gene: TBCE was added
gene: TBCE was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: TBCE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCE were set to 28138323; 35935360
Phenotypes for gene: TBCE were set to Hypoparathyroidism-retardation-dysmorphism syndrome, MIM# 241410
Review for gene: TBCE was set to AMBER
Added comment: PMID 35935360 reports a total of 63 patients with hypoparathyroidism-retardation-dysmorphism (HRD) Syndrome, of which 32 had brain calcifications. Although the paper states that 25 of 63 patients had genetic diagnoses, the number of patients with brain calcification carrying TBCE variants is unclear.
Sources: Expert list
Mendeliome v1.875 RECQL4 Zornitza Stark Phenotypes for gene: RECQL4 were changed from Baller-Gerold syndrome, MIM# 218600; RAPADILINO syndrome, MIM# 266280; Rothmund-Thomson syndrome, type 2,MIM# 268400 to Baller-Gerold syndrome, MIM# 218600; RAPADILINO syndrome, MIM# 266280; Rothmund-Thomson syndrome, type 2,MIM# 268400; RECON progeroid syndrome, MIM# 620370
Mendeliome v1.874 RECQL4 Zornitza Stark Publications for gene: RECQL4 were set to
Chromosome Breakage Disorders v1.19 RECQL4 Zornitza Stark changed review comment from: Two families reported with a progeroid disorder, however all individuals had the same homozygous missense variant, suggestive of founder effect.; to: PMID 35025765: Two families reported with a progeroid disorder, however all individuals had the same homozygous missense variant, suggestive of founder effect.
Mendeliome v1.873 RECQL4 Zornitza Stark reviewed gene: RECQL4: Rating: RED; Mode of pathogenicity: None; Publications: 35025765; Phenotypes: RECON progeroid syndrome, MIM# 620370; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Chromosome Breakage Disorders v1.19 RECQL4 Zornitza Stark Phenotypes for gene: RECQL4 were changed from Rothmund-Thomson syndrome, type 2, MIM# 268400; RAPADILINO syndrome, MIM# 266280; Baller-Gerold syndrome, MIM# 218600 to Rothmund-Thomson syndrome, type 2, MIM# 268400; RAPADILINO syndrome, MIM# 266280; Baller-Gerold syndrome, MIM# 218600; RECON progeroid syndrome, MIM# 620370
Chromosome Breakage Disorders v1.18 RECQL4 Zornitza Stark Publications for gene: RECQL4 were set to 10319867; 12952869; 15964893
Chromosome Breakage Disorders v1.17 RECQL4 Zornitza Stark edited their review of gene: RECQL4: Added comment: Two families reported with a progeroid disorder, however all individuals had the same homozygous missense variant, suggestive of founder effect.; Changed publications: 10319867, 12952869, 15964893, 35025765
Chromosome Breakage Disorders v1.17 RECQL4 Zornitza Stark edited their review of gene: RECQL4: Changed phenotypes: Rothmund-Thomson syndrome, type 2, MIM# 268400, RAPADILINO syndrome, MIM# 266280, Baller-Gerold syndrome, MIM# 218600, RECON progeroid syndrome, MIM# 620370
Mitochondrial disease v0.868 ATP5O Zornitza Stark Marked gene: ATP5O as ready
Mitochondrial disease v0.868 ATP5O Zornitza Stark Gene: atp5o has been classified as Green List (High Evidence).
Mitochondrial disease v0.868 ATP5O Zornitza Stark Classified gene: ATP5O as Green List (high evidence)
Mitochondrial disease v0.868 ATP5O Zornitza Stark Gene: atp5o has been classified as Green List (High Evidence).
Mitochondrial disease v0.867 ATP5O Zornitza Stark gene: ATP5O was added
gene: ATP5O was added to Mitochondrial disease. Sources: Literature
Mode of inheritance for gene: ATP5O was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP5O were set to 34954817; 35621276
Phenotypes for gene: ATP5O were set to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7, MIM# 620359
Review for gene: ATP5O was set to GREEN
Added comment: 4 individuals from three unrelated families reported. Onset in infancy. Features included intrauterine growth retardation, hypotonia, neonatal respiratory distress, and global developmental delay, seizures.
Sources: Literature
Mendeliome v1.873 ATP5O Zornitza Stark Phenotypes for gene: ATP5O were changed from mitochondrial disease, ATP5F1E-related MONDO:0044970 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7, MIM# 620359
Mendeliome v1.872 ATP5O Zornitza Stark Publications for gene: ATP5O were set to 34954817
Mendeliome v1.871 ATP5O Zornitza Stark Classified gene: ATP5O as Green List (high evidence)
Mendeliome v1.871 ATP5O Zornitza Stark Gene: atp5o has been classified as Green List (High Evidence).
Mendeliome v1.870 ATP5O Zornitza Stark reviewed gene: ATP5O: Rating: GREEN; Mode of pathogenicity: None; Publications: 35621276; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 7, MIM# 620359; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5227 SLITRK2 Zornitza Stark Phenotypes for gene: SLITRK2 were changed from Neurodevelopmental disorder, SLITRK2-related MONDO:0700092 to Intellectual developmental disorder, X-linked 111, MIM# 301107
Intellectual disability syndromic and non-syndromic v0.5226 SLITRK2 Zornitza Stark reviewed gene: SLITRK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, X-linked 111, MIM# 301107; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genetic Epilepsy v0.1848 SLITRK2 Zornitza Stark Phenotypes for gene: SLITRK2 were changed from Neurodevelopmental disorder, SLITRK2-related MONDO:0700092 to Intellectual developmental disorder, X-linked 111, MIM# 301107
Genetic Epilepsy v0.1847 SLITRK2 Zornitza Stark reviewed gene: SLITRK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, X-linked 111, MIM# 301107; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.870 SLITRK2 Zornitza Stark Phenotypes for gene: SLITRK2 were changed from Neurodevelopmental disorder, SLITRK2-related MONDO:0700092 to Intellectual developmental disorder, X-linked 111, MIM# 301107
Mendeliome v1.869 SLITRK2 Zornitza Stark reviewed gene: SLITRK2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, X-linked 111, MIM# 301107; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.869 AMFR Yetong Chen gene: AMFR was added
gene: AMFR was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AMFR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AMFR were set to 37119330
Phenotypes for gene: AMFR were set to Hereditary spastic paraplegia, MONDO:0019064
Review for gene: AMFR was set to GREEN
Added comment: PMID 37119330 reports 20 individuals harbouring AMFR variants from 8 unrelated, consanguineous families. All patients had early disease onset (<3 years), including motor delay, lower limb hyperreflexia and spastic paraplegia that match the typical phenotypes of hereditary spastic paraplegia.
Sources: Literature
Hereditary Spastic Paraplegia v1.61 AMFR Yetong Chen gene: AMFR was added
gene: AMFR was added to Hereditary Spastic Paraplegia - paediatric. Sources: Literature
Mode of inheritance for gene: AMFR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AMFR were set to 37119330
Phenotypes for gene: AMFR were set to Hereditary spastic paraplegia, MONDO:0019064
Review for gene: AMFR was set to GREEN
Added comment: PMID 37119330 reports 20 individuals harbouring AMFR variants from 8 unrelated, consanguineous families. All patients had early disease onset (<3 years), including motor delay, lower limb hyperreflexia and spastic paraplegia that match the typical phenotypes of hereditary spastic paraplegia.
Sources: Literature
Severe Combined Immunodeficiency v1.3 POLD3 Bryony Thompson Marked gene: POLD3 as ready
Severe Combined Immunodeficiency v1.3 POLD3 Bryony Thompson Gene: pold3 has been classified as Amber List (Moderate Evidence).
Severe Combined Immunodeficiency v1.3 POLD3 Bryony Thompson Phenotypes for gene: POLD3 were changed from Severe combined immunodeficiency to Severe combined immunodeficiency MONDO:0015974
Severe Combined Immunodeficiency v1.2 POLD3 Bryony Thompson Publications for gene: POLD3 were set to PMID: 37030525
Severe Combined Immunodeficiency v1.2 POLD3 Bryony Thompson Classified gene: POLD3 as Amber List (moderate evidence)
Severe Combined Immunodeficiency v1.2 POLD3 Bryony Thompson Gene: pold3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.869 POLD3 Bryony Thompson Classified gene: POLD3 as Amber List (moderate evidence)
Mendeliome v1.869 POLD3 Bryony Thompson Gene: pold3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.868 POLD3 Bryony Thompson Marked gene: POLD3 as ready
Mendeliome v1.868 POLD3 Bryony Thompson Gene: pold3 has been classified as Red List (Low Evidence).
Mendeliome v1.868 POLD3 Bryony Thompson gene: POLD3 was added
gene: POLD3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLD3 were set to 37030525; 36395985; 27524497
Phenotypes for gene: POLD3 were set to Severe combined immunodeficiency MONDO:0015974
Review for gene: POLD3 was set to AMBER
Added comment: Homozygous missense variant (NM_006591.3; p.Ile10Thr) identified in a single Lebanese patient, the product of a consanguineous family, presenting with a syndromic severe combined immunodeficiency with neurodevelopmental delay and hearing loss. POLD3 as well as POLD1 and POLD2 expression was abolished in the patient's cells. Null mouse models are embryonic lethal and demonstrate Pold3 is essential for DNA replication in murine B cells.
Sources: Literature
Osteopetrosis v0.32 SLC4A2 Zornitza Stark Marked gene: SLC4A2 as ready
Osteopetrosis v0.32 SLC4A2 Zornitza Stark Gene: slc4a2 has been classified as Amber List (Moderate Evidence).
Muscular dystrophy and myopathy_Paediatric v0.128 NEB Sangavi Sivagnanasundram gene: NEB was added
gene: NEB was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: NEB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEB were set to 25205138
Phenotypes for gene: NEB were set to Nemaline Myopathy 2 (MIM#256030; MONDO: 0009725)
Review for gene: NEB was set to GREEN
Added comment: PMID: 25205138
Multiple individuals diagnosed with nemaline myopathy 2 in a well-established gene with variable age of onset
Sources: Other
Combined Immunodeficiency v1.37 POLD2 Bryony Thompson Phenotypes for gene: POLD2 were changed from Low CD4 T cells; Low B cells, normal maturation; recurrent respiratory tract infections, skin infections, warts and molluscum; short stature; intellectual disability to Non-severe combined immunodeficiency due to polymerase delta deficiency MONDO:0800145; Low CD4 T cells; Low B cells, normal maturation; recurrent respiratory tract infections, skin infections, warts and molluscum; short stature; intellectual disability
Combined Immunodeficiency v1.36 POLD2 Bryony Thompson Classified gene: POLD2 as Amber List (moderate evidence)
Combined Immunodeficiency v1.36 POLD2 Bryony Thompson Gene: pold2 has been classified as Amber List (Moderate Evidence).
Combined Immunodeficiency v1.35 POLD2 Bryony Thompson Publications for gene: POLD2 were set to 31449058
Combined Immunodeficiency v1.35 POLD2 Bryony Thompson Classified gene: POLD2 as Amber List (moderate evidence)
Combined Immunodeficiency v1.35 POLD2 Bryony Thompson Gene: pold2 has been classified as Amber List (Moderate Evidence).
Combined Immunodeficiency v1.34 POLD2 Bryony Thompson reviewed gene: POLD2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31449058, 36528861; Phenotypes: Non-severe combined immunodeficiency due to polymerase delta deficiency MONDO:0800145; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.867 POLD2 Bryony Thompson edited their review of gene: POLD2: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.867 POLD2 Bryony Thompson Phenotypes for gene: POLD2 were changed from Intellectual disability; immunodeficiency to Non-severe combined immunodeficiency due to polymerase delta deficiency MONDO:0800145
Mendeliome v1.866 POLD2 Bryony Thompson Publications for gene: POLD2 were set to 31449058
Muscular dystrophy and myopathy_Paediatric v0.128 MYPN Sangavi Sivagnanasundram gene: MYPN was added
gene: MYPN was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: MYPN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYPN were set to 28017374
Phenotypes for gene: MYPN were set to Nemaline Myopathy (MIM#617336; MONDO:0018958)
Review for gene: MYPN was set to GREEN
Added comment: PMID: 28017374
Slowly progressive myopathy with onset in childhood
Identified in at least 4 individuals
Sources: Other
Mendeliome v1.865 POLD2 Bryony Thompson Classified gene: POLD2 as Amber List (moderate evidence)
Mendeliome v1.865 POLD2 Bryony Thompson Gene: pold2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.864 POLD2 Bryony Thompson reviewed gene: POLD2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31449058, 36528861; Phenotypes: Non-severe combined immunodeficiency due to polymerase delta deficiency MONDO:0800145; Mode of inheritance: None
Mendeliome v1.864 SLC4A2 Zornitza Stark Marked gene: SLC4A2 as ready
Mendeliome v1.864 SLC4A2 Zornitza Stark Gene: slc4a2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.864 SLC4A2 Zornitza Stark Classified gene: SLC4A2 as Amber List (moderate evidence)
Mendeliome v1.864 SLC4A2 Zornitza Stark Gene: slc4a2 has been classified as Amber List (Moderate Evidence).
Osteopetrosis v0.32 SLC4A2 Zornitza Stark Classified gene: SLC4A2 as Amber List (moderate evidence)
Osteopetrosis v0.32 SLC4A2 Zornitza Stark Gene: slc4a2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.863 SLC4A2 Zornitza Stark gene: SLC4A2 was added
gene: SLC4A2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC4A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC4A2 were set to 34668226; 20507629
Phenotypes for gene: SLC4A2 were set to Osteopetrosis, autosomal recessive 9, MIM# 620366
Review for gene: SLC4A2 was set to AMBER
Added comment: Single individual reported with homozygous missense variant. However, cattle and mouse models support gene-disease association.
Sources: Literature
Muscular dystrophy and myopathy_Paediatric v0.128 DNM2 Sangavi Sivagnanasundram gene: DNM2 was added
gene: DNM2 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: DNM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DNM2 were set to 17932957; 19122038
Phenotypes for gene: DNM2 were set to Centronuclear Myopathy 1 (MIM#160150; MONDO:0008048)
Review for gene: DNM2 was set to GREEN
Added comment: PMID: 17932957, 19122038
Multiple individuals with centronuclear myopathy.
Age of onset is variable but typically in the early childhood.
Sources: Other
Osteopetrosis v0.31 SLC4A2 Zornitza Stark gene: SLC4A2 was added
gene: SLC4A2 was added to Osteopetrosis. Sources: Literature
Mode of inheritance for gene: SLC4A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC4A2 were set to 34668226; 20507629
Phenotypes for gene: SLC4A2 were set to Osteopetrosis, autosomal recessive 9, MIM# 620366
Review for gene: SLC4A2 was set to AMBER
Added comment: Single individual reported with homozygous missense variant. However, cattle and mouse models support gene-disease association.
Sources: Literature
Muscular dystrophy and myopathy_Paediatric v0.128 DNAJB4 Sangavi Sivagnanasundram gene: DNAJB4 was added
gene: DNAJB4 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: DNAJB4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAJB4 were set to 36264506
Phenotypes for gene: DNAJB4 were set to Congenital Myopathy 21 with early respiratory failure (MIM#620326; MONDO:005336)
Review for gene: DNAJB4 was set to GREEN
Added comment: PMID: 36264506
4 individuals from unrelated families with congenital myopathy with variable age of onset
Sources: Other
Disorders of immune dysregulation v0.172 DOCK2 Bryony Thompson Marked gene: DOCK2 as ready
Disorders of immune dysregulation v0.172 DOCK2 Bryony Thompson Gene: dock2 has been classified as Amber List (Moderate Evidence).
Inflammatory bowel disease v0.100 C17orf62 Bryony Thompson Marked gene: C17orf62 as ready
Inflammatory bowel disease v0.100 C17orf62 Bryony Thompson Gene: c17orf62 has been classified as Amber List (Moderate Evidence).
Disorders of immune dysregulation v0.172 DOCK2 Bryony Thompson Phenotypes for gene: DOCK2 were changed from HLH to Genetic hemophagocytic lymphohistiocytosis MONDO:0015541
Disorders of immune dysregulation v0.171 DOCK2 Bryony Thompson Classified gene: DOCK2 as Amber List (moderate evidence)
Disorders of immune dysregulation v0.171 DOCK2 Bryony Thompson Gene: dock2 has been classified as Amber List (Moderate Evidence).
Inflammatory bowel disease v0.100 C17orf62 Bryony Thompson Classified gene: C17orf62 as Amber List (moderate evidence)
Inflammatory bowel disease v0.100 C17orf62 Bryony Thompson Gene: c17orf62 has been classified as Amber List (Moderate Evidence).
Muscular dystrophy and myopathy_Paediatric v0.128 BIN1 Sangavi Sivagnanasundram gene: BIN1 was added
gene: BIN1 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: BIN1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: BIN1 were set to 17676042; 29950440
Phenotypes for gene: BIN1 were set to Centronuclear myopathy 2 (MONDO: 0009709; MIM#255200)
Review for gene: BIN1 was set to GREEN
Added comment: PMID: 17676042
3 unrelated consanguineous families with centronuclear myopathy 2.
Age of onset ranged from birth to childhood

PMID: 29950440
Homozygous patients have a more specific and severe phenotype compared to compound heterozygous patients with similar age of onset
Sources: Other
Bone Marrow Failure v1.40 ZCCHC8 Bryony Thompson Marked gene: ZCCHC8 as ready
Bone Marrow Failure v1.40 ZCCHC8 Bryony Thompson Gene: zcchc8 has been classified as Amber List (Moderate Evidence).
Bone Marrow Failure v1.40 ZCCHC8 Bryony Thompson Classified gene: ZCCHC8 as Amber List (moderate evidence)
Bone Marrow Failure v1.40 ZCCHC8 Bryony Thompson Gene: zcchc8 has been classified as Amber List (Moderate Evidence).
Bone Marrow Failure v1.39 ZCCHC8 Bryony Thompson gene: ZCCHC8 was added
gene: ZCCHC8 was added to Bone Marrow Failure. Sources: Literature
Mode of inheritance for gene: ZCCHC8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZCCHC8 were set to 31488579
Phenotypes for gene: ZCCHC8 were set to Pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148
Review for gene: ZCCHC8 was set to AMBER
Added comment: A missense variant (P186L) segregates over 3 generations in a single family, and supporting in vitro assays and mouse model.
Sources: Literature
Pulmonary Fibrosis_Interstitial Lung Disease v0.53 ZCCHC8 Bryony Thompson Phenotypes for gene: ZCCHC8 were changed from Pulmonary fibrosis to Pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148
Pulmonary Fibrosis_Interstitial Lung Disease v0.52 ZCCHC8 Bryony Thompson edited their review of gene: ZCCHC8: Changed phenotypes: Pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148
Mendeliome v1.862 ZCCHC8 Bryony Thompson Phenotypes for gene: ZCCHC8 were changed from Pulmonary fibrosis to pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148
Mendeliome v1.861 ZCCHC8 Bryony Thompson edited their review of gene: ZCCHC8: Changed phenotypes: pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148
Bone Marrow Failure v1.38 NOP10 Bryony Thompson Classified gene: NOP10 as Amber List (moderate evidence)
Bone Marrow Failure v1.38 NOP10 Bryony Thompson Gene: nop10 has been classified as Amber List (Moderate Evidence).
Bone Marrow Failure v1.37 NOP10 Bryony Thompson reviewed gene: NOP10: Rating: AMBER; Mode of pathogenicity: None; Publications: 17507419, 32554502; Phenotypes: Dyskeratosis congenita, autosomal recessive 1, MIM#224230, Telomere syndrome MONDO:0100137; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.861 NOP10 Bryony Thompson Phenotypes for gene: NOP10 were changed from Dyskeratosis congenita, autosomal recessive 1, MIM#224230 to Dyskeratosis congenita, autosomal recessive 1, MIM#224230; Telomere syndrome MONDO:0100137
Mendeliome v1.860 NOP10 Bryony Thompson Publications for gene: NOP10 were set to 17507419
Mendeliome v1.859 NOP10 Bryony Thompson Classified gene: NOP10 as Amber List (moderate evidence)
Mendeliome v1.859 NOP10 Bryony Thompson Gene: nop10 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.858 NOP10 Bryony Thompson reviewed gene: NOP10: Rating: AMBER; Mode of pathogenicity: None; Publications: 17507419, 32554502; Phenotypes: Telomere syndrome MONDO:0100137; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pulmonary Fibrosis_Interstitial Lung Disease v0.52 ACD Bryony Thompson Marked gene: ACD as ready
Pulmonary Fibrosis_Interstitial Lung Disease v0.52 ACD Bryony Thompson Gene: acd has been classified as Amber List (Moderate Evidence).
Pulmonary Fibrosis_Interstitial Lung Disease v0.52 ACD Bryony Thompson Classified gene: ACD as Amber List (moderate evidence)
Pulmonary Fibrosis_Interstitial Lung Disease v0.52 ACD Bryony Thompson Gene: acd has been classified as Amber List (Moderate Evidence).
Pulmonary Fibrosis_Interstitial Lung Disease v0.51 ACD Bryony Thompson gene: ACD was added
gene: ACD was added to Pulmonary Fibrosis_Interstitial Lung Disease. Sources: Literature
Mode of inheritance for gene: ACD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACD were set to 31515401; 27807141; 25205116
Phenotypes for gene: ACD were set to pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148
Mode of pathogenicity for gene: ACD was set to Other
Review for gene: ACD was set to AMBER
Added comment: 3 probands reported with heterozygous variants (only 2 of the variants including p.Lys170 look to possibly relevant)
PMID: 31515401 - proband 1 with bone marrow failure and pulmonary fibrosis in the context of a telomere syndrome heterozygous for recurrent p.Lys170del. Proband 2 with idiopathic pulmonary fibrosis heterozygous for p.Lys170Glu. Proband 3 with idiopathic pulmonary fibrosis heterozygous for p.Ala72Glu (9 hets in gnomAD - VUS), which was also found in the unaffected 83 yo father. All patients had a leukocyte telomere length <1st percentiles for age.
PMID: 27807141 - in vitro functional assays suggesting that the recurrent variant p.Lys170del is sufficient to cause the cellular underpinnings of dyskeratosis congenita, acting in a dosage-dependent mechanism rather than dominant-negative.
PMID: 25205116 - Lys170del identified in 18-yo proband, mother, and maternal grandmother presented with bone marrow failure of varying severity, and decreasing ages of presentation in successive generations. All with short telomeres. In vitro assays demonstrate the variant localises to telomeres but fails to recruit telomerase to telomeres.
Sources: Literature
Bone Marrow Failure v1.37 ACD Bryony Thompson Phenotypes for gene: ACD were changed from Dyskeratosis congenita, MIM# 616553 to telomere syndrome MONDO:0100137; dyskeratosis congenita, autosomal dominant 6 MONDO:0014690; Hoyeraal-Hreidarsson syndrome MONDO:0018045
Bone Marrow Failure v1.36 ACD Bryony Thompson Publications for gene: ACD were set to 25205116; 25233904
Bone Marrow Failure v1.35 ACD Bryony Thompson Classified gene: ACD as Green List (high evidence)
Bone Marrow Failure v1.35 ACD Bryony Thompson Gene: acd has been classified as Green List (High Evidence).
Bone Marrow Failure v1.34 ACD Bryony Thompson reviewed gene: ACD: Rating: GREEN; Mode of pathogenicity: None; Publications: 27807141, 31515401, 30995915, 27528712, 25205116, 24316971, 30064976, 33446513, 25233904; Phenotypes: telomere syndrome MONDO:0100137, dyskeratosis congenita, autosomal dominant 6 MONDO:0014690, Hoyeraal-Hreidarsson syndrome MONDO:0018045; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.858 ACD Bryony Thompson Phenotypes for gene: ACD were changed from Dyskeratosis congenita, MIM# 616553 to telomere syndrome MONDO:0100137; dyskeratosis congenita, autosomal dominant 6 MONDO:0014690; Hoyeraal-Hreidarsson syndrome MONDO:0018045
Mendeliome v1.857 ACD Bryony Thompson Publications for gene: ACD were set to 25205116; 25233904
Mendeliome v1.856 ACD Bryony Thompson Classified gene: ACD as Green List (high evidence)
Mendeliome v1.856 ACD Bryony Thompson Gene: acd has been classified as Green List (High Evidence).
Mendeliome v1.855 ACD Bryony Thompson reviewed gene: ACD: Rating: GREEN; Mode of pathogenicity: None; Publications: 27807141, 31515401, 30995915, 27528712, 25205116, 24316971, 30064976, 33446513, 25233904; Phenotypes: telomere syndrome MONDO:0100137, dyskeratosis congenita, autosomal dominant 6 MONDO:0014690, Hoyeraal-Hreidarsson syndrome MONDO:0018045; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Muscular dystrophy and myopathy_Paediatric v0.128 ADSSL1 Sangavi Sivagnanasundram gene: ADSSL1 was added
gene: ADSSL1 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: ADSSL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADSSL1 were set to PMID: 3650622; 28268051; 32646962
Phenotypes for gene: ADSSL1 were set to Myopathy Distal 5 (MONDO:0014877; MIM#617030)
Review for gene: ADSSL1 was set to GREEN
Added comment: PMID: 3650622; 28268051
Age of onset 13-17 years in multiple individuals of unrelated families

PMID: 32646962 - Multiple individuals diagnosed with distal myopathy 5 (MD5)
Sources: Other
Brain Calcification v1.83 MT-ATP6 Zornitza Stark Marked gene: MT-ATP6 as ready
Brain Calcification v1.83 MT-ATP6 Zornitza Stark Gene: mt-atp6 has been classified as Red List (Low Evidence).
Brain Calcification v1.83 MT-ATP6 Zornitza Stark Phenotypes for gene: MT-ATP6 were changed from Leigh syndrome, MIM# 256000 to Leigh syndrome, MONDO:0009723
Brain Calcification v1.82 MT-ATP6 Zornitza Stark Classified gene: MT-ATP6 as Red List (low evidence)
Brain Calcification v1.82 MT-ATP6 Zornitza Stark Gene: mt-atp6 has been classified as Red List (Low Evidence).
Brain Calcification v1.81 MT-ATP6 Zornitza Stark reviewed gene: MT-ATP6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Leigh syndrome, MONDO:0009723; Mode of inheritance: MITOCHONDRIAL
Brain Calcification v1.81 GNAS Zornitza Stark Marked gene: GNAS as ready
Brain Calcification v1.81 GNAS Zornitza Stark Gene: gnas has been classified as Green List (High Evidence).
Brain Calcification v1.81 GNAS Zornitza Stark Classified gene: GNAS as Green List (high evidence)
Brain Calcification v1.81 GNAS Zornitza Stark Gene: gnas has been classified as Green List (High Evidence).
Brain Calcification v1.80 MOCS1 Zornitza Stark Marked gene: MOCS1 as ready
Brain Calcification v1.80 MOCS1 Zornitza Stark Gene: mocs1 has been classified as Amber List (Moderate Evidence).
Brain Calcification v1.80 MOCS1 Zornitza Stark Classified gene: MOCS1 as Amber List (moderate evidence)
Brain Calcification v1.80 MOCS1 Zornitza Stark Gene: mocs1 has been classified as Amber List (Moderate Evidence).
Brain Calcification v1.79 MOCS1 Zornitza Stark reviewed gene: MOCS1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Molybdenum cofactor deficiency A, MIM# 252150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.79 ISG15 Zornitza Stark Marked gene: ISG15 as ready
Brain Calcification v1.79 ISG15 Zornitza Stark Gene: isg15 has been classified as Green List (High Evidence).
Brain Calcification v1.79 ISG15 Zornitza Stark Classified gene: ISG15 as Green List (high evidence)
Brain Calcification v1.79 ISG15 Zornitza Stark Gene: isg15 has been classified as Green List (High Evidence).
Brain Calcification v1.78 PLXNA1 Zornitza Stark Marked gene: PLXNA1 as ready
Brain Calcification v1.78 PLXNA1 Zornitza Stark Gene: plxna1 has been classified as Red List (Low Evidence).
Brain Calcification v1.78 PLXNA1 Zornitza Stark Classified gene: PLXNA1 as Red List (low evidence)
Brain Calcification v1.78 PLXNA1 Zornitza Stark Gene: plxna1 has been classified as Red List (Low Evidence).
Brain Calcification v1.77 TRPM6 Zornitza Stark Marked gene: TRPM6 as ready
Brain Calcification v1.77 TRPM6 Zornitza Stark Gene: trpm6 has been classified as Red List (Low Evidence).
Brain Calcification v1.77 TRPM6 Zornitza Stark Classified gene: TRPM6 as Red List (low evidence)
Brain Calcification v1.77 TRPM6 Zornitza Stark Gene: trpm6 has been classified as Red List (Low Evidence).
Muscular dystrophy and myopathy_Paediatric v0.128 ACTN2 Sangavi Sivagnanasundram gene: ACTN2 was added
gene: ACTN2 was added to Muscular dystrophy_Paediatric. Sources: Other
Mode of inheritance for gene: ACTN2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ACTN2 were set to 30701273
Phenotypes for gene: ACTN2 were set to Congenital Myopathy 8 (MIM#618654; MONDO: 0032852)
Penetrance for gene: ACTN2 were set to unknown
Review for gene: ACTN2 was set to GREEN
Added comment: PMID: 30701273
2 unrelated individuals with congenital myopathy plus an in vivo zebrafish model showed a loss in protein function resulting in zebrafish embryo hatching defect and impaired motor function.
- Age of onset in both individuals was in the first decade of life
Sources: Other
Mendeliome v1.855 RRAGC Naomi Baker reviewed gene: RRAGC: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:37057673, 27234373, 33057194; Phenotypes: Dilated cardiomyopathy (MONDO:0005021), RRAGC-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cardiomyopathy_Paediatric v0.157 RRAGC Naomi Baker reviewed gene: RRAGC: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:37057673, 27234373, 33057194; Phenotypes: Dilated cardiomyopathy (MONDO:0005021), RRAGC-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5226 INTS11 Zornitza Stark Phenotypes for gene: INTS11 were changed from Global developmental delay; launguage delay; intellectual disability; impaired motor development; brain atrophy to intellectual disability, MONDO:0001071
Mendeliome v1.855 MCAT Zornitza Stark reviewed gene: MCAT: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Leber hereditary optic neuropathy, autosomal recessive, MONDO:0030309; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.855 MCAT Zornitza Stark Phenotypes for gene: MCAT were changed from progressive autosomal recessive optic neuropathy to Leber hereditary optic neuropathy, autosomal recessive, MONDO:0030309
Mendeliome v1.854 DNAH7 Zornitza Stark Phenotypes for gene: DNAH7 were changed from non-syndromic male infertility due to sperm motility disorder (MONDO#0017173), DNAH7-related to Primary ciliary dyskinesia, MONDO:0016575, DNAH7-related
Mendeliome v1.853 DNAH7 Zornitza Stark reviewed gene: DNAH7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ciliary dyskinesia, MONDO:0016575, DNAH7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ciliary Dyskinesia v1.30 DNAH7 Zornitza Stark Phenotypes for gene: DNAH7 were changed from non-syndromic male infertility due to sperm motility disorder (MONDO#0017173), DNAH7-related to Primary ciliary dyskinesia, MONDO:0016575, DNAH7-related
Mendeliome v1.853 RARA Zornitza Stark commented on gene: RARA: PMID: 37086723 identified a recurrent, heterozygous de novo missense variant in the RARA gene - c.865G>A; (p.Gly289Arg) - in two unrelated individuals. The variant is absent from gnomAD, highly conserved, major grantham score (125) and is located in the hormone receptor domain (DECIPHER).

Both individuals had severe craniosynostosis (sagittal or bicoronal).

Other shared phenotypic features included:
- Limb anomalies (rocker-bottom feet, bowing of the legs, and short upper/lower limbs)
- Additional craniofacial manifestations(microtia, conductive hearing loss, ankyloglossia, esotropia, hypoplastic
nasal bones, and oligodontia)
- Other additional anomalies included renal dysplasia with cysts, tracheomalacia, pulmonary arterial hypertension, developmental delays, hypotonia, cryptorchidism, seizures and adrenal insufficiency.

The authors postulate a gain of function mechanism. No functional studies provided. The gene encodes the retinoic acid receptor. Overlapping phenotypic features in these 2 affected individuals with retinoic acid embryopathy noted by the authors.
Ciliary Dyskinesia v1.29 DNAH7 Zornitza Stark reviewed gene: DNAH7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ciliary dyskinesia, MONDO:0016575, DNAH7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic Atrophy v1.17 NDUFA12 Suliman Khan changed review comment from: 9 individual form 6 unrelated families presented with movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. Basal ganglia abnormalities were observed in 6 patients, two patients had optic atrophy, and one was unremarkable. All patients carried homozygous truncating variants in the NDUFA12 gene PMID: 35141356.
Sources: Literature; to: 9 individuals form 6 unrelated families presented with movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. Basal ganglia abnormalities were observed in 6 patients, two patients had optic atrophy, and one was unremarkable. All patients carried homozygous truncating variants in the NDUFA12 gene PMID: 35141356.
Sources: Literature
Mendeliome v1.853 RARA Zornitza Stark Phenotypes for gene: RARA were changed from Syndromic chorioretinal coloboma to Craniosynostosis - MONDO:0015469; Syndromic chorioretinal coloboma
Mendeliome v1.852 RARA Zornitza Stark Publications for gene: RARA were set to 31343737
Mendeliome v1.851 RARA Zornitza Stark Classified gene: RARA as Amber List (moderate evidence)
Mendeliome v1.851 RARA Zornitza Stark Gene: rara has been classified as Amber List (Moderate Evidence).
Mendeliome v1.850 RARA Zornitza Stark edited their review of gene: RARA: Added comment: PMID: 37086723 identified a recurrent, heterozygous de novo missense variant in the RARA gene - c.865G>A; (p.Gly289Arg) - in two unrelated individuals. The variant is absent from gnomAD, highly conserved, major grantham score (125) and is located in the hormone receptor domain (DECIPHER).

Both individuals had severe craniosynostosis (sagittal or bicoronal).

Other shared phenotypic features included:
- Limb anomalies (rocker-bottom feet, bowing of the legs, and short upper/lower limbs)
- Additional craniofacial manifestations(microtia, conductive hearing loss, ankyloglossia, esotropia, hypoplastic
nasal bones, and oligodontia)
- Other additional anomalies included renal dysplasia with cysts, tracheomalacia, pulmonary arterial hypertension, developmental delays, hypotonia, cryptorchidism, seizures and adrenal insufficiency.

The authors postulate a gain of function mechanism. No functional studies provided. The gene encodes the retinoic acid receptor. Overlapping phenotypic features in these 2 affected individuals with retinoic acid embryopathy noted by the authors.; Changed rating: AMBER; Changed publications: 31343737, 37086723; Changed phenotypes: Craniosynostosis - MONDO:0015469, Syndromic chorioretinal coloboma; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Optic Atrophy v1.17 NDUFA12 Zornitza Stark Marked gene: NDUFA12 as ready
Optic Atrophy v1.17 NDUFA12 Zornitza Stark Gene: ndufa12 has been classified as Green List (High Evidence).
Optic Atrophy v1.17 NDUFA12 Zornitza Stark Classified gene: NDUFA12 as Green List (high evidence)
Optic Atrophy v1.17 NDUFA12 Zornitza Stark Gene: ndufa12 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.78 PMEPA1 Zornitza Stark Marked gene: PMEPA1 as ready
Aortopathy_Connective Tissue Disorders v1.78 PMEPA1 Zornitza Stark Gene: pmepa1 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.78 PMEPA1 Zornitza Stark Classified gene: PMEPA1 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v1.78 PMEPA1 Zornitza Stark Gene: pmepa1 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.77 PMEPA1 Zornitza Stark gene: PMEPA1 was added
gene: PMEPA1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: PMEPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PMEPA1 were set to 36928819
Phenotypes for gene: PMEPA1 were set to Hereditary disorder of connective tissue, MONDO:0023603, PMEPA1-related
Mode of pathogenicity for gene: PMEPA1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: PMEPA1 was set to AMBER
Added comment: PMID: 36928819; Greene, D. et al. (2023) Nat Med. 29(3):679-688.
A paper by Genomics England Research Consortium. Genetic association analysis of 77,539 genomes .

Eight families with truncating variants affecting the same stretch of cytosines in this gene.

In the 100KGP discovery cohort, in three families with Familial thoracic aortic aneurysm disease (FTAAD) of European ancestry, the variant found was an insertion of a cytosine within a seven-cytosine stretch in the last exon, predicted to cause p.(S209Qfs*3). This variant was also identified independently in eight affected members of three pedigrees of Japanese ancestry in a separate Japanese patient group.
(Note: the variant is present in gnomAD v2.1.1 in 22 heterozygotes as a filtered out variant.).

Also, this study found a deletion of one of those cytosines causing p.(S209Afs*61), in one individual or family.
Also, there was one family in Belgium in which the affected members carried a 5-bp deletion in the same stretch of polycytosines inducing a frameshift p.(P207Qfs*3).

Phenotypic analysis of the individuals suggest that the phenotype of these FTAAD individuals and families is more like Loeys-Dietz syndrome.
Sources: Literature
Mendeliome v1.850 PMEPA1 Zornitza Stark Phenotypes for gene: PMEPA1 were changed from Familial thoracic aortic aneurysm disease (FTAAD); Loeys-Dietz syndrome to Hereditary disorder of connective tissue, MONDO:0023603, PMEPA1-related
Mendeliome v1.849 PMEPA1 Zornitza Stark reviewed gene: PMEPA1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Hereditary disorder of connective tissue, MONDO:0023603, PMEPA1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bone Marrow Failure v1.34 NAF1 Bryony Thompson Marked gene: NAF1 as ready
Bone Marrow Failure v1.34 NAF1 Bryony Thompson Gene: naf1 has been classified as Green List (High Evidence).
Bone Marrow Failure v1.34 NAF1 Bryony Thompson Classified gene: NAF1 as Green List (high evidence)
Bone Marrow Failure v1.34 NAF1 Bryony Thompson Added comment: Comment on list classification: Included because of the increased risk for progressive bone marrow failure associated with telomere biology disorders
Bone Marrow Failure v1.34 NAF1 Bryony Thompson Gene: naf1 has been classified as Green List (High Evidence).
Pulmonary Fibrosis_Interstitial Lung Disease v0.50 NAF1 Bryony Thompson Marked gene: NAF1 as ready
Pulmonary Fibrosis_Interstitial Lung Disease v0.50 NAF1 Bryony Thompson Gene: naf1 has been classified as Green List (High Evidence).
Pulmonary Fibrosis_Interstitial Lung Disease v0.50 NAF1 Bryony Thompson Classified gene: NAF1 as Green List (high evidence)
Pulmonary Fibrosis_Interstitial Lung Disease v0.50 NAF1 Bryony Thompson Gene: naf1 has been classified as Green List (High Evidence).
Pulmonary Fibrosis_Interstitial Lung Disease v0.49 NAF1 Bryony Thompson gene: NAF1 was added
gene: NAF1 was added to Pulmonary Fibrosis_Interstitial Lung Disease. Sources: Literature
Mode of inheritance for gene: NAF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NAF1 were set to 27510903
Phenotypes for gene: NAF1 were set to Pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148
Review for gene: NAF1 was set to GREEN
Added comment: At least 3 probands/families with telomere-related pulmonary fibrosis and a supporting mouse model
PMID: 27510903 - 5 individuals from 2 unrelated families with pulmonary fibrosis-emphysema and extrapulmonary manifestations including myelodysplastic syndrome and liver disease, with LoF variants. Truncated NAF1 was detected in cells derived from patients, and, in cells in which a frameshift mutation was introduced by genome editing telomerase RNA levels were reduced. Shortened telomere length also segregated with the variants. A Naf1+/- mouse model had reduced telomerase RNA levels

ClinVar - 1 nonsense and 2 splice site variants (ID: 2443185, 1338525, 2443184) called LP by the Genetic Services Laboratory, University of Chicago but no clinical details were provided
- SCV002547372.1 - Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center - at least one individual with pulmonary fibrosis and leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted
Sources: Literature
Bone Marrow Failure v1.33 NAF1 Bryony Thompson gene: NAF1 was added
gene: NAF1 was added to Bone Marrow Failure. Sources: Literature
Mode of inheritance for gene: NAF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NAF1 were set to 27510903
Phenotypes for gene: NAF1 were set to Pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148
Review for gene: NAF1 was set to GREEN
Added comment: At least 3 probands/families with telomere-related pulmonary fibrosis and a supporting mouse model
PMID: 27510903 - 5 individuals from 2 unrelated families with pulmonary fibrosis-emphysema and extrapulmonary manifestations including myelodysplastic syndrome and liver disease, with LoF variants. Truncated NAF1 was detected in cells derived from patients, and, in cells in which a frameshift mutation was introduced by genome editing telomerase RNA levels were reduced. Shortened telomere length also segregated with the variants. A Naf1+/- mouse model had reduced telomerase RNA levels

ClinVar - 1 nonsense and 2 splice site variants (ID: 2443185, 1338525, 2443184) called LP by the Genetic Services Laboratory, University of Chicago but no clinical details were provided
- SCV002547372.1 - Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center - at least one individual with pulmonary fibrosis and leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5225 LHX2 Zornitza Stark Marked gene: LHX2 as ready
Intellectual disability syndromic and non-syndromic v0.5225 LHX2 Zornitza Stark Gene: lhx2 has been classified as Green List (High Evidence).
Mendeliome v1.849 NAF1 Bryony Thompson Marked gene: NAF1 as ready
Mendeliome v1.849 NAF1 Bryony Thompson Gene: naf1 has been classified as Green List (High Evidence).
Mendeliome v1.849 NAF1 Bryony Thompson Classified gene: NAF1 as Green List (high evidence)
Mendeliome v1.849 NAF1 Bryony Thompson Gene: naf1 has been classified as Green List (High Evidence).
Mendeliome v1.848 NAF1 Bryony Thompson gene: NAF1 was added
gene: NAF1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: NAF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NAF1 were set to 27510903
Phenotypes for gene: NAF1 were set to Pulmonary fibrosis and/or bone marrow failure, telomere-related MONDO:0000148
Review for gene: NAF1 was set to GREEN
Added comment: At least 3 probands/families with telomere-related pulmonary fibrosis and a supporting mouse model
PMID: 27510903 - 5 individuals from 2 unrelated families with pulmonary fibrosis-emphysema and extrapulmonary manifestations including myelodysplastic syndrome and liver disease, with LoF variants. Truncated NAF1 was detected in cells derived from patients, and, in cells in which a frameshift mutation was introduced by genome editing telomerase RNA levels were reduced. Shortened telomere length also segregated with the variants. A Naf1+/- mouse model had reduced telomerase RNA levels

ClinVar - 1 nonsense and 2 splice site variants (ID: 2443185, 1338525, 2443184) called LP by the Genetic Services Laboratory, University of Chicago but no clinical details were provided
- SCV002547372.1 - Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center - at least one individual with pulmonary fibrosis and leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted
Sources: Expert list
Mendeliome v1.847 PMEPA1 Hazel Phillimore changed review comment from: PMID: 36928819; Greene, D. et al. (2023) Nat Med. 29(3):679-688.
A paper by Genomics England Research Consortium. Genetic association analysis of 77,539 genomes .

Eight families with truncating variants affecting the same stretch of cytosines in this gene.

In the 100KGP discovery cohort, in three families with Familial thoracic aortic aneurysm disease (FTAAD) of European ancestry, the variant found was an insertion of a cytosine within a seven-cytosine stretch in the last exon, predicted to cause p.(S209Qfs*3). This variant was also identified independently in eight affected members of three pedigrees of Japanese ancestry in a separate Japanese patient group.
Also, this study found a deletion of one of those cytosines causing p.(S209Afs*61), in one individual or family.
Also, there was one family in Belgium in which the affected members carried a 5-bp deletion in the same stretch of polycytosines inducing a frameshift p.(P207Qfs*3).

Phenotypic analysis of the individuals suggest that the phenotype of these FTAAD individuals and families is more like Loeys-Dietz syndrome.
Sources: Literature; to: PMID: 36928819; Greene, D. et al. (2023) Nat Med. 29(3):679-688.
A paper by Genomics England Research Consortium. Genetic association analysis of 77,539 genomes .

Eight families with truncating variants affecting the same stretch of cytosines in this gene.

In the 100KGP discovery cohort, in three families with Familial thoracic aortic aneurysm disease (FTAAD) of European ancestry, the variant found was an insertion of a cytosine within a seven-cytosine stretch in the last exon, predicted to cause p.(S209Qfs*3). This variant was also identified independently in eight affected members of three pedigrees of Japanese ancestry in a separate Japanese patient group.
(Note: the variant is present in gnomAD v2.1.1 in 22 heterozygotes as a filtered out variant.).

Also, this study found a deletion of one of those cytosines causing p.(S209Afs*61), in one individual or family.
Also, there was one family in Belgium in which the affected members carried a 5-bp deletion in the same stretch of polycytosines inducing a frameshift p.(P207Qfs*3).

Phenotypic analysis of the individuals suggest that the phenotype of these FTAAD individuals and families is more like Loeys-Dietz syndrome.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5225 LHX2 Zornitza Stark Publications for gene: LHX2 were set to PMID:
Intellectual disability syndromic and non-syndromic v0.5224 LHX2 Zornitza Stark Phenotypes for gene: LHX2 were changed from to Neurodevelopmental disorder (MONDO: 0700092)
Intellectual disability syndromic and non-syndromic v0.5223 LHX2 Zornitza Stark Classified gene: LHX2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5223 LHX2 Zornitza Stark Gene: lhx2 has been classified as Green List (High Evidence).
Mendeliome v1.847 PMEPA1 Seb Lunke Marked gene: PMEPA1 as ready
Mendeliome v1.847 PMEPA1 Seb Lunke Gene: pmepa1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.847 PMEPA1 Seb Lunke Classified gene: PMEPA1 as Amber List (moderate evidence)
Mendeliome v1.847 PMEPA1 Seb Lunke Gene: pmepa1 has been classified as Amber List (Moderate Evidence).
Microcephaly v1.204 LHX2 Zornitza Stark Marked gene: LHX2 as ready
Microcephaly v1.204 LHX2 Zornitza Stark Gene: lhx2 has been classified as Green List (High Evidence).
Microcephaly v1.204 LHX2 Zornitza Stark Classified gene: LHX2 as Green List (high evidence)
Microcephaly v1.204 LHX2 Zornitza Stark Gene: lhx2 has been classified as Green List (High Evidence).
Mendeliome v1.846 LHX2 Zornitza Stark Marked gene: LHX2 as ready
Mendeliome v1.846 LHX2 Zornitza Stark Gene: lhx2 has been classified as Green List (High Evidence).
Mendeliome v1.846 LHX2 Zornitza Stark Classified gene: LHX2 as Green List (high evidence)
Mendeliome v1.846 LHX2 Zornitza Stark Gene: lhx2 has been classified as Green List (High Evidence).
Microcephaly v1.203 LHX2 Manny Jacobs gene: LHX2 was added
gene: LHX2 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: LHX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LHX2 were set to PMID: 37057675
Phenotypes for gene: LHX2 were set to Neurodevelopmental disorder (MONDO: 0700092)
Review for gene: LHX2 was set to GREEN
Added comment: PMID: 37057675

Case series of 19 individuals across 18 families.
1 whole gene deletion, 7 missense, 10 predicted LoF variants.
Proposed loss-of-function mechanism.
Variable phenotype, with variable intellectual disability and behavioural (ASD/ADHD) features common.
Microcephaly in 7 individuals.
1 variant inherited from a mildly affected parent, all other variants with parental genotype available shown to be de novo.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5222 CBX1 Zornitza Stark Marked gene: CBX1 as ready
Intellectual disability syndromic and non-syndromic v0.5222 CBX1 Zornitza Stark Gene: cbx1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5222 CNOT9 Zornitza Stark Marked gene: CNOT9 as ready
Intellectual disability syndromic and non-syndromic v0.5222 CNOT9 Zornitza Stark Gene: cnot9 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5222 CNOT9 Zornitza Stark Mode of inheritance for gene: CNOT9 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5221 CNOT9 Zornitza Stark Classified gene: CNOT9 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5221 CNOT9 Zornitza Stark Gene: cnot9 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5220 LHX2 Manny Jacobs reviewed gene: LHX2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37057675; Phenotypes: Neurodevelopmental disorder (MONDO: 0700092); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1847 CNOT9 Zornitza Stark Marked gene: CNOT9 as ready
Genetic Epilepsy v0.1847 CNOT9 Zornitza Stark Gene: cnot9 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1847 CNOT9 Zornitza Stark Mode of inheritance for gene: CNOT9 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1846 CNOT9 Zornitza Stark Classified gene: CNOT9 as Green List (high evidence)
Genetic Epilepsy v0.1846 CNOT9 Zornitza Stark Gene: cnot9 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1846 CNOT9 Zornitza Stark Classified gene: CNOT9 as Green List (high evidence)
Genetic Epilepsy v0.1846 CNOT9 Zornitza Stark Gene: cnot9 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5220 CNOT9 Karina Sandoval edited their review of gene: CNOT9: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Optic Atrophy v1.16 NDUFA12 Suliman Khan changed review comment from: 9 individual form 6 unrelated families presented with movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. Basal ganglia abnormalities were observed in 6 patients, two patients have optic atrophy, and one was unremarkable. All patients carried homozygous truncating variants in the NDUFA12 gene PMID: 35141356.
Sources: Literature; to: 9 individual form 6 unrelated families presented with movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. Basal ganglia abnormalities were observed in 6 patients, two patients had optic atrophy, and one was unremarkable. All patients carried homozygous truncating variants in the NDUFA12 gene PMID: 35141356.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5220 CBX1 Seb Lunke Classified gene: CBX1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5220 CBX1 Seb Lunke Gene: cbx1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5219 LHX2 Manny Jacobs gene: LHX2 was added
gene: LHX2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: LHX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LHX2 were set to PMID:
Optic Atrophy v1.16 NDUFA12 Suliman Khan gene: NDUFA12 was added
gene: NDUFA12 was added to Optic Atrophy. Sources: Literature
Mode of inheritance for gene: NDUFA12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFA12 were set to PMID: 35141356
Phenotypes for gene: NDUFA12 were set to isolated optic atrophy; MONDO:0003608
Review for gene: NDUFA12 was set to GREEN
Added comment: 9 individual form 6 unrelated families presented with movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. Basal ganglia abnormalities were observed in 6 patients, two patients have optic atrophy, and one was unremarkable. All patients carried homozygous truncating variants in the NDUFA12 gene PMID: 35141356.
Sources: Literature
Mendeliome v1.845 CNOT9 Karina Sandoval edited their review of gene: CNOT9: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.845 CNOT9 Zornitza Stark Marked gene: CNOT9 as ready
Mendeliome v1.845 CNOT9 Zornitza Stark Gene: cnot9 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1845 CNOT9 Karina Sandoval edited their review of gene: CNOT9: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.845 CBX1 Seb Lunke Marked gene: CBX1 as ready
Mendeliome v1.845 CBX1 Seb Lunke Gene: cbx1 has been classified as Green List (High Evidence).
Craniosynostosis v1.56 RARA Krithika Murali reviewed gene: RARA: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 37086723; Phenotypes: Craniosynostosis - MONDO:0015469; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.845 CNOT9 Zornitza Stark Mode of inheritance for gene: CNOT9 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.844 CBX1 Seb Lunke Classified gene: CBX1 as Green List (high evidence)
Mendeliome v1.844 CBX1 Seb Lunke Gene: cbx1 has been classified as Green List (High Evidence).
Mendeliome v1.843 CNOT9 Zornitza Stark Classified gene: CNOT9 as Green List (high evidence)
Mendeliome v1.843 CNOT9 Zornitza Stark Gene: cnot9 has been classified as Green List (High Evidence).
Craniosynostosis v1.56 RARA Krithika Murali Deleted their review
Mendeliome v1.842 LHX2 Manny Jacobs gene: LHX2 was added
gene: LHX2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LHX2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LHX2 were set to PMID: 37057675
Phenotypes for gene: LHX2 were set to Neurodevelopmental disorder (MONDO: 0700092)
Review for gene: LHX2 was set to GREEN
Added comment: PMID: 37057675

Case series of 19 individuals across 18 families.
1 whole gene deletion, 7 missense, 10 predicted LoF variants.
Proposed loss-of-function mechanism.
Variable phenotype, with variable intellectual disability and behavioural (ASD/ADHD) features.
Microcephaly in 7 individuals.
1 variant inherited from a mildly affected parent, all other variants with parental genotype available shown to be de novo.
Sources: Literature
Craniosynostosis v1.56 RARA Krithika Murali reviewed gene: RARA: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.842 DNAH7 Seb Lunke Marked gene: DNAH7 as ready
Mendeliome v1.842 DNAH7 Seb Lunke Gene: dnah7 has been classified as Green List (High Evidence).
Mendeliome v1.842 DNAH7 Seb Lunke Classified gene: DNAH7 as Green List (high evidence)
Mendeliome v1.842 DNAH7 Seb Lunke Gene: dnah7 has been classified as Green List (High Evidence).
Deafness_IsolatedAndComplex v1.157 GPR156 Zornitza Stark Marked gene: GPR156 as ready
Deafness_IsolatedAndComplex v1.157 GPR156 Zornitza Stark Gene: gpr156 has been classified as Green List (High Evidence).
Mendeliome v1.842 MRPL39 Zornitza Stark Phenotypes for gene: MRPL39 were changed from Leigh syndrome MONDO:0009723 to Mitochondrial disease MONDO:0044970
Deafness_IsolatedAndComplex v1.157 GPR156 Zornitza Stark Classified gene: GPR156 as Green List (high evidence)
Deafness_IsolatedAndComplex v1.157 GPR156 Zornitza Stark Gene: gpr156 has been classified as Green List (High Evidence).
Mendeliome v1.841 PMEPA1 Hazel Phillimore gene: PMEPA1 was added
gene: PMEPA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PMEPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PMEPA1 were set to PMID: 36928819
Phenotypes for gene: PMEPA1 were set to Familial thoracic aortic aneurysm disease (FTAAD); Loeys-Dietz syndrome
Mode of pathogenicity for gene: PMEPA1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: PMEPA1 was set to AMBER
Added comment: PMID: 36928819; Greene, D. et al. (2023) Nat Med. 29(3):679-688.
A paper by Genomics England Research Consortium. Genetic association analysis of 77,539 genomes .

Eight families with truncating variants affecting the same stretch of cytosines in this gene.

In the 100KGP discovery cohort, in three families with Familial thoracic aortic aneurysm disease (FTAAD) of European ancestry, the variant found was an insertion of a cytosine within a seven-cytosine stretch in the last exon, predicted to cause p.(S209Qfs*3). This variant was also identified independently in eight affected members of three pedigrees of Japanese ancestry in a separate Japanese patient group.
Also, this study found a deletion of one of those cytosines causing p.(S209Afs*61), in one individual or family.
Also, there was one family in Belgium in which the affected members carried a 5-bp deletion in the same stretch of polycytosines inducing a frameshift p.(P207Qfs*3).

Phenotypic analysis of the individuals suggest that the phenotype of these FTAAD individuals and families is more like Loeys-Dietz syndrome.
Sources: Literature
Ciliary Dyskinesia v1.29 DNAH7 Seb Lunke Marked gene: DNAH7 as ready
Ciliary Dyskinesia v1.29 DNAH7 Seb Lunke Gene: dnah7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5219 INTS11 Seb Lunke Marked gene: INTS11 as ready
Intellectual disability syndromic and non-syndromic v0.5219 INTS11 Seb Lunke Gene: ints11 has been classified as Green List (High Evidence).
Ciliary Dyskinesia v1.29 DNAH7 Seb Lunke Classified gene: DNAH7 as Green List (high evidence)
Ciliary Dyskinesia v1.29 DNAH7 Seb Lunke Gene: dnah7 has been classified as Green List (High Evidence).
Mendeliome v1.841 GPR156 Zornitza Stark Marked gene: GPR156 as ready
Mendeliome v1.841 GPR156 Zornitza Stark Gene: gpr156 has been classified as Green List (High Evidence).
Mendeliome v1.841 GPR156 Zornitza Stark Classified gene: GPR156 as Green List (high evidence)
Mendeliome v1.841 GPR156 Zornitza Stark Gene: gpr156 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1845 CNOT9 Karina Sandoval gene: CNOT9 was added
gene: CNOT9 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: CNOT9 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CNOT9 were set to PMID: 37092538
Phenotypes for gene: CNOT9 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: CNOT9 was set to GREEN
Added comment: 7 individuals with de novo variants. In silico predictions of functional relevance. All affected persons have DD/ID, with five of them showing seizures. Other symptoms include.

Symptoms: Neuro dev disorder. ID, Epilepsy. All affected persons have DD/ID, with five of them showing seizures. Other symptoms include muscular hypotonia, facial dysmorphism, and behavioral abnormalities.
Sources: Literature
Mendeliome v1.840 MRPL39 Zornitza Stark Classified gene: MRPL39 as Green List (high evidence)
Mendeliome v1.840 MRPL39 Zornitza Stark Gene: mrpl39 has been classified as Green List (High Evidence).
Craniosynostosis v1.56 RARA Zornitza Stark Marked gene: RARA as ready
Craniosynostosis v1.56 RARA Zornitza Stark Gene: rara has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5219 CNOT9 Karina Sandoval gene: CNOT9 was added
gene: CNOT9 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CNOT9 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CNOT9 were set to PMID: 37092538
Phenotypes for gene: CNOT9 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: CNOT9 was set to GREEN
Added comment: 7 individuals with de novo variants. In silico predictions of functional relevance. All affected persons have DD/ID, with five of them showing seizures. Other symptoms include.

Symptoms: Neuro dev disorder. ID, Epilepsy. All affected persons have DD/ID, with five of them showing seizures. Other symptoms include muscular hypotonia, facial dysmorphism, and behavioral abnormalities.
Sources: Literature
Mendeliome v1.839 CBX1 Daniel Flanagan gene: CBX1 was added
gene: CBX1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CBX1 were set to PMID: 37087635
Phenotypes for gene: CBX1 were set to Neurodevelopmental disorder (MONDO#0700092), CBX1-related
Review for gene: CBX1 was set to GREEN
Added comment: Three different de novo missense variants identified in three unrelated individuals with developmental delay, hypotonia, autistic features, and variable dysmorphic features such as broad forehead and head circumference above average. Mutant mice displayed increased latency-to-peak response, suggesting the possibility of synaptic delay or myelination deficits. Functional studies confirmed the reduction of mutant HP1β binding to heterochromatin.
Sources: Expert list
Craniosynostosis v1.56 RARA Zornitza Stark Classified gene: RARA as Amber List (moderate evidence)
Craniosynostosis v1.56 RARA Zornitza Stark Gene: rara has been classified as Amber List (Moderate Evidence).
Mendeliome v1.839 MCAT Seb Lunke Classified gene: MCAT as Amber List (moderate evidence)
Mendeliome v1.839 MCAT Seb Lunke Gene: mcat has been classified as Amber List (Moderate Evidence).
Optic Atrophy v1.16 MCAT Seb Lunke Phenotypes for gene: MCAT were changed from Leber hereditary optic neuropathy, autosomal recessive, MONDO:0030309 to Leber hereditary optic neuropathy, autosomal recessive, MONDO:0030309
Mitochondrial disease v0.866 MRPL39 Zornitza Stark Phenotypes for gene: MRPL39 were changed from Mitochondrial disease MONDO:0044970 to Mitochondrial disease MONDO:0044970
Mendeliome v1.838 SRSF1 Zornitza Stark Marked gene: SRSF1 as ready
Mendeliome v1.838 SRSF1 Zornitza Stark Gene: srsf1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5219 CBX1 Daniel Flanagan gene: CBX1 was added
gene: CBX1 was added to Intellectual disability syndromic and non-syndromic. Sources: Expert list
Mode of inheritance for gene: CBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CBX1 were set to PMID: 37087635
Phenotypes for gene: CBX1 were set to Neurodevelopmental disorder (MONDO#0700092), CBX1-related
Review for gene: CBX1 was set to GREEN
Added comment: Three different de novo missense variants identified in three unrelated individuals with developmental delay, hypotonia, autistic features, and variable dysmorphic features such as broad forehead and head circumference above average. Mutant mice displayed increased latency-to-peak response, suggesting the possibility of synaptic delay or myelination deficits. Functional studies confirmed the reduction of mutant HP1β binding to heterochromatin.
Sources: Expert list
Mendeliome v1.838 CNOT9 Karina Sandoval gene: CNOT9 was added
gene: CNOT9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CNOT9 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CNOT9 were set to PMID: 37092538
Phenotypes for gene: CNOT9 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: CNOT9 was set to GREEN
Added comment: 7 individuals with de novo variants. In silico predictions of functional relevance. All affected persons have DD/ID, with five of them showing seizures. Other symptoms include.

Symptoms: Neuro dev disorder. ID, Epilepsy. All affected persons have DD/ID, with five of them showing seizures. Other symptoms include muscular hypotonia, facial dysmorphism, and behavioral abnormalities.
Sources: Literature
Mitochondrial disease v0.866 MRPL39 Zornitza Stark Phenotypes for gene: MRPL39 were changed from Mitochondrial disease MONDO:0044970 to Mitochondrial disease MONDO:0044970
Mitochondrial disease v0.866 MRPL39 Zornitza Stark Marked gene: MRPL39 as ready
Mitochondrial disease v0.866 MRPL39 Zornitza Stark Gene: mrpl39 has been classified as Green List (High Evidence).
Optic Atrophy v1.15 MCAT Seb Lunke Phenotypes for gene: MCAT were changed from progressive autosomal recessive optic neuropathy to Leber hereditary optic neuropathy, autosomal recessive, MONDO:0030309
Mitochondrial disease v0.866 MRPL39 Zornitza Stark Phenotypes for gene: MRPL39 were changed from Leigh Syndrome MONDO:0009723 to Mitochondrial disease MONDO:0044970
Mendeliome v1.838 SRSF1 Zornitza Stark Classified gene: SRSF1 as Green List (high evidence)
Mendeliome v1.838 SRSF1 Zornitza Stark Gene: srsf1 has been classified as Green List (High Evidence).
Craniosynostosis v1.55 RARA Krithika Murali Deleted their review
Mitochondrial disease v0.865 MRPL39 Zornitza Stark Classified gene: MRPL39 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5219 INTS11 Seb Lunke Classified gene: INTS11 as Green List (high evidence)
Mitochondrial disease v0.865 MRPL39 Zornitza Stark Gene: mrpl39 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5219 INTS11 Seb Lunke Gene: ints11 has been classified as Green List (High Evidence).
Optic Atrophy v1.14 MCAT Seb Lunke Classified gene: MCAT as Amber List (moderate evidence)
Optic Atrophy v1.14 MCAT Seb Lunke Gene: mcat has been classified as Amber List (Moderate Evidence).
Genetic Epilepsy v0.1845 POLR1A Elena Savva Classified gene: POLR1A as Amber List (moderate evidence)
Genetic Epilepsy v0.1845 POLR1A Elena Savva Gene: polr1a has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5218 SRSF1 Zornitza Stark Classified gene: SRSF1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5218 SRSF1 Zornitza Stark Gene: srsf1 has been classified as Green List (High Evidence).
Mitochondrial disease v0.865 MRPL39 Zornitza Stark Classified gene: MRPL39 as Green List (high evidence)
Mitochondrial disease v0.865 MRPL39 Zornitza Stark Gene: mrpl39 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1845 POLR1A Elena Savva Classified gene: POLR1A as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5218 INTS11 Seb Lunke Classified gene: INTS11 as Green List (high evidence)
Genetic Epilepsy v0.1845 POLR1A Elena Savva Gene: polr1a has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5218 INTS11 Seb Lunke Gene: ints11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5218 SRSF1 Zornitza Stark Marked gene: SRSF1 as ready
Intellectual disability syndromic and non-syndromic v0.5218 SRSF1 Zornitza Stark Gene: srsf1 has been classified as Green List (High Evidence).
Optic Atrophy v1.13 MCAT Seb Lunke Publications for gene: MCAT were set to 31915829
Mitochondrial disease v0.865 MRPL39 Zornitza Stark Classified gene: MRPL39 as Green List (high evidence)
Mitochondrial disease v0.865 MRPL39 Zornitza Stark Gene: mrpl39 has been classified as Green List (High Evidence).
Mendeliome v1.837 DNAH7 Chern Lim gene: DNAH7 was added
gene: DNAH7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DNAH7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH7 were set to 34476482; 35543642
Phenotypes for gene: DNAH7 were set to non-syndromic male infertility due to sperm motility disorder (MONDO#0017173), DNAH7-related
Review for gene: DNAH7 was set to GREEN
gene: DNAH7 was marked as current diagnostic
Added comment: PMID: 34476482 (Wei et al 2021):
- Hom/chet missense DNAH7 variants in three unrelated infertile patients with idiopathic asthenozoospermia, presented with primary ciliary dyskinesia (PCD)-associated symptoms.
- Functional studies showed expression of DNAH7 in the spermatozoa from the DNAH7-defective patients was significantly decreased.

PMID: 35543642 (Gao et al 2022):
- One proband with idiopathic asthenozoospermia, presented a history of PCD-like symptoms. Hom frameshift variant predicted to cause NMD, both parents are heterozygous.
- Immunofluorescent staining showed DNAH7 signal significantly decreased or was even completely absent in the sperm from the investigated patient.
Sources: Literature
Genetic Epilepsy v0.1845 POLR1A Elena Savva Classified gene: POLR1A as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5218 SRSF1 Zornitza Stark Classified gene: SRSF1 as Green List (high evidence)
Genetic Epilepsy v0.1845 POLR1A Elena Savva Gene: polr1a has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5218 SRSF1 Zornitza Stark Gene: srsf1 has been classified as Green List (High Evidence).
Mitochondrial disease v0.864 MRPL39 Lilian Downie edited their review of gene: MRPL39: Changed phenotypes: Mitochondrial disease MONDO:0044970
Deafness_IsolatedAndComplex v1.156 GPR156 Anna Ritchie gene: GPR156 was added
gene: GPR156 was added to Deafness_IsolatedAndComplex. Sources: Literature
Mode of inheritance for gene: GPR156 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPR156 were set to PMID: 36928819
Phenotypes for gene: GPR156 were set to Sensorineural hearing loss, MONDO:60700002, GPR156-related
Review for gene: GPR156 was set to GREEN
Added comment: Eight affected individuals from three unrelated families all had congenital nonsyndromic bilateral sensorineural hearing loss. Homozygous and compound heterozygous loss of function variants were reported in these families.
Sources: Literature
Ciliary Dyskinesia v1.28 DNAH7 Chern Lim gene: DNAH7 was added
gene: DNAH7 was added to Ciliary Dyskinesia. Sources: Literature
Mode of inheritance for gene: DNAH7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH7 were set to 34476482; 35543642
Phenotypes for gene: DNAH7 were set to non-syndromic male infertility due to sperm motility disorder (MONDO#0017173), DNAH7-related
Review for gene: DNAH7 was set to GREEN
gene: DNAH7 was marked as current diagnostic
Added comment: PMID: 34476482 (Wei et al 2021):
- Hom/chet missense DNAH7 variants in three unrelated infertile patients with idiopathic asthenozoospermia, presented with primary ciliary dyskinesia (PCD)-associated symptoms.
- Functional studies showed expression of DNAH7 in the spermatozoa from the DNAH7-defective patients was significantly decreased.

PMID: 35543642 (Gao et al 2022):
- One proband with idiopathic asthenozoospermia, presented a history of PCD-like symptoms. Hom frameshift variant predicted to cause NMD, both parents are heterozygous.
- Immunofluorescent staining showed DNAH7 signal significantly decreased or was even completely absent in the sperm from the investigated patient.
Sources: Literature
Mendeliome v1.837 MRPL39 Lilian Downie edited their review of gene: MRPL39: Changed rating: GREEN; Changed phenotypes: Mitochondrial disease MONDO:0044970
Genetic Epilepsy v0.1845 POLR1A Elena Savva Classified gene: POLR1A as Amber List (moderate evidence)
Genetic Epilepsy v0.1845 POLR1A Elena Savva Gene: polr1a has been classified as Amber List (Moderate Evidence).
Mendeliome v1.837 INTS11 Seb Lunke Marked gene: INTS11 as ready
Mendeliome v1.837 INTS11 Seb Lunke Gene: ints11 has been classified as Green List (High Evidence).
Mendeliome v1.837 MRPL39 Lilian Downie changed review comment from: AR
3 unrelated individuals, confirmed variants in trans
Functional studies on patient fibroblasts
Multisystem disease, variable onset
2x infants with a clinical diagnosis of Leigh syndrome (congestive cardiac
failure, increased lactates, seizures, apnea, poor feeding, and global developmental delay, leading
to early death (< 1 year of age))
Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD
Sources: Literature; to: AR
3 unrelated individuals, confirmed variants in trans
Functional studies on patient fibroblasts
Multisystem disease, variable onset
2x infants with a clinical diagnosis of Leigh syndrome (congestive cardiac
failure, increased lactates, seizures, apnea, poor feeding, and global developmental delay, leading
to early death (< 1 year of age))
Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD
Sources: Literature
Genetic Epilepsy v0.1844 POLR1A Elena Savva Marked gene: POLR1A as ready
Genetic Epilepsy v0.1844 POLR1A Elena Savva Gene: polr1a has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5217 POLR1A Elena Savva Classified gene: POLR1A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5217 POLR1A Elena Savva Gene: polr1a has been classified as Green List (High Evidence).
Mendeliome v1.837 INTS11 Seb Lunke Phenotypes for gene: INTS11 were changed from to intellectual disability, MONDO:0001071
Mendeliome v1.836 INTS11 Melanie Marty changed review comment from: PMID: 37054711 - 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy.; to: PMID: 37054711 - 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy.

Functional studies in Drosophila showed that dIntS11 (fly ortholog of INTS11) is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages.
Mendeliome v1.836 SRSF1 Paul De Fazio gene: SRSF1 was added
gene: SRSF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SRSF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SRSF1 were set to 37071997
Phenotypes for gene: SRSF1 were set to Neurodevelopmental disorder, SRSF1-related MONDO:0700092
Review for gene: SRSF1 was set to GREEN
gene: SRSF1 was marked as current diagnostic
Added comment: 17 individuals from 16 families reported with mostly de novo variants. Variants were a mixture of missense, nonsense/frameshift (both NMD-predicted and not NMD-predicted) and microdeletions. In one family, only one parent was available for testing. In another family, 2 affected siblings had the variant but the variant was not identified in either parent suggesting germline mosaicism.

Functional testing of a subset of variants in Drosophila supported pathogenicity in most, but 2 missense variants showed no functional effect and were classified VUS. Episignature analysis (EpiSign) on patient DNA from blood showed a specific DNA methylation signature in patients with the variants classified pathogenic but not those classified VUS.

Phenotypes included mainly neurological abnormalities (mild to moderate ID/dev delay, motor delay, speech delay, and behavioural disorders) and facial dysmorphisms.

Other features included hypotonia (11/16), variable brain abnormalities on MRI (6/12), variable cardiac malformations (6/14). urogenital malformations e.g. hypospadias, cryptorchidism (6/13), scoliosis (5/17) and/or variable other skeletal abnormalities (10/17).
Sources: Literature
Mendeliome v1.836 INTS11 Seb Lunke Classified gene: INTS11 as Green List (high evidence)
Mendeliome v1.836 INTS11 Seb Lunke Gene: ints11 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.281 POLR1A Elena Savva Classified gene: POLR1A as Green List (high evidence)
Congenital Heart Defect v0.281 POLR1A Elena Savva Gene: polr1a has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1844 POLR1A Elena Savva gene: POLR1A was added
gene: POLR1A was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: POLR1A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POLR1A were set to PMID: 37075751
Phenotypes for gene: POLR1A were set to Acrofacial dysostosis, Cincinnati type MIM#616462
Review for gene: POLR1A was set to AMBER
Added comment: PMID: 37075751 - reports individuals with epilepsy but an infrequent occurrence, found in 1/4 of the cohort
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5216 INTS11 Melanie Marty gene: INTS11 was added
gene: INTS11 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: INTS11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTS11 were set to PMID: 37054711
Phenotypes for gene: INTS11 were set to Global developmental delay; launguage delay; intellectual disability; impaired motor development; brain atrophy
Review for gene: INTS11 was set to GREEN
Added comment: PMID: 37054711 - 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy.

Functional studies in Drosophila showed that dIntS11 (fly ortholog of INTS11) is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages.
Sources: Literature
Craniosynostosis v1.55 RARA Krithika Murali changed review comment from: PMID: 37086723 - a study of 526 probands with syndromic craniosynostosis and analysis of trio exome sequencing data.

The authors report 2 unrelated individuals with a similar phenotype and a recurrent de novo heterozygous missense RARA variant - c.865G>A; p.(Gly289Arg). Gain of function mechanism postulated. No functional studies. Gene encodes retinoic acid receptor with some phenotypic features overlapping with prenatal retionic acid teratogen exposure.

The variant is absent from gnomAD, major GS (125), highly conserved residue in the hormone receptor domain.

Both affected individuals had severe craniosynostosis (sagittal or bicoronal).

Other shared phenotypic features included:
- limb anomalies (rocker-bottom feet, bowing of the legs, and short uppe rand lower limbs)
- other craniofacial anomalies (microtia,conductive hearing loss, ankyloglossia, esotropia, hypo-plastic nasal bones, and oligodontia)
- renal dysplasia with cysts, tracheomalacia, pulmonary arterial hypertension, developmental delays, hypotonia, cryptorchidism, seizures, adrenal insufficiency
Sources: Literature; to: PMID: 37086723 - a study of 526 probands with syndromic craniosynostosis and analysis of trio exome sequencing data.

The authors report 2 unrelated individuals with a similar phenotype and a recurrent de novo heterozygous missense RARA variant - c.865G>A; p.(Gly289Arg). Gain of function mechanism postulated. No functional studies. Gene encodes retinoic acid receptor with some phenotypic features overlapping with prenatal retionic acid teratogen exposure.

The variant is absent from gnomAD, major GS (125), highly conserved residue in the hormone receptor domain.

Both affected individuals had severe craniosynostosis (sagittal or bicoronal).

Other shared phenotypic features included:
- limb anomalies (rocker-bottom feet, bowing of the legs, and short upper and lower limbs)
- other craniofacial anomalies (microtia,conductive hearing loss, ankyloglossia, esotropia, hypo-plastic nasal bones, and oligodontia)
- renal dysplasia with cysts, tracheomalacia, pulmonary arterial hypertension, developmental delays, hypotonia, cryptorchidism, seizures, adrenal insufficiency
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5216 SRSF1 Paul De Fazio edited their review of gene: SRSF1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Craniosynostosis v1.55 RARA Krithika Murali changed review comment from: PMID: 37086723 - a study of 526 probands with syndromic craniosynostosis and analysis of exome sequencing data.

The authors report 2 unrelated individuals with a similar phenotype and a recurrent de novo heterozygous missense RARA variant - c.865G>A; p.(Gly289Arg). Gain of function mechanism postulated. No functional studies. Gene encodes retinoic acid receptor with some phenotypic features overlapping with prenatal retionic acid teratogen exposure.

The variant is absent from gnomAD, major GS (125), highly conserved residue in the hormone receptor domain.

Both affected individuals had severe craniosynostosis (sagittal or bicoronal).

Other shared phenotypic features included:
- limb anomalies (rocker-bottom feet, bowing of the legs, and short uppe rand lower limbs)
- other craniofacial anomalies (microtia,conductive hearing loss, ankyloglossia, esotropia, hypo-plastic nasal bones, and oligodontia)
- renal dysplasia with cysts, tracheomalacia, pulmonary arterial hypertension, developmental delays, hypotonia, cryptorchidism, seizures, adrenal insufficiency
Sources: Literature; to: PMID: 37086723 - a study of 526 probands with syndromic craniosynostosis and analysis of trio exome sequencing data.

The authors report 2 unrelated individuals with a similar phenotype and a recurrent de novo heterozygous missense RARA variant - c.865G>A; p.(Gly289Arg). Gain of function mechanism postulated. No functional studies. Gene encodes retinoic acid receptor with some phenotypic features overlapping with prenatal retionic acid teratogen exposure.

The variant is absent from gnomAD, major GS (125), highly conserved residue in the hormone receptor domain.

Both affected individuals had severe craniosynostosis (sagittal or bicoronal).

Other shared phenotypic features included:
- limb anomalies (rocker-bottom feet, bowing of the legs, and short uppe rand lower limbs)
- other craniofacial anomalies (microtia,conductive hearing loss, ankyloglossia, esotropia, hypo-plastic nasal bones, and oligodontia)
- renal dysplasia with cysts, tracheomalacia, pulmonary arterial hypertension, developmental delays, hypotonia, cryptorchidism, seizures, adrenal insufficiency
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5216 POLR1A Elena Savva Marked gene: POLR1A as ready
Intellectual disability syndromic and non-syndromic v0.5216 POLR1A Elena Savva Gene: polr1a has been classified as Red List (Low Evidence).
Craniosynostosis v1.55 RARA Krithika Murali gene: RARA was added
gene: RARA was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: RARA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RARA were set to PMID: 37086723
Phenotypes for gene: RARA were set to Craniosynostosis - MONDO:0015469
Review for gene: RARA was set to AMBER
Added comment: PMID: 37086723 - a study of 526 probands with syndromic craniosynostosis and analysis of exome sequencing data.

The authors report 2 unrelated individuals with a similar phenotype and a recurrent de novo heterozygous missense RARA variant - c.865G>A; p.(Gly289Arg). Gain of function mechanism postulated. No functional studies. Gene encodes retinoic acid receptor with some phenotypic features overlapping with prenatal retionic acid teratogen exposure.

The variant is absent from gnomAD, major GS (125), highly conserved residue in the hormone receptor domain.

Both affected individuals had severe craniosynostosis (sagittal or bicoronal).

Other shared phenotypic features included:
- limb anomalies (rocker-bottom feet, bowing of the legs, and short uppe rand lower limbs)
- other craniofacial anomalies (microtia,conductive hearing loss, ankyloglossia, esotropia, hypo-plastic nasal bones, and oligodontia)
- renal dysplasia with cysts, tracheomalacia, pulmonary arterial hypertension, developmental delays, hypotonia, cryptorchidism, seizures, adrenal insufficiency
Sources: Literature
Mitochondrial disease v0.864 MRPL39 Lilian Downie gene: MRPL39 was added
gene: MRPL39 was added to Mitochondrial disease. Sources: Literature
Mode of inheritance for gene: MRPL39 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL39 were set to PMID: 37133451
Phenotypes for gene: MRPL39 were set to Leigh Syndrome MONDO:0009723
Review for gene: MRPL39 was set to GREEN
Added comment: 3 unrelated individuals, confirmed variants in trans
Functional studies on patient fibroblasts
Multisystem disease, variable onset
2x infants with a clinical diagnosis of Leigh syndrome (congestive cardiac
failure, increased lactates, seizures, apnea, poor feeding, and global developmental delay, leading
to early death (< 1 year of age))
Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5216 SRSF1 Paul De Fazio gene: SRSF1 was added
gene: SRSF1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SRSF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRSF1 were set to 37071997
Phenotypes for gene: SRSF1 were set to Neurodevelopmental disorder, SRSF1-related MONDO:0700092
Review for gene: SRSF1 was set to GREEN
gene: SRSF1 was marked as current diagnostic
Added comment: 17 individuals from 16 families reported with mostly de novo variants. Variants were a mixture of missense, nonsense/frameshift (both NMD-predicted and not NMD-predicted) and microdeletions. In one family, only one parent was available for testing. In another family, 2 affected siblings had the variant but the variant was not identified in either parent suggesting germline mosaicism.

Functional testing of a subset of variants in Drosophila supported pathogenicity in most, but 2 missense variants showed no functional effect and were classified VUS. Episignature analysis (EpiSign) on patient DNA from blood showed a specific DNA methylation signature in patients with the variants classified pathogenic but not those classified VUS.

Phenotypes included mainly neurological abnormalities (mild to moderate ID/dev delay, motor delay, speech delay, and behavioural disorders) and facial dysmorphisms.

Other features included hypotonia (11/16), variable brain abnormalities on MRI (6/12), variable cardiac malformations (6/14). urogenital malformations e.g. hypospadias, cryptorchidism (6/13), scoliosis (5/17) and/or variable other skeletal abnormalities (10/17).
Sources: Literature
Congenital Heart Defect v0.280 POLR1A Elena Savva Marked gene: POLR1A as ready
Congenital Heart Defect v0.280 POLR1A Elena Savva Gene: polr1a has been classified as Red List (Low Evidence).
Mendeliome v1.835 SLC30A9 Zornitza Stark Marked gene: SLC30A9 as ready
Mendeliome v1.835 SLC30A9 Zornitza Stark Gene: slc30a9 has been classified as Green List (High Evidence).
Photosensitivity Syndromes v1.5 DNA2 Seb Lunke Marked gene: DNA2 as ready
Photosensitivity Syndromes v1.5 DNA2 Seb Lunke Gene: dna2 has been classified as Amber List (Moderate Evidence).
Photosensitivity Syndromes v1.5 DNA2 Seb Lunke Classified gene: DNA2 as Amber List (moderate evidence)
Photosensitivity Syndromes v1.5 DNA2 Seb Lunke Gene: dna2 has been classified as Amber List (Moderate Evidence).
Cataract v0.354 DNA2 Seb Lunke Classified gene: DNA2 as Amber List (moderate evidence)
Cataract v0.354 DNA2 Seb Lunke Gene: dna2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.835 SLC30A9 Zornitza Stark Classified gene: SLC30A9 as Green List (high evidence)
Mendeliome v1.835 SLC30A9 Zornitza Stark Gene: slc30a9 has been classified as Green List (High Evidence).
Cataract v0.353 DNA2 Seb Lunke Marked gene: DNA2 as ready
Cataract v0.353 DNA2 Seb Lunke Gene: dna2 has been classified as Red List (Low Evidence).
Photosensitivity Syndromes v1.4 DNA2 Seb Lunke gene: DNA2 was added
gene: DNA2 was added to Photosensitivity Syndromes. Sources: Literature
deep intronic, founder tags were added to gene: DNA2.
Mode of inheritance for gene: DNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNA2 were set to 37133451
Phenotypes for gene: DNA2 were set to Rothmund-Thomson syndrome, MONDO:0010002, DNA2 associated
Review for gene: DNA2 was set to AMBER
Added comment: A phenotypic expansion has been proposed based on a cohort of six Brazilian probands that in addition to classic RTS also presented with poikiloderma and congenital cataracts. All shared the same deep intronic splice variant, c.588–2214 A>G, in trans with other LoF variants. The deep intronic variant has been shown to result in the inclusion of a cryptic exon in the mature RNA, resulting in a frame shift and premature termination codon. The authors speculate that the shared intronic variant, which they attribute to a founder effect, has residual normal splicing responsible for the phenotypic variation.
Sources: Literature
Dystonia and Chorea v0.223 SLC30A9 Zornitza Stark Marked gene: SLC30A9 as ready
Dystonia and Chorea v0.223 SLC30A9 Zornitza Stark Gene: slc30a9 has been classified as Green List (High Evidence).
Mendeliome v1.834 SLC30A9 Lucy Spencer gene: SLC30A9 was added
gene: SLC30A9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC30A9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC30A9 were set to 37041080
Phenotypes for gene: SLC30A9 were set to Birk-Landau-Perez syndrome (MIM#617595)
Review for gene: SLC30A9 was set to GREEN
Added comment: PMID:37041080 - 2 families previously reported and this paper describes 4 more with biallelic SLC30A9 variants. Original 2 families: 6 affected members all hom for Ala350del, and 1 affected member chet for 2 frameshifts. 4 families from this paper: 2 families have the same homozygous missense (Gly418Val), family 3 has 4 affected sibs hom for Ala350del, family 4 1 affected chet for a frameshift and a synonymous. So 2 fams homs for Ala350del and 2 fams hom for Gly418Val.
All have Brik-Landau-Perez syndrome: all with ID, movement disorder and dystonia, and many with oculomotor apraxia, renal abnormalitie, ptosis, some had hearing impairment.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5216 POLR1A Elena Savva gene: POLR1A was added
gene: POLR1A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: POLR1A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POLR1A were set to PMID: 37075751
Phenotypes for gene: POLR1A were set to Acrofacial dysostosis, Cincinnati type MIM#616462
Review for gene: POLR1A was set to GREEN
Added comment: PMID: 37075751 - >10 patients with developmental delay
Sources: Literature
Dystonia and Chorea v0.223 SLC30A9 Zornitza Stark Classified gene: SLC30A9 as Green List (high evidence)
Dystonia and Chorea v0.223 SLC30A9 Zornitza Stark Gene: slc30a9 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5216 SLC30A9 Zornitza Stark Classified gene: SLC30A9 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5216 SLC30A9 Zornitza Stark Gene: slc30a9 has been classified as Green List (High Evidence).
Cataract v0.353 DNA2 Seb Lunke gene: DNA2 was added
gene: DNA2 was added to Cataract. Sources: Literature
Mode of inheritance for gene: DNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNA2 were set to 37133451
Phenotypes for gene: DNA2 were set to Rothmund-Thomson syndrome, MONDO:0010002, DNA2 associated
Review for gene: DNA2 was set to AMBER
Added comment: A phenotypic expansion has been proposed based on a cohort of six Brazilian probands that in addition to classic RTS also presented with poikiloderma and congenital cataracts. All shared the same deep intronic splice variant, c.588–2214 A>G, in trans with other LoF variants. The deep intronic variant has been shown to result in the inclusion of a cryptic exon in the mature RNA, resulting in a frame shift and premature termination codon. The authors speculate that the shared intronic variant, which they attribute to a founder effect, has residual normal splicing responsible for the phenotypic variation.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5216 SLC30A9 Zornitza Stark Marked gene: SLC30A9 as ready
Intellectual disability syndromic and non-syndromic v0.5216 SLC30A9 Zornitza Stark Gene: slc30a9 has been classified as Green List (High Evidence).
Mendeliome v1.834 GPR156 Anna Ritchie gene: GPR156 was added
gene: GPR156 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GPR156 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPR156 were set to PMID: 36928819
Phenotypes for gene: GPR156 were set to Sensorineural hearing loss, MONDO:60700002, GPR156-related
Review for gene: GPR156 was set to GREEN
Added comment: Eight affected individuals from three unrelated families with congenital nonsyndromic bilateral sensorineural hearing loss. Homozygous or compound heterozygous loss of function variants were reported in these families.
Sources: Literature
Optic Atrophy v1.12 MCAT Belinda Chong reviewed gene: MCAT: Rating: AMBER; Mode of pathogenicity: None; Publications: 33918393, 31915829; Phenotypes: Progressive autosomal recessive optic neuropathy, Leber hereditary optic neuropathy (LHON)-like; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5216 SLC30A9 Zornitza Stark Classified gene: SLC30A9 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5216 SLC30A9 Zornitza Stark Gene: slc30a9 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5216 SLC30A9 Zornitza Stark Classified gene: SLC30A9 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5216 SLC30A9 Zornitza Stark Gene: slc30a9 has been classified as Green List (High Evidence).
Cataract v0.353 DNA2 Seb Lunke gene: DNA2 was added
gene: DNA2 was added to Cataract. Sources: Literature
deep intronic, founder tags were added to gene: DNA2.
Mode of inheritance for gene: DNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNA2 were set to 37133451
Phenotypes for gene: DNA2 were set to Rothmund-Thomson syndrome, MONDO:0010002, DNA2 associated
Review for gene: DNA2 was set to AMBER
Added comment: A phenotypic expansion has been proposed based on a cohort of six Brazilian probands that in addition to classic RTS also presented with poikiloderma and congenital cataracts. All shared the same deep intronic splice variant, c.588–2214 A>G, in trans with other LoF variants. The deep intronic variant has been shown to result in the inclusion of a cryptic exon in the mature RNA, resulting in a frame shift and premature termination codon. The authors speculate that the shared intronic variant, which they attribute to a founder effect, has residual normal splicing responsible for the phenotypic variation.
Sources: Literature
Congenital Heart Defect v0.280 POLR1A Elena Savva gene: POLR1A was added
gene: POLR1A was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: POLR1A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POLR1A were set to PMID: 37075751
Phenotypes for gene: POLR1A were set to Acrofacial dysostosis, Cincinnati type MIM#616462
Review for gene: POLR1A was set to GREEN
Added comment: PMID: 37075751 - 8/21 patients had congenital heart disease (mostly septal defect, one patient had bicuspid aortic valve, aortic aneurysm). Het mouse model had heart defects including truncus arteriosus
Sources: Literature
Mendeliome v1.834 MRPL39 Lilian Downie changed review comment from: AR
3 unrelated individuals, confirmed variants in trans
Functional studies on patient fibroblasts
Multisystem disease, variable onset
2x infants with a clinical diagnosis of Leigh syndrome (MIM 256000)
Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD
Sources: Literature; to: AR
3 unrelated individuals, confirmed variants in trans
Functional studies on patient fibroblasts
Multisystem disease, variable onset
2x infants with a clinical diagnosis of Leigh syndrome (congestive cardiac
failure, increased lactates, seizures, apnea, poor feeding, and global developmental delay, leading
to early death (< 1 year of age))
Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD
Sources: Literature
Mendeliome v1.834 DPP9 Sarah Pantaleo reviewed gene: DPP9: Rating: GREEN; Mode of pathogenicity: None; Publications: 36112693; Phenotypes: Hatipoglu immunodeficiency syndrome MIM#620331; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.280 POLR1A Elena Savva gene: POLR1A was added
gene: POLR1A was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: POLR1A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POLR1A were set to PMID: 37075751
Phenotypes for gene: POLR1A were set to Acrofacial dysostosis, Cincinnati type MIM#616462
Review for gene: POLR1A was set to GREEN
Added comment: PMID: 37075751 - 8/21 patients had congenital heart disease (mostly septal defect, one patient had bicuspid aortic valve, aortic aneurysm). Het mouse model had heart defects including truncus arteriosus
Sources: Literature
Mendeliome v1.834 MRPL39 Lilian Downie gene: MRPL39 was added
gene: MRPL39 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MRPL39 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL39 were set to PMID: 37133451
Phenotypes for gene: MRPL39 were set to Leigh syndrome MONDO:0009723
Added comment: AR
3 unrelated individuals, confirmed variants in trans
Functional studies on patient fibroblasts
Multisystem disease, variable onset
2x infants with a clinical diagnosis of Leigh syndrome (MIM 256000)
Adult with hypertrophic cardiomyopathy, lactic acidosis, ADHD
Sources: Literature
Mendeliome v1.834 INTS11 Melanie Marty reviewed gene: INTS11: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37054711; Phenotypes: Global developmental delay, launguage delay, intellectual disability, impaired motor development, brain atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Autoinflammatory Disorders v1.4 DPP9 Sarah Pantaleo reviewed gene: DPP9: Rating: GREEN; Mode of pathogenicity: None; Publications: 36112693; Phenotypes: Hatipoglu immunodeficiency syndrome MIM#620331; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia and Chorea v0.222 SLC30A9 Lucy Spencer gene: SLC30A9 was added
gene: SLC30A9 was added to Dystonia - complex. Sources: Literature
Mode of inheritance for gene: SLC30A9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC30A9 were set to 37041080
Phenotypes for gene: SLC30A9 were set to Birk-Landau-Perez syndrome (MIM#617595)
Review for gene: SLC30A9 was set to GREEN
Added comment: PMID:37041080 - 2 families previously reported and this paper describes 4 more with biallelic SLC30A9 variants. Original 2 families: 6 affected members all hom for Ala350del, and 1 affected member chet for 2 frameshifts. 4 families from this paper: 2 families have the same homozygous missense (Gly418Val), family 3 has 4 affected sibs hom for Ala350del, family 4 1 affected chet for a frameshift and a synonymous. So 2 fams homs for Ala350del and 2 fams hom for Gly418Val.
All have Brik-Landau-Perez syndrome: all with ID, movement disorder and dystonia, and many with oculomotor apraxia, renal abnormalitie, ptosis, some had hearing impairment.
Sources: Literature
Clefting disorders v0.196 POLR1A Elena Savva Marked gene: POLR1A as ready
Clefting disorders v0.196 POLR1A Elena Savva Gene: polr1a has been classified as Green List (High Evidence).
Craniosynostosis v1.55 POLR1A Elena Savva Marked gene: POLR1A as ready
Craniosynostosis v1.55 POLR1A Elena Savva Gene: polr1a has been classified as Amber List (Moderate Evidence).
Craniosynostosis v1.55 POLR1A Elena Savva Classified gene: POLR1A as Amber List (moderate evidence)
Craniosynostosis v1.55 POLR1A Elena Savva Gene: polr1a has been classified as Amber List (Moderate Evidence).
Clefting disorders v0.196 POLR1A Elena Savva Phenotypes for gene: POLR1A were changed from cleft palte to Acrofacial dysostosis, Cincinnati type MIM#616462
Clefting disorders v0.195 POLR1A Elena Savva Classified gene: POLR1A as Green List (high evidence)
Clefting disorders v0.195 POLR1A Elena Savva Gene: polr1a has been classified as Green List (High Evidence).
Clefting disorders v0.194 POLR1A Elena Savva reviewed gene: POLR1A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37075751; Phenotypes: Acrofacial dysostosis, Cincinnati type MIM#616462; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.834 ERG Ain Roesley Publications for gene: ERG were set to
Craniosynostosis v1.54 POLR1A Elena Savva gene: POLR1A was added
gene: POLR1A was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: POLR1A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POLR1A were set to PMID: 37075751
Phenotypes for gene: POLR1A were set to Acrofacial dysostosis, Cincinnati type MIM#616462
Review for gene: POLR1A was set to AMBER
Added comment: PMID: 37075751 - craniosynostosis shown in 3/21 patients
Sources: Literature
Fetal anomalies v1.106 GATAD2A Zornitza Stark Marked gene: GATAD2A as ready
Fetal anomalies v1.106 GATAD2A Zornitza Stark Gene: gatad2a has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.106 GATAD2A Zornitza Stark Classified gene: GATAD2A as Amber List (moderate evidence)
Fetal anomalies v1.106 GATAD2A Zornitza Stark Gene: gatad2a has been classified as Amber List (Moderate Evidence).
Mendeliome v1.833 ERG Ain Roesley Phenotypes for gene: ERG were changed from to primary lymphoedema MONDO#0019175, ERG-related
Mendeliome v1.832 ERG Ain Roesley Mode of inheritance for gene: ERG was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.832 ERG Ain Roesley Classified gene: ERG as Green List (high evidence)
Mendeliome v1.832 ERG Ain Roesley Gene: erg has been classified as Green List (High Evidence).
Mendeliome v1.831 ERG Ain Roesley reviewed gene: ERG: Rating: GREEN; Mode of pathogenicity: None; Publications: 36928819; Phenotypes: primary lymphoedema MONDO#0019175, ERG-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Fetal anomalies v1.105 GATAD2A Zornitza Stark gene: GATAD2A was added
gene: GATAD2A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: GATAD2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GATAD2A were set to https://doi.org/10.1016/j.xhgg.2023.100198; 17565372
Phenotypes for gene: GATAD2A were set to Neurodevelopmental disorder, MONDO:0700092, GATAD2A-related
Review for gene: GATAD2A was set to AMBER
Added comment: Inconsistent pattern of congenital abnormalities.

https://doi.org/10.1016/j.xhgg.2023.100198 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5
PMID: 17565372 - null mouse model is embryonic lethal.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5215 SLC30A9 Lucy Spencer gene: SLC30A9 was added
gene: SLC30A9 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SLC30A9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC30A9 were set to 37041080
Phenotypes for gene: SLC30A9 were set to Birk-Landau-Perez syndrome (MIM#617595)
Review for gene: SLC30A9 was set to GREEN
Added comment: PMID:37041080 - 2 families previously reported and this paper describes 4 more with biallelic SLC30A9 variants. Original 2 families: 6 affected members all hom for Ala350del, and 1 affected member chet for 2 frameshifts. 4 families from this paper: 2 families have the same homozygous missense (Gly418Val), family 3 has 4 affected sibs hom for Ala350del, family 4 1 affected chet for a frameshift and a synonymous. So 2 fams homs for Ala350del and 2 fams hom for Gly418Val.
All have Brik-Landau-Perez syndrome: all with ID, movement disorder and dystonia, and many with oculomotor apraxia, renal abnormalitie, ptosis, some had hearing impairment.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5215 GATAD2A Bryony Thompson Marked gene: GATAD2A as ready
Intellectual disability syndromic and non-syndromic v0.5215 GATAD2A Bryony Thompson Gene: gatad2a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5215 GATAD2A Bryony Thompson Classified gene: GATAD2A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5215 GATAD2A Bryony Thompson Gene: gatad2a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5214 GATAD2A Bryony Thompson gene: GATAD2A was added
gene: GATAD2A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: GATAD2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GATAD2A were set to https://doi.org/10.1016/j.xhgg.2023.100198; 17565372
Phenotypes for gene: GATAD2A were set to Neurodevelopmental disorder, MONDO:0700092, GATAD2A-related
Review for gene: GATAD2A was set to GREEN
Added comment: https://doi.org/10.1016/j.xhgg.2023.100198 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5
PMID: 17565372 - null mouse model is embryonic lethal.
Sources: Literature
Mendeliome v1.831 GATAD2A Bryony Thompson Marked gene: GATAD2A as ready
Mendeliome v1.831 GATAD2A Bryony Thompson Gene: gatad2a has been classified as Green List (High Evidence).
Mendeliome v1.831 GATAD2A Bryony Thompson Classified gene: GATAD2A as Green List (high evidence)
Mendeliome v1.831 GATAD2A Bryony Thompson Gene: gatad2a has been classified as Green List (High Evidence).
Mendeliome v1.830 GATAD2A Bryony Thompson gene: GATAD2A was added
gene: GATAD2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GATAD2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GATAD2A were set to https://doi.org/10.1016/j.xhgg.2023.100198; 17565372
Phenotypes for gene: GATAD2A were set to Neurodevelopmental disorder, MONDO:0700092, GATAD2A-related
Review for gene: GATAD2A was set to GREEN
Added comment: https://doi.org/10.1016/j.xhgg.2023.100198 - Five unrelated individuals with a neurodevelopmental disorder identified with 3 missense & 2 LoF (4 de novo & 1 unknown inheritance). The shared clinical features with variable expressivity include global developmental delay (4/4), craniofacial dysmorphism (3/5), structural brain defects (2/3), musculoskeletal anomalies (3/5), vision/hearing defects (2/3), gastrointestinal/renal defects (2/3). Loss of function is the expected mechanism of disease. In vitro assays of one of the missense variants (p.Cys420Tyr) demonstrates disruption of GATAD2A integration with CHD3, CHD4, and CHD5
PMID: 17565372 - null mouse model is embryonic lethal.
Sources: Literature
Mendeliome v1.829 RNF212B Bryony Thompson Publications for gene: RNF212B were set to https://doi.org/10.1016/j.xhgg.2023.100189
Brain Calcification v1.76 TRPM6 Yetong Chen gene: TRPM6 was added
gene: TRPM6 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: TRPM6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRPM6 were set to 22982920
Phenotypes for gene: TRPM6 were set to Hypomagnesemia 1, intestinal, MIM# 602014
Review for gene: TRPM6 was set to RED
Added comment: Insufficient evidence supports the gene-disease association.
PMID 22982920 reports a patient with a novel homozygous variant (ins 2999T) of the TRPM6 gene who had bilateral basal ganglia calci­fication. The authors state that brain calcification has never been reported in hypomagnesemia patients before.
Sources: Expert list
Brain Calcification v1.76 TREX1 Yetong Chen reviewed gene: TREX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34949589, 26581299, 29386495; Phenotypes: Aicardi-Goutieres syndrome 1, dominant and recessive, MIM# 225750; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Brain Calcification v1.76 TREM2 Yetong Chen reviewed gene: TREM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33969597, 35705056; Phenotypes: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, MIM# 618193; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Disorders of immune dysregulation v0.170 LIG4 Zornitza Stark Marked gene: LIG4 as ready
Disorders of immune dysregulation v0.170 LIG4 Zornitza Stark Gene: lig4 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v0.170 LIG4 Zornitza Stark Phenotypes for gene: LIG4 were changed from Immune dysregulation to LIG4 syndrome, MIM# 606593; Immune dysregulation
Disorders of immune dysregulation v0.169 LIG4 Zornitza Stark Classified gene: LIG4 as Green List (high evidence)
Disorders of immune dysregulation v0.169 LIG4 Zornitza Stark Gene: lig4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5213 KDM5A Zornitza Stark Marked gene: KDM5A as ready
Intellectual disability syndromic and non-syndromic v0.5213 KDM5A Zornitza Stark Gene: kdm5a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5213 KDM5A Zornitza Stark Classified gene: KDM5A as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5213 KDM5A Zornitza Stark Gene: kdm5a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5212 KDM5A Zornitza Stark gene: KDM5A was added
gene: KDM5A was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: KDM5A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: KDM5A were set to 21937992; 33350388
Phenotypes for gene: KDM5A were set to Neurodevelopmental disorder MONDO:0700092, KDM5A-related
Review for gene: KDM5A was set to GREEN
Added comment: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms.

PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment.

In addition, loss of KDM5A has resulted in repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis in mice.

This gene has already been associated with phenotype in Gene2Phenotype (biallelic inheritance with 'limited' rating), but not in OMIM.
Sources: Literature
Mendeliome v1.828 KDM5A Zornitza Stark Marked gene: KDM5A as ready
Mendeliome v1.828 KDM5A Zornitza Stark Gene: kdm5a has been classified as Green List (High Evidence).
Mendeliome v1.828 KDM5A Zornitza Stark Classified gene: KDM5A as Green List (high evidence)
Mendeliome v1.828 KDM5A Zornitza Stark Gene: kdm5a has been classified as Green List (High Evidence).
Craniosynostosis v1.53 BCL11B Zornitza Stark Marked gene: BCL11B as ready
Craniosynostosis v1.53 BCL11B Zornitza Stark Gene: bcl11b has been classified as Green List (High Evidence).
Craniosynostosis v1.53 BCL11B Zornitza Stark Phenotypes for gene: BCL11B were changed from Craniosynostosis to Craniosynostosis, MONDO:0015469, BCL11B-related
Craniosynostosis v1.52 BCL11B Zornitza Stark Classified gene: BCL11B as Green List (high evidence)
Craniosynostosis v1.52 BCL11B Zornitza Stark Gene: bcl11b has been classified as Green List (High Evidence).
Craniosynostosis v1.51 NFIA Zornitza Stark Marked gene: NFIA as ready
Craniosynostosis v1.51 NFIA Zornitza Stark Gene: nfia has been classified as Green List (High Evidence).
Craniosynostosis v1.51 NFIA Zornitza Stark Phenotypes for gene: NFIA were changed from Craniosynostosis to Craniosynostosis MONDO:0015469, NFIA-related
Craniosynostosis v1.50 NFIA Zornitza Stark Classified gene: NFIA as Green List (high evidence)
Craniosynostosis v1.50 NFIA Zornitza Stark Gene: nfia has been classified as Green List (High Evidence).
Craniosynostosis v1.49 NFIA Zornitza Stark reviewed gene: NFIA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Craniosynostosis MONDO:0015469, NFIA-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Craniosynostosis v1.49 PRRX1 Zornitza Stark Marked gene: PRRX1 as ready
Craniosynostosis v1.49 PRRX1 Zornitza Stark Gene: prrx1 has been classified as Green List (High Evidence).
Craniosynostosis v1.49 PRRX1 Zornitza Stark Phenotypes for gene: PRRX1 were changed from Craniosynostosis to Craniosynostosis, MONDO:0015469, PRRX1-related
Craniosynostosis v1.48 PRRX1 Zornitza Stark Classified gene: PRRX1 as Green List (high evidence)
Craniosynostosis v1.48 PRRX1 Zornitza Stark Gene: prrx1 has been classified as Green List (High Evidence).
Mendeliome v1.827 YWHAE Zornitza Stark Marked gene: YWHAE as ready
Mendeliome v1.827 YWHAE Zornitza Stark Gene: ywhae has been classified as Green List (High Evidence).
Mendeliome v1.827 YWHAE Zornitza Stark Classified gene: YWHAE as Green List (high evidence)
Mendeliome v1.827 YWHAE Zornitza Stark Gene: ywhae has been classified as Green List (High Evidence).
Mendeliome v1.826 YWHAE Zornitza Stark gene: YWHAE was added
gene: YWHAE was added to Mendeliome. Sources: Literature
SV/CNV tags were added to gene: YWHAE.
Mode of inheritance for gene: YWHAE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: YWHAE were set to 36999555
Phenotypes for gene: YWHAE were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: YWHAE was set to GREEN
Added comment: PMID 36999555 reports 10 patients with YWHAE variants (1 intragenic deletion and 5 large deletions encompassing YWHEA but not PAFAH1B1) who have mild to severe intellectual disability. 3 individuals with SNVs. Mouse model supports gene-disease association.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5211 YWHAE Zornitza Stark Marked gene: YWHAE as ready
Intellectual disability syndromic and non-syndromic v0.5211 YWHAE Zornitza Stark Gene: ywhae has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5211 YWHAE Zornitza Stark Classified gene: YWHAE as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5211 YWHAE Zornitza Stark Gene: ywhae has been classified as Green List (High Evidence).
Callosome v0.489 YWHAE Zornitza Stark Marked gene: YWHAE as ready
Callosome v0.489 YWHAE Zornitza Stark Gene: ywhae has been classified as Green List (High Evidence).
Callosome v0.489 YWHAE Zornitza Stark Classified gene: YWHAE as Green List (high evidence)
Callosome v0.489 YWHAE Zornitza Stark Gene: ywhae has been classified as Green List (High Evidence).
Brain Calcification v1.76 TINF2 Yetong Chen reviewed gene: TINF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33734615, 32966588, 28095086; Phenotypes: Dyskeratosis congenita, autosomal dominant 3, MIM# 613990; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Brain Calcification v1.76 PANK2 Zornitza Stark Marked gene: PANK2 as ready
Brain Calcification v1.76 PANK2 Zornitza Stark Gene: pank2 has been classified as Amber List (Moderate Evidence).
Brain Calcification v1.76 PANK2 Zornitza Stark Classified gene: PANK2 as Amber List (moderate evidence)
Brain Calcification v1.76 PANK2 Zornitza Stark Gene: pank2 has been classified as Amber List (Moderate Evidence).
Brain Calcification v1.75 PANK2 Zornitza Stark reviewed gene: PANK2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration with brain iron accumulation 1, MIM# 234200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.75 PANK2 Zornitza Stark Classified gene: PANK2 as Red List (low evidence)
Brain Calcification v1.75 PANK2 Zornitza Stark Gene: pank2 has been classified as Red List (Low Evidence).
Brain Calcification v1.74 PCDH12 Zornitza Stark Marked gene: PCDH12 as ready
Brain Calcification v1.74 PCDH12 Zornitza Stark Gene: pcdh12 has been classified as Green List (High Evidence).
Brain Calcification v1.74 PCDH12 Zornitza Stark Classified gene: PCDH12 as Green List (high evidence)
Brain Calcification v1.74 PCDH12 Zornitza Stark Gene: pcdh12 has been classified as Green List (High Evidence).
Brain Calcification v1.73 PSMB8 Zornitza Stark Marked gene: PSMB8 as ready
Brain Calcification v1.73 PSMB8 Zornitza Stark Gene: psmb8 has been classified as Red List (Low Evidence).
Brain Calcification v1.73 PSMB8 Zornitza Stark Classified gene: PSMB8 as Red List (low evidence)
Brain Calcification v1.73 PSMB8 Zornitza Stark Gene: psmb8 has been classified as Red List (Low Evidence).
Brain Calcification v1.72 PSMG2 Zornitza Stark Classified gene: PSMG2 as Red List (low evidence)
Brain Calcification v1.72 PSMG2 Zornitza Stark Gene: psmg2 has been classified as Red List (Low Evidence).
Brain Calcification v1.71 PTH Zornitza Stark Marked gene: PTH as ready
Brain Calcification v1.71 PTH Zornitza Stark Gene: pth has been classified as Red List (Low Evidence).
Brain Calcification v1.71 PTH Zornitza Stark Classified gene: PTH as Red List (low evidence)
Brain Calcification v1.71 PTH Zornitza Stark Gene: pth has been classified as Red List (Low Evidence).
Brain Calcification v1.71 PTS Zornitza Stark Marked gene: PTS as ready
Brain Calcification v1.71 PTS Zornitza Stark Gene: pts has been classified as Red List (Low Evidence).
Brain Calcification v1.71 PTS Zornitza Stark Classified gene: PTS as Red List (low evidence)
Brain Calcification v1.71 PTS Zornitza Stark Gene: pts has been classified as Red List (Low Evidence).
Brain Calcification v1.70 QDPR Zornitza Stark Marked gene: QDPR as ready
Brain Calcification v1.70 QDPR Zornitza Stark Gene: qdpr has been classified as Red List (Low Evidence).
Brain Calcification v1.70 QDPR Zornitza Stark Classified gene: QDPR as Red List (low evidence)
Brain Calcification v1.70 QDPR Zornitza Stark Gene: qdpr has been classified as Red List (Low Evidence).
Brain Calcification v1.69 GNA11 Zornitza Stark Marked gene: GNA11 as ready
Brain Calcification v1.69 GNA11 Zornitza Stark Gene: gna11 has been classified as Red List (Low Evidence).
Brain Calcification v1.69 GNA11 Zornitza Stark Classified gene: GNA11 as Red List (low evidence)
Brain Calcification v1.69 GNA11 Zornitza Stark Gene: gna11 has been classified as Red List (Low Evidence).
Brain Calcification v1.68 GLA Zornitza Stark Marked gene: GLA as ready
Brain Calcification v1.68 GLA Zornitza Stark Gene: gla has been classified as Amber List (Moderate Evidence).
Brain Calcification v1.68 GLA Zornitza Stark Classified gene: GLA as Amber List (moderate evidence)
Brain Calcification v1.68 GLA Zornitza Stark Gene: gla has been classified as Amber List (Moderate Evidence).
Brain Calcification v1.67 GCM2 Zornitza Stark Marked gene: GCM2 as ready
Brain Calcification v1.67 GCM2 Zornitza Stark Gene: gcm2 has been classified as Green List (High Evidence).
Brain Calcification v1.67 GCM2 Zornitza Stark Classified gene: GCM2 as Green List (high evidence)
Brain Calcification v1.67 GCM2 Zornitza Stark Gene: gcm2 has been classified as Green List (High Evidence).
Brain Calcification v1.66 FOLR1 Zornitza Stark Marked gene: FOLR1 as ready
Brain Calcification v1.66 FOLR1 Zornitza Stark Gene: folr1 has been classified as Red List (Low Evidence).
Brain Calcification v1.66 GATA3 Zornitza Stark Marked gene: GATA3 as ready
Brain Calcification v1.66 GATA3 Zornitza Stark Gene: gata3 has been classified as Green List (High Evidence).
Brain Calcification v1.66 GATA3 Zornitza Stark Classified gene: GATA3 as Green List (high evidence)
Brain Calcification v1.66 GATA3 Zornitza Stark Gene: gata3 has been classified as Green List (High Evidence).
Brain Calcification v1.65 FOLR1 Zornitza Stark Phenotypes for gene: FOLR1 were changed from to Neurodegeneration due to cerebral folate transport deficiency, MIM# 613068
Brain Calcification v1.64 FAM20C Zornitza Stark Marked gene: FAM20C as ready
Brain Calcification v1.64 FAM20C Zornitza Stark Gene: fam20c has been classified as Green List (High Evidence).
Brain Calcification v1.64 FAM20C Zornitza Stark Publications for gene: FAM20C were set to 27862258; 20825432; 36914045; 34259997; 32299476; 29341424
Brain Calcification v1.63 FAM20C Zornitza Stark Publications for gene: FAM20C were set to 27862258; 20825432
Brain Calcification v1.63 FOLR1 Zornitza Stark Classified gene: FOLR1 as Red List (low evidence)
Brain Calcification v1.63 FOLR1 Zornitza Stark Gene: folr1 has been classified as Red List (Low Evidence).
Brain Calcification v1.62 FAM20C Zornitza Stark Classified gene: FAM20C as Green List (high evidence)
Brain Calcification v1.62 FAM20C Zornitza Stark Gene: fam20c has been classified as Green List (High Evidence).
Brain Calcification v1.61 SUOX Zornitza Stark Marked gene: SUOX as ready
Brain Calcification v1.61 SUOX Zornitza Stark Gene: suox has been classified as Green List (High Evidence).
Brain Calcification v1.61 FAM20C Zornitza Stark reviewed gene: FAM20C: Rating: GREEN; Mode of pathogenicity: None; Publications: 36914045, 34259997, 32299476, 29341424; Phenotypes: Raine syndrome, MIM# 259775; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.61 SUOX Zornitza Stark Classified gene: SUOX as Green List (high evidence)
Brain Calcification v1.61 SUOX Zornitza Stark Gene: suox has been classified as Green List (High Evidence).
Brain Calcification v1.60 TBC1D20 Zornitza Stark Marked gene: TBC1D20 as ready
Brain Calcification v1.60 TBC1D20 Zornitza Stark Gene: tbc1d20 has been classified as Red List (Low Evidence).
Brain Calcification v1.60 TBC1D20 Zornitza Stark Phenotypes for gene: TBC1D20 were changed from Cerebroretinal microangiopathy with calcifications and cysts 2, MIM# 617341 to Warburg micro syndrome 4, MIM# 615663
Brain Calcification v1.59 TBC1D20 Zornitza Stark Classified gene: TBC1D20 as Red List (low evidence)
Brain Calcification v1.59 TBC1D20 Zornitza Stark Gene: tbc1d20 has been classified as Red List (Low Evidence).
Brain Calcification v1.58 TBC1D20 Zornitza Stark reviewed gene: TBC1D20: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Warburg micro syndrome 4, MIM# 615663; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.58 STN1 Zornitza Stark Publications for gene: STN1 were set to 27432940; 32627942
Brain Calcification v1.57 SNORD118 Zornitza Stark Publications for gene: SNORD118 were set to 27571260
Brain Calcification v1.56 SLC46A1 Zornitza Stark Marked gene: SLC46A1 as ready
Brain Calcification v1.56 SLC46A1 Zornitza Stark Gene: slc46a1 has been classified as Green List (High Evidence).
Brain Calcification v1.56 SLC46A1 Zornitza Stark Classified gene: SLC46A1 as Green List (high evidence)
Brain Calcification v1.56 SLC46A1 Zornitza Stark Gene: slc46a1 has been classified as Green List (High Evidence).
Brain Calcification v1.55 SUOX Yetong Chen gene: SUOX was added
gene: SUOX was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: SUOX was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SUOX were set to 27289259; 23250141; 24384336
Phenotypes for gene: SUOX were set to Sulfite oxidase deficiency, MIM# 272300
Review for gene: SUOX was set to GREEN
Added comment: PMID 27289259 reports 2 unrelated patients with different homozygous SUOX variants (c.713G > A(p.G238Q*) and c.884G > A (p.G295E)) who had thalami calcifications.
PMID 23250141 reports a patient with homozygous SUOX variant (c.1232-1233 delTG) who had faint calcification in the thalami.
PMID 24384336 reports a patient (patient 2) with homozygous SUOX variant (c.1232-1233delT) who had faint calcification in both thalami.
Sources: Expert list
Mendeliome v1.825 OXGR1 Bryony Thompson Publications for gene: OXGR1 were set to PMID:35671463
Brain Calcification v1.55 TBC1D20 Yetong Chen gene: TBC1D20 was added
gene: TBC1D20 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: TBC1D20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D20 were set to 32740904
Phenotypes for gene: TBC1D20 were set to Cerebroretinal microangiopathy with calcifications and cysts 2, MIM# 617341
Review for gene: TBC1D20 was set to RED
Added comment: Limited evidence supports the causal role of TBC1D20 in brain calcification.
PMID 32740904 reports one patient (case 34) with homozygous TBC1D20 variant (c.199C>T (p.Arg67*)) who developed bilateral faint calcification in basal ganglia.
Sources: Expert list
Brain Calcification v1.55 STN1 Yetong Chen reviewed gene: STN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34110109; Phenotypes: Cerebroretinal microangiopathy with calcifications and cysts 2, MIM# 617341; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.55 SNORD118 Yetong Chen reviewed gene: SNORD118: Rating: GREEN; Mode of pathogenicity: None; Publications: 34220662, 28177126, 34986804; Phenotypes: Leukoencephalopathy, brain calcifications, and cysts, MIM# 614561; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.55 SLC46A1 Yetong Chen gene: SLC46A1 was added
gene: SLC46A1 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: SLC46A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC46A1 were set to 33146883; 28685492; 24534056; 27938595
Phenotypes for gene: SLC46A1 were set to Folate malabsorption, hereditary, MIM# 229050
Review for gene: SLC46A1 was set to GREEN
Added comment: PMID 33146883 reports a patient with homozygous SLC46A1 variant (c.620dupG (p.Y208Lfs *25)) who had calcifications in bilateral basal ganglia, thalamus, and subcortical white matter.
PMID 28685492 reports a patient (case 2) with homozygous SLC46A1 variant (c.198C>A (p.Cys66*)) who developed basal ganglia calcification.
PMID 24534056 reports a patient with compound heterozygous SLC46A1 variants (c.1A>T (MIL) and c.194-195insG (p.Cys66LeufsX99)) who developed calcifications in bilateral frontal, temporal, parietal and occipital lobes, and basal ganglia.
PMID 27938595 reports 2 patients harbouring SLC46A1 variants who had progressive bilateral symmetrical calcification. Both patients had compound heterozygous variants. Patient 1 had c. 1238T>C (L413P) and c. 194-195insG (p.Cys66LeufsX99) while patient 2 had c. 1A>T (M1L) and c. 194-195insG (p.Cys66LeufsX99). It should be noted that this publication is written in Chinese and only the abstract is available in English, so details about the calcifications are not available.
Sources: Expert list
Mendeliome v1.824 KPNA7 Zornitza Stark Phenotypes for gene: KPNA7 were changed from Epilepsy; intellectual disability to Oocyte/zygote/embryo maturation arrest 17, MIM# 620319; Neurodevelopmental disorder
Mendeliome v1.823 KPNA7 Zornitza Stark Publications for gene: KPNA7 were set to 24045845; 32179771
Mendeliome v1.822 KPNA7 Zornitza Stark Classified gene: KPNA7 as Amber List (moderate evidence)
Mendeliome v1.822 KPNA7 Zornitza Stark Gene: kpna7 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.821 KPNA7 Zornitza Stark reviewed gene: KPNA7: Rating: AMBER; Mode of pathogenicity: None; Publications: 36647821; Phenotypes: Oocyte/zygote/embryo maturation arrest 17, MIM# 620319; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Diarrhoea v1.13 ACSL5 Zornitza Stark Marked gene: ACSL5 as ready
Congenital Diarrhoea v1.13 ACSL5 Zornitza Stark Gene: acsl5 has been classified as Red List (Low Evidence).
Congenital Diarrhoea v1.13 ACSL5 Zornitza Stark gene: ACSL5 was added
gene: ACSL5 was added to Congenital Diarrhoea. Sources: Literature
Mode of inheritance for gene: ACSL5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACSL5 were set to 33191500
Phenotypes for gene: ACSL5 were set to Diarrhoea 13, MIM# 620357
Review for gene: ACSL5 was set to RED
Added comment: 6 individuals of a large consanguineous family presented in the neonatal period with recurrent vomiting and diarrhea, leading to severe FTT. Autozygosity mapping and WES identified homozygous variant (c.1358C>A:p.(Thr453Lys) in ACSL5. Segregated with affected individuals.

Functional in vitro analysis of the ACSL5 variant by immunofluorescence, western blotting and enzyme assay suggested that Thr453Lys is a loss‐of‐function mutation without any remaining activity.

Affected individuals were treated with total parenteral nutrition or medium‐chain triglyceride‐based formula restricted in long‐chain triglycerides. They responded well and follow up suggests that treatment is only required during early life.
Sources: Literature
Fatty Acid Oxidation Defects v1.14 ACSL5 Zornitza Stark Phenotypes for gene: ACSL5 were changed from Diarrhoea 13, MIM# 620357 to Diarrhoea 13, MIM# 620357
Mendeliome v1.821 ACSL5 Zornitza Stark Phenotypes for gene: ACSL5 were changed from severe FTT (no OMIM #) to Diarrhoea 13, MIM# 620357
Fatty Acid Oxidation Defects v1.14 ACSL5 Zornitza Stark Phenotypes for gene: ACSL5 were changed from Diarrhea 13, MIM# 620357 to Diarrhoea 13, MIM# 620357
Fatty Acid Oxidation Defects v1.13 ACSL5 Zornitza Stark Phenotypes for gene: ACSL5 were changed from Diarrhea 13, MIM# 620357 to Diarrhea 13, MIM# 620357
Fatty Acid Oxidation Defects v1.13 ACSL5 Zornitza Stark Phenotypes for gene: ACSL5 were changed from severe FTT (no OMIM #) to Diarrhea 13, MIM# 620357
Polycystic liver disease v1.8 LRP5 Zornitza Stark edited their review of gene: LRP5: Changed publications: 25920554, 24706814
Brain Calcification v1.55 RAB39B Bryony Thompson Marked gene: RAB39B as ready
Brain Calcification v1.55 RAB39B Bryony Thompson Gene: rab39b has been classified as Red List (Low Evidence).
Brain Calcification v1.55 RAB39B Bryony Thompson Classified gene: RAB39B as Red List (low evidence)
Brain Calcification v1.55 RAB39B Bryony Thompson Gene: rab39b has been classified as Red List (Low Evidence).
Brain Calcification v1.54 GJA1 Bryony Thompson Classified gene: GJA1 as Green List (high evidence)
Brain Calcification v1.54 GJA1 Bryony Thompson Added comment: Comment on list classification: Brain calcification appears to be a variable feature of the ODDD phenotype
Brain Calcification v1.54 GJA1 Bryony Thompson Gene: gja1 has been classified as Green List (High Evidence).
Brain Calcification v1.53 GJA1 Bryony Thompson Marked gene: GJA1 as ready
Brain Calcification v1.53 GJA1 Bryony Thompson Gene: gja1 has been classified as Green List (High Evidence).
Brain Calcification v1.53 GJA1 Bryony Thompson Deleted their comment
Brain Calcification v1.53 GJA1 Bryony Thompson Added comment: Comment on mode of inheritance: Brain calcification appears to be a variable feature of the ODDD phenotype
Brain Calcification v1.53 GJA1 Bryony Thompson Mode of inheritance for gene: GJA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Brain Calcification v1.52 GJA1 Bryony Thompson Classified gene: GJA1 as Green List (high evidence)
Brain Calcification v1.52 GJA1 Bryony Thompson Gene: gja1 has been classified as Green List (High Evidence).
Mosaic skin disorders v1.9 PORCN Bryony Thompson Marked gene: PORCN as ready
Mosaic skin disorders v1.9 PORCN Bryony Thompson Gene: porcn has been classified as Green List (High Evidence).
Mosaic skin disorders v1.9 PORCN Bryony Thompson Classified gene: PORCN as Green List (high evidence)
Mosaic skin disorders v1.9 PORCN Bryony Thompson Added comment: Comment on list classification: Added from PanelApp UK mosaic skin disorders panel
Mosaic skin disorders v1.9 PORCN Bryony Thompson Gene: porcn has been classified as Green List (High Evidence).
Mosaic skin disorders v1.8 BRAF Bryony Thompson Classified gene: BRAF as Green List (high evidence)
Mosaic skin disorders v1.8 BRAF Bryony Thompson Added comment: Comment on list classification: Added from PanelApp UK Mosaic skin disorders panel
Mosaic skin disorders v1.8 BRAF Bryony Thompson Gene: braf has been classified as Green List (High Evidence).
Mosaic skin disorders v1.7 BRAF Bryony Thompson Marked gene: BRAF as ready
Mosaic skin disorders v1.7 BRAF Bryony Thompson Gene: braf has been classified as Green List (High Evidence).
Mosaic skin disorders v1.7 BRAF Bryony Thompson Classified gene: BRAF as Green List (high evidence)
Mosaic skin disorders v1.7 BRAF Bryony Thompson Gene: braf has been classified as Green List (High Evidence).
Fetal anomalies v1.104 DNM1 Zornitza Stark Phenotypes for gene: DNM1 were changed from Developmental and epileptic encephalopathy 31, OMIM:616346 to Developmental and epileptic encephalopathy 31A, autosomal dominant, MIM# 616346; Developmental and epileptic encephalopathy 31B, autosomal recessive, MIM# 620352
Fetal anomalies v1.103 DNM1 Zornitza Stark edited their review of gene: DNM1: Changed phenotypes: Developmental and epileptic encephalopathy 31A, autosomal dominant, MIM# 616346, Developmental and epileptic encephalopathy 31B, autosomal recessive, MIM# 620352
Intellectual disability syndromic and non-syndromic v0.5210 DNM1 Zornitza Stark Phenotypes for gene: DNM1 were changed from Developmental and epileptic encephalopathy 31, OMIM:616346 to Developmental and epileptic encephalopathy 31A, autosomal dominant, MIM# 616346; Developmental and epileptic encephalopathy 31B, autosomal recessive, MIM# 620352
Intellectual disability syndromic and non-syndromic v0.5209 DNM1 Zornitza Stark edited their review of gene: DNM1: Changed phenotypes: Developmental and epileptic encephalopathy 31A, autosomal dominant, MIM# 616346, Developmental and epileptic encephalopathy 31B, autosomal recessive, MIM# 620352
Genetic Epilepsy v0.1843 DNM1 Zornitza Stark Marked gene: DNM1 as ready
Genetic Epilepsy v0.1843 DNM1 Zornitza Stark Gene: dnm1 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1843 DNM1 Zornitza Stark Phenotypes for gene: DNM1 were changed from Developmental and epileptic encephalopathy 31, OMIM:616346 to Developmental and epileptic encephalopathy 31A, autosomal dominant, MIM# 616346; Developmental and epileptic encephalopathy 31B, autosomal recessive, MIM# 620352
Genetic Epilepsy v0.1842 DNM1 Zornitza Stark edited their review of gene: DNM1: Changed phenotypes: Developmental and epileptic encephalopathy 31A, autosomal dominant, MIM# 616346, Developmental and epileptic encephalopathy 31B, autosomal recessive, MIM# 620352
Mendeliome v1.820 DNM1 Zornitza Stark Phenotypes for gene: DNM1 were changed from Developmental and epileptic encephalopathy 31, OMIM:616346 to Developmental and epileptic encephalopathy 31A, autosomal dominant, MIM# 616346; Developmental and epileptic encephalopathy 31B, autosomal recessive, MIM# 620352
Mendeliome v1.819 DNM1 Zornitza Stark edited their review of gene: DNM1: Changed phenotypes: Developmental and epileptic encephalopathy 31A, autosomal dominant, MIM# 616346, Developmental and epileptic encephalopathy 31B, autosomal recessive, MIM# 620352
Brain Calcification v1.51 SLC20A2 Yetong Chen reviewed gene: SLC20A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28162874, 31267306, 35850697, 34025715; Phenotypes: Basal ganglia calcification, idiopathic, 1, MIM# 213600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Brain Calcification v1.51 SAMHD1 Yetong Chen reviewed gene: SAMHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35418820, 36405817; Phenotypes: Aicardi-Goutieres syndrome 5, MIM# 612952; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.51 RNASEH2C Yetong Chen reviewed gene: RNASEH2C: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301648, 33681774, 27411419; Phenotypes: Aicardi-Goutieres syndrome 3, MIM# 610329; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.51 RNASEH2B Yetong Chen reviewed gene: RNASEH2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301648, 33482855, 30826161, 26581299; Phenotypes: Aicardi-Goutieres syndrome 2, MIM# 610181; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic Atrophy v1.12 SPG7 Elena Savva reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 32548275, 36367250, 35243150; Phenotypes: Optical atrophy MONDO#0003608); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.5209 RBSN Elena Savva commented on gene: RBSN
Mendeliome v1.819 INTS11 Achchuthan Shanmugasundram edited their review of gene: INTS11: Changed phenotypes: intellectual disability, MONDO:0001071
Mendeliome v1.819 INTS11 Achchuthan Shanmugasundram gene: INTS11 was added
gene: INTS11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: INTS11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTS11 were set to 37054711
Review for gene: INTS11 was set to GREEN
Added comment: Comment on gene rating: This gene should be rated GREEN in Intellectual disability panel as it has 10 unrelated cases and functional evidence in support of this association.

PMID:37054711 reported ten unrelated families with biallelic variants in INTS11 gene and they present with intellectual disability, global developmental and language delay, impaired motor development, and brain atrophy.

Functional studies in Drosophila showed that dIntS11 (fly ortholog of INTS11) is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. In addition, genes with two variants (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants in the Drosophila model, indicating that they are strong loss-of-function variants. The other five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5209 DNAH14 Zornitza Stark Tag disputed tag was added to gene: DNAH14.
Genetic Epilepsy v0.1842 DNAH14 Zornitza Stark Tag disputed tag was added to gene: DNAH14.
Mendeliome v1.819 DNAH14 Zornitza Stark Tag disputed tag was added to gene: DNAH14.
Intellectual disability syndromic and non-syndromic v0.5209 DNAH14 Elena Savva Classified gene: DNAH14 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.5209 DNAH14 Elena Savva Gene: dnah14 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5209 DNAH14 Elena Savva Classified gene: DNAH14 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.5209 DNAH14 Elena Savva Gene: dnah14 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5208 DNAH14 Elena Savva reviewed gene: DNAH14: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1842 DNAH14 Elena Savva Classified gene: DNAH14 as Red List (low evidence)
Genetic Epilepsy v0.1842 DNAH14 Elena Savva Gene: dnah14 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1842 DNAH14 Elena Savva Classified gene: DNAH14 as Red List (low evidence)
Genetic Epilepsy v0.1842 DNAH14 Elena Savva Gene: dnah14 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1841 DNAH14 Elena Savva reviewed gene: DNAH14: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.819 DNAH14 Elena Savva commented on gene: DNAH14
Mendeliome v1.819 DNAH14 Elena Savva Classified gene: DNAH14 as Red List (low evidence)
Mendeliome v1.819 DNAH14 Elena Savva Gene: dnah14 has been classified as Red List (Low Evidence).
Brain Calcification v1.51 MT-ATP6 Yetong Chen edited their review of gene: MT-ATP6: Changed phenotypes: Leigh syndrome, MIM* 516060
Brain Calcification v1.51 QDPR Yetong Chen changed review comment from: There is insufficient evidence supporting the causal role of the QDPR gene in brain calcification.
Sources: Expert list; to: There is insufficient evidence supporting the causal role of the QDPR gene in brain calcification.
The suggested literature (PMID 2135679) is not accessible in PubMed. A similar paper, PMID 2785251, reports intracranial calcification in a patient with dihydropteridine reductase deficiency. DNA sequencing was not available when the case was reported.
Sources: Expert list
Brain Calcification v1.51 QDPR Yetong Chen gene: QDPR was added
gene: QDPR was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: QDPR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: QDPR were set to 2135679
Phenotypes for gene: QDPR were set to Dihydropteridine Reductase (DHPR) Deficiency, MIM* 612676
Review for gene: QDPR was set to RED
Added comment: There is insufficient evidence supporting the causal role of the QDPR gene in brain calcification.
Sources: Expert list
Brain Calcification v1.51 RAB39B Yetong Chen gene: RAB39B was added
gene: RAB39B was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: RAB39B was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: RAB39B were set to 27943471
Phenotypes for gene: RAB39B were set to Intellectual developmental disorder, X-linked 72, MIM# 300271
Review for gene: RAB39B was set to RED
Added comment: Only one 2 cases from the same family are reported, insufficient evidence supports the causal role of the RAB39B gene in brain calcification.
PMID 27943471 reports 2 patients (II-2 and III-1) from the same family harbouring a RAB39B variant (c.536dupA, p.E179fsX48) who developed brain calcification.
Sources: Expert list
Brain Calcification v1.51 PTS Yetong Chen gene: PTS was added
gene: PTS was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: PTS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTS were set to 16601879; 32734340
Phenotypes for gene: PTS were set to Hyperphenylalaninemia, BH4-deficient, A, MIM# 261640
Review for gene: PTS was set to RED
Added comment: Although brain calcification might be seen in patients with BH4 deficiency, none of the papers mentions PTS variants found in the affected patients.
Further, there are multiple genes that can cause BH4 deficiency, of which PTS is one of them.
The suggested literature, PMID 16601879, reports a BH4 deficiency patient with brain calcification (No.544). However, the mutation analysis was not done for this patient.
Insufficient evidence suggests the causal role of the PTS gene in brain calcification.
Sources: Expert list
Brain Calcification v1.51 PTH Yetong Chen gene: PTH was added
gene: PTH was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: PTH was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PTH were set to 29383229
Phenotypes for gene: PTH were set to Hypoparathyroidism, familial isolated 1, MIM# 146200
Review for gene: PTH was set to RED
Added comment: Several publications report brain calcifications found in patients with hyperparathyroidism (e.g. PMID 29383229); however, none of them reports the genetic profiles of the patients.
In addition, less than 10% of hyperparathyroidism cases are due to genetic causes.
Thus, limited evidence suggests a causal role of the PTH gene in brain calcification.
Sources: Expert list
Brain Calcification v1.51 PSMB8 Yetong Chen gene: PSMB8 was added
gene: PSMB8 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: PSMB8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMB8 were set to 28895430; 23768303
Phenotypes for gene: PSMB8 were set to Proteasome-associated autoinflammatory syndrome 1 and digenic forms, MIM# 256040
Review for gene: PSMB8 was set to RED
Added comment: Insufficient evidence supports the causal role of the PSMB8 gene in brain calcification.
PMID 28895430 report a patient with homozygous PSMB8 variants (p.A92T) who developed basal ganglia calcification.
PMID 23768303 reports a patient with heterozygous PSMB8 variants (p.A92T/p.T75M) who had brain calcification.
Sources: Expert list
Brain Calcification v1.51 PSMG2 Yetong Chen gene: PSMG2 was added
gene: PSMG2 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: PSMG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMG2 were set to 30664889
Phenotypes for gene: PSMG2 were set to Proteasome-associated autoinflammatory syndrome 4, MIM# 619183
Review for gene: PSMG2 was set to RED
Added comment: There is limited evidence supporting the causal role of PSMG2 in brain calcification.
PMID 30664889 reports a patient with heterozygous PSMG2 variants (c.666_667delGT, p.Y223Sfs*2 and c.675 T>G, p.N225K) who had bilateral basal ganglia calcifications.
Sources: Expert list
Brain Calcification v1.51 PLXNA1 Yetong Chen gene: PLXNA1 was added
gene: PLXNA1 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: PLXNA1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PLXNA1 were set to 34054129
Phenotypes for gene: PLXNA1 were set to Dworschak-Punetha neurodevelopmental syndrome, MIM# 619955
Review for gene: PLXNA1 was set to RED
Added comment: There is limited evidence supporting the causal role of the PLXNA1 gene in brain calcification.
PMID 34054129 reports a patient (H:II-1) with a PLXNA1 variant (c.5242C>T) who developed basal ganglia calcifications.
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.5208 RFX7 Zornitza Stark Phenotypes for gene: RFX7 were changed from ID, ASD, ADHD to Intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalities, MIM# 620330
Mendeliome v1.818 RFX7 Zornitza Stark Phenotypes for gene: RFX7 were changed from ID, ASD, ADHD to Intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalities, MIM# 620330
Mendeliome v1.817 RFX7 Zornitza Stark edited their review of gene: RFX7: Changed phenotypes: Intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalities, MIM# 620330
Intellectual disability syndromic and non-syndromic v0.5207 MED11 Zornitza Stark Phenotypes for gene: MED11 were changed from neurodevelopmental disorder MONDO#0700092, MED11-related to Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, MIM# 620327
Intellectual disability syndromic and non-syndromic v0.5206 MED11 Zornitza Stark reviewed gene: MED11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, MIM# 620327; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.103 MED11 Zornitza Stark Phenotypes for gene: MED11 were changed from neurodevelopmental disorder MONDO#0700092, MED11-related to Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, MIM# 620327
Genetic Epilepsy v0.1841 MED11 Zornitza Stark Phenotypes for gene: MED11 were changed from neurodevelopmental disorder MONDO#0700092, MED11-related to Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, MIM# 620327
Genetic Epilepsy v0.1840 MED11 Zornitza Stark reviewed gene: MED11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, MIM# 620327; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.817 MED11 Zornitza Stark Phenotypes for gene: MED11 were changed from neurodevelopmental disorder MONDO#0700092, MED11-related to Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, MIM# 620327
Mendeliome v1.816 MED11 Zornitza Stark reviewed gene: MED11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, MIM# 620327; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v0.398 MED11 Zornitza Stark Phenotypes for gene: MED11 were changed from neurodevelopmental disorder MONDO#0700092, MED11-related to Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, MIM# 620327
Arthrogryposis v0.397 MED11 Zornitza Stark reviewed gene: MED11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, MIM# 620327; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.816 MARS Zornitza Stark Phenotypes for gene: MARS were changed from Interstitial lung and liver disease, MIM#615486; Charcot-Marie-Tooth disease, axonal, type 2U, MIM# 616280; Trichothiodystrophy 9, nonphotosensitive, MIM# 619692 to Interstitial lung and liver disease, MIM#615486; Charcot-Marie-Tooth disease, axonal, type 2U, MIM# 616280; Trichothiodystrophy 9, nonphotosensitive, MIM# 619692; Spastic paraplegia 70, autosomal recessive, MIM# 620323
Mendeliome v1.815 MARS Zornitza Stark Publications for gene: MARS were set to 23729695; 24354524; 29655802; 24103465; 25913036; 33909043
Mendeliome v1.814 MARS Zornitza Stark edited their review of gene: MARS: Added comment: Six individuals from two unrelated families reported with SPG.; Changed publications: 23729695, 24354524, 29655802, 24103465, 25913036, 24482476, 34585293; Changed phenotypes: Interstitial lung and liver disease, MIM#615486, Charcot-Marie-Tooth disease, axonal, type 2U, MIM# 616280, Spastic paraplegia 70, autosomal recessive, MIM# 620323
Hereditary Spastic Paraplegia v1.61 MARS Zornitza Stark Phenotypes for gene: MARS were changed from Complicated hereditary spastic paraplegia; Charcot-Marie-Tooth disease, axonal, type 2U, MIM# 616280 to Spastic paraplegia 70, autosomal recessive, MIM# 620323
Hereditary Spastic Paraplegia v1.60 MARS Zornitza Stark Publications for gene: MARS were set to 24482476
Hereditary Spastic Paraplegia v1.59 MARS Zornitza Stark Classified gene: MARS as Amber List (moderate evidence)
Hereditary Spastic Paraplegia v1.59 MARS Zornitza Stark Gene: mars has been classified as Amber List (Moderate Evidence).
Hereditary Spastic Paraplegia v1.58 MARS Zornitza Stark reviewed gene: MARS: Rating: AMBER; Mode of pathogenicity: None; Publications: 34585293; Phenotypes: Spastic paraplegia 70, autosomal recessive, MIM# 620323; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Leukodystrophy v0.286 WARS Zornitza Stark Phenotypes for gene: WARS were changed from Neurodevelopmental disorder (MONDO:0700092), WARS-related to Neurodevelopmental disorder withmicrocephaly and speech delay, with or without brain abnormalities,MIM# 620317
Leukodystrophy v0.285 WARS Zornitza Stark reviewed gene: WARS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder withmicrocephaly and speech delay, with or without brain abnormalities,MIM# 620317; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5206 WARS Zornitza Stark Phenotypes for gene: WARS were changed from Neurodevelopmental disorder (MONDO:0700092), WARS-related to Neurodevelopmental disorder withmicrocephaly and speech delay, with or without brain abnormalities,MIM# 620317
Intellectual disability syndromic and non-syndromic v0.5205 WARS Zornitza Stark reviewed gene: WARS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder withmicrocephaly and speech delay, with or without brain abnormalities,MIM# 620317; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Microcephaly v1.203 WARS Zornitza Stark Phenotypes for gene: WARS were changed from Neurodevelopmental disorder (MONDO:0700092), WARS-related to Neurodevelopmental disorder withmicrocephaly and speech delay, with or without brain abnormalities,MIM# 620317
Microcephaly v1.202 WARS Zornitza Stark reviewed gene: WARS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder withmicrocephaly and speech delay, with or without brain abnormalities,MIM# 620317; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.814 WARS Zornitza Stark Phenotypes for gene: WARS were changed from Neuronopathy, distal hereditary motor, type IX (OMIM:617721); juvenile to adult onset (15-23 years); Neurodevelopmental disorder (MONDO:0700092), WARS-related to Neuronopathy, distal hereditary motor, type IX (OMIM:617721); juvenile to adult onset (15-23 years); Neurodevelopmental disorder withmicrocephaly and speech delay, with or without brain abnormalities, MIM# 620317
Cone-rod Dystrophy v0.50 UNC119 Zornitza Stark Phenotypes for gene: UNC119 were changed from Cone-rod dystrophy, MONDO:0015993 to Cone-rod dystrophy 24, MIM# 620342
Cone-rod Dystrophy v0.49 UNC119 Zornitza Stark reviewed gene: UNC119: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cone-rod dystrophy 24, MIM# 620342; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.813 UNC119 Zornitza Stark Phenotypes for gene: UNC119 were changed from Cone-rod dystrophy, MONDO:0015993; Immunodeficiency 13 MIM#615518 to Cone-rod dystrophy 24, MIM# 620342; Immunodeficiency 13 MIM#615518
Mendeliome v1.812 UNC119 Zornitza Stark edited their review of gene: UNC119: Changed phenotypes: Cone-rod dystrophy 24, MIM# 620342, Immunodeficiency 13 MIM#615518
Brain Calcification v1.51 PDGFRB Yetong Chen reviewed gene: PDGFRB: Rating: ; Mode of pathogenicity: None; Publications: 29955172, 23255827; Phenotypes: Basal ganglia calcification, idiopathic, 4, MIM# 615007; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Brain Calcification v1.51 PDGFB Yetong Chen reviewed gene: PDGFB: Rating: GREEN; Mode of pathogenicity: None; Publications: 27433546, 35747618, 25211641, 29955172, 31267306, 28162874; Phenotypes: Basal ganglia calcification, idiopathic, 5, MIM# 615483; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Brain Calcification v1.51 PCDH12 Yetong Chen gene: PCDH12 was added
gene: PCDH12 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: PCDH12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCDH12 were set to 28804758; 34773825; 30178464
Phenotypes for gene: PCDH12 were set to Diencephalic-mesencephalic junction dysplasia syndrome 1, MIM# 251280
Review for gene: PCDH12 was set to GREEN
Added comment: PMID 28804758 reports a patient with a homozygous PCDH12 nonsense variant who developed brain calcification. The authors also screen the PCDH12 gene in 79 patients with unknown causes of brain calcification and detected 4 rare PCDH12 variants in 4 unrelated patients. This finding confirms the association between PCDH12 and brain calcification, supported by very low frequencies in the ExAC database, functional studies of the variants, studies of patient cells, and segregation studies.
PMID 34773825 reports a patient with a homozygous truncating variant (c.1176G>A; p.Trp392*) in PCDH12 who developed brain calcification.
PMID 30178464 described 14 affected individuals from 8 families who carried PCDH12 variants. The authors report 6 patients with PCDH12 variants who developed subtle brain calcifications; however, the relationship between these patients is unclear and the results of CT studies of these 6 patients are not shown in the article.
Sources: Expert list
Brain Calcification v1.51 PANK2 Yetong Chen gene: PANK2 was added
gene: PANK2 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: PANK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PANK2 were set to 23968566; 29642163; 28024710
Phenotypes for gene: PANK2 were set to Neurodegeneration with brain iron accumulation 1, MIM# 234200
Review for gene: PANK2 was set to RED
Added comment: The 3 cases were reported within 5 years (2013-2018); however, no more new cases are reported after 2018. Hence, limited evidence supports the causal role of the MOCS1 gene in brain calcification.
PMID 23968566 reports a patient with heterozygous PANK2 variants (p.G521R and p.T528M) who exhibited basal ganglia calcifications.
PMID 29642163 reports a patient with heterozygous PANK2 variants (p.D217G and p.D447E) who developed basal ganglia calcifications.
PMID 28024710 reports a patient with 2 homozygous PANK2 variants (p.Asp403Val) who developed bilateral calcification of globus pallidus.
Sources: Expert list
Brain Calcification v1.51 MT-ATP6 Yetong Chen gene: MT-ATP6 was added
gene: MT-ATP6 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene gene: MT-ATP6 was set to MITOCHONDRIAL
Publications for gene: MT-ATP6 were set to 32042910; 29929013
Phenotypes for gene: MT-ATP6 were set to Leigh syndrome, MIM# 256000
Review for gene: MT-ATP6 was set to RED
Added comment: Limited evidence supports the causal role of the MT-ATP6 gene in brain calcification.
PMID 32042910 reports a patient (patient P2) with the m.8782G>A: p.(Gly86*) variant in MT-ATP6 who developed basal ganglia calcification.
PMID PMID: 29929013 reports a patient with the m.8936T > A variant in MT-ATP6 who developed brain calcification.
Sources: Expert list
Brain Calcification v1.51 MOCS1 Yetong Chen gene: MOCS1 was added
gene: MOCS1 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: MOCS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MOCS1 were set to 27289259
Phenotypes for gene: MOCS1 were set to Molybdenum cofactor deficiency A, MIM# 252150
Review for gene: MOCS1 was set to RED
Added comment: Limited evidence supports the causal role of the MOCS1 gene in brain calcification.
PMID reports 2 patients (patients 1 and 5) with different homozygous MOCS1 variants (c.253C > T (p.Q85*) and c.722_722delT (p.L241Rfs*6)) who developed brain calcification.
Sources: Expert list
Brain Calcification v1.51 JAM2 Yetong Chen reviewed gene: JAM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32142645; Phenotypes: Basal ganglia calcification, idiopathic, 8, autosomal recessive, MIM# 618824; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.51 ISG15 Yetong Chen gene: ISG15 was added
gene: ISG15 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: ISG15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ISG15 were set to 25307056; 32944031
Phenotypes for gene: ISG15 were set to Immunodeficiency 38 with BG calcification, MIM# 616126
Review for gene: ISG15 was set to GREEN
Added comment: Brain calcification is consistently observed in patients with biallelic pathogenic variants in ISG15.
PMID 25307056 reports 5 patients (patients P1-3, P5 and P6) from 3 unrelated families who had ISG15 variants and developed brain calcification. In this paper, patient P4 was from the same family as patients P5 and P6; however, P4 only had inferred genotype so she is not counted here.
PMID 32944031 reports a patient with compound heterozygous ISG15 variants who developed brain calcification.
Sources: Expert list
Mendeliome v1.812 DNAJB4 Zornitza Stark Phenotypes for gene: DNAJB4 were changed from Congenital myopathy 21 with early respiratory failure, MIM# 620326 to Congenital myopathy 21 with early respiratory failure, MIM# 620326; distal myopathy MONDO:0018949
Mendeliome v1.811 DNAJB4 Zornitza Stark Publications for gene: DNAJB4 were set to PMID: 36264506
Mendeliome v1.810 DNAJB4 Zornitza Stark Mode of inheritance for gene: DNAJB4 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.809 DNAJB4 Zornitza Stark Phenotypes for gene: DNAJB4 were changed from Myopathy, MONDO:0005336, DNAJB4-related to Congenital myopathy 21 with early respiratory failure, MIM# 620326
Mendeliome v1.808 DNAJB4 Zornitza Stark reviewed gene: DNAJB4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital myopathy 21 with early respiratory failure, MIM# 620326; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.51 IFIH1 Yetong Chen reviewed gene: IFIH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301648, 31898846, 29782060; Phenotypes: Aicardi-Goutieres syndrome 7, MIM# 615846; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.230 VAPB Sangavi Sivagnanasundram reviewed gene: VAPB: Rating: AMBER; Mode of pathogenicity: None; Publications: 18322265, 15372378, 23771029; Phenotypes: Amyotrophic lateral sclerosis 8 (MONDO:0012077, MIM 608627); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Incidentalome v0.230 VCP Sangavi Sivagnanasundram reviewed gene: VCP: Rating: GREEN; Mode of pathogenicity: None; Publications: 21145000, 33004675; Phenotypes: Frontotemporal dementia and/or Amyotrophic lateral sclerosis 6 (MONDO:0013501, MIM 613954), Inclusion body myopathy with early-onset Paget Disease and FTD [IBMPFD] (MONDO:0000507MIM 167320); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.145 POMGNT1 Bryony Thompson Marked gene: POMGNT1 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.145 POMGNT1 Bryony Thompson Gene: pomgnt1 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.145 POMGNT1 Bryony Thompson Phenotypes for gene: POMGNT1 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type to Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8 MIM#618135
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.144 POMGNT1 Bryony Thompson Publications for gene: POMGNT1 were set to
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.143 PLEC Bryony Thompson Marked gene: PLEC as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.143 PLEC Bryony Thompson Gene: plec has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.143 PLEC Bryony Thompson Publications for gene: PLEC were set to
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.142 LAMA2 Bryony Thompson Marked gene: LAMA2 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.142 LAMA2 Bryony Thompson Gene: lama2 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.142 LAMA2 Bryony Thompson Phenotypes for gene: LAMA2 were changed from Muscular dystrophy, congenital, merosin deficient or partially deficient, 607855 to Muscular dystrophy, congenital, merosin deficient or partially deficient, MIM# 607855; Muscular dystrophy, limb-girdle, autosomal recessive 23, MIM# 618138
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.141 LAMA2 Bryony Thompson Publications for gene: LAMA2 were set to
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.140 GMPPB Bryony Thompson Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type to Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 615352
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.139 FKTN Bryony Thompson Marked gene: FKTN as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.139 FKTN Bryony Thompson Gene: fktn has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.139 FKTN Bryony Thompson Publications for gene: FKTN were set to
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.138 FKRP Bryony Thompson Marked gene: FKRP as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.138 FKRP Bryony Thompson Gene: fkrp has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.138 FKRP Bryony Thompson Publications for gene: FKRP were set to
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.137 FHL1 Bryony Thompson Marked gene: FHL1 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.137 FHL1 Bryony Thompson Gene: fhl1 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.137 FHL1 Bryony Thompson Phenotypes for gene: FHL1 were changed from Emery-Dreifuss muscular dystrophy to Reducing body myopathy MONDO:0019948; X-linked Emery-Dreifuss muscular dystrophy MONDO:0010680
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.136 FHL1 Bryony Thompson Publications for gene: FHL1 were set to
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.135 EMD Bryony Thompson Marked gene: EMD as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.135 EMD Bryony Thompson Gene: emd has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.135 EMD Bryony Thompson Publications for gene: EMD were set to
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.134 DPM3 Bryony Thompson Marked gene: DPM3 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.134 DPM3 Bryony Thompson Gene: dpm3 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.134 DOK7 Bryony Thompson Marked gene: DOK7 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.134 DOK7 Bryony Thompson Gene: dok7 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.134 DOK7 Bryony Thompson Publications for gene: DOK7 were set to PMID: 31453852; 32360404
Motor Neurone Disease v0.138 GLT8D1 Sarah Leigh reviewed gene: GLT8D1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30811981, 35525134:33581933:31653410:33714647:34746377; Phenotypes: familial amyotrophic lateral sclerosis, MONDO:0005144; Mode of inheritance: None
Eye Anterior Segment Abnormalities v1.5 ASPH Chirag Patel Classified gene: ASPH as Green List (high evidence)
Eye Anterior Segment Abnormalities v1.5 ASPH Chirag Patel Gene: asph has been classified as Green List (High Evidence).
Eye Anterior Segment Abnormalities v1.4 ASPH Chirag Patel gene: ASPH was added
gene: ASPH was added to Eye Anterior Segment Abnormalities. Sources: Literature
Mode of inheritance for gene: ASPH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASPH were set to PMID: 24768550, 30194805, 34018898, 35918038
Phenotypes for gene: ASPH were set to Traboulsi syndrome , MIM#601552
Added comment: Traboulsi syndrome, otherwise known as facial dysmorphism, lens dislocation, anterior-segment abnormalities and spontaneous filtering blebs, is an autosomal recessive condition associated with characteristic ocular features including dislocated crystalline lenses, anterior segment abnormalities and in some individuals, non-traumatic conjunctival cysts. There is a distinctive facial appearance which includes flattened malar region with convex nasal ridge. Alterations in the aspartate beta-hydroxylase (ASPH) gene are known to be the cause of the condition. Numerous families reported.
Sources: Literature
Multiple pterygium syndrome_Fetal akinesia sequence v1.3 KIF21A Chirag Patel Classified gene: KIF21A as Amber List (moderate evidence)
Multiple pterygium syndrome_Fetal akinesia sequence v1.3 KIF21A Chirag Patel Gene: kif21a has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.397 KIF21A Chirag Patel Classified gene: KIF21A as Amber List (moderate evidence)
Arthrogryposis v0.397 KIF21A Chirag Patel Gene: kif21a has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.102 KIF21A Chirag Patel Classified gene: KIF21A as Amber List (moderate evidence)
Fetal anomalies v1.102 KIF21A Chirag Patel Gene: kif21a has been classified as Amber List (Moderate Evidence).
Multiple pterygium syndrome_Fetal akinesia sequence v1.2 KIF21A Chirag Patel gene: KIF21A was added
gene: KIF21A was added to Multiple pterygium syndrome_Fetal akinesia sequence. Sources: Literature
Mode of inheritance for gene: KIF21A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF21A were set to PMID: 34740919
Phenotypes for gene: KIF21A were set to Severe fetal akinesia with arthrogryposis multiplex
Review for gene: KIF21A was set to AMBER
Added comment: 2 unrelated consanguineous Turkish families with 5 affected fetuses with severe fetal akinesia with arthrogryposis multiplex. WES identified different homozygous LOF variants in KIF21A gene (p.Leu449* and p.Arg791Glufs*8). Parents and a healthy sibling were heterozygous carriers. No functional studies.
Sources: Literature
Arthrogryposis v0.396 KIF21A Chirag Patel gene: KIF21A was added
gene: KIF21A was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: KIF21A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF21A were set to PMID: 34740919
Phenotypes for gene: KIF21A were set to Severe fetal akinesia with arthrogryposis multiplex
Review for gene: KIF21A was set to AMBER
Added comment: 2 unrelated consanguineous Turkish families with 5 affected fetuses with severe fetal akinesia with arthrogryposis multiplex. WES identified different homozygous LOF variants in KIF21A gene (p.Leu449* and p.Arg791Glufs*8). Parents and a healthy sibling were heterozygous carriers. No functional studies.
Sources: Literature
Fetal anomalies v1.101 KIF21A Chirag Patel gene: KIF21A was added
gene: KIF21A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: KIF21A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF21A were set to PMID: 34740919
Phenotypes for gene: KIF21A were set to Severe fetal akinesia with arthrogryposis multiplex
Review for gene: KIF21A was set to AMBER
Added comment: 2 unrelated consanguineous Turkish families with 5 affected fetuses with severe fetal akinesia with arthrogryposis multiplex. WES identified different homozygous LOF variants in KIF21A gene (p.Leu449* and p.Arg791Glufs*8). Parents and a healthy sibling were heterozygous carriers. No functional studies.
Sources: Literature
Anophthalmia_Microphthalmia_Coloboma v1.32 WNT7B Chirag Patel Classified gene: WNT7B as Green List (high evidence)
Anophthalmia_Microphthalmia_Coloboma v1.32 WNT7B Chirag Patel Gene: wnt7b has been classified as Green List (High Evidence).
Anophthalmia_Microphthalmia_Coloboma v1.31 WNT7B Chirag Patel reviewed gene: WNT7B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35790350; Phenotypes: Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia and Cardiac defects syndrome, Multiple congenital anomalies/dysmorphic features syndrome MONDO:0043005, WNT7B-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.808 C16orf62 Chirag Patel Classified gene: C16orf62 as Green List (high evidence)
Mendeliome v1.808 C16orf62 Chirag Patel Gene: c16orf62 has been classified as Green List (High Evidence).
Mendeliome v1.808 C16orf62 Chirag Patel Classified gene: C16orf62 as Green List (high evidence)
Mendeliome v1.808 C16orf62 Chirag Patel Gene: c16orf62 has been classified as Green List (High Evidence).
Mendeliome v1.807 C16orf62 Chirag Patel reviewed gene: C16orf62: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36113987; Phenotypes: Ritscher-Schinzel syndrome-3 (RTSC3), MIM#619135; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5205 C16orf62 Chirag Patel Classified gene: C16orf62 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5205 C16orf62 Chirag Patel Gene: c16orf62 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5204 C16orf62 Chirag Patel reviewed gene: C16orf62: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36113987; Phenotypes: Ritscher-Schinzel syndrome-3 (RTSC3), MIM#619135; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.100 C16orf62 Chirag Patel Classified gene: C16orf62 as Green List (high evidence)
Fetal anomalies v1.100 C16orf62 Chirag Patel Gene: c16orf62 has been classified as Green List (High Evidence).
Fetal anomalies v1.99 C16orf62 Chirag Patel reviewed gene: C16orf62: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36113987; Phenotypes: Ritscher-Schinzel syndrome-3 (RTSC3), MIM#619135; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.51 GNAS Yetong Chen gene: GNAS was added
gene: GNAS was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: GNAS was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: GNAS were set to 28296742; 35600030; 20444925
Phenotypes for gene: GNAS were set to Pseudohypoparathyroidism Ib, MIM# 603233
Review for gene: GNAS was set to GREEN
Added comment: The imprinting of GNAS is complex. While GNAS is primarily expressed from the maternal allele, only the paternal allele is expressed in some tissues.
Although the number of cases is limited, patients are reported by different authors across the years.
PMID 28296742 reports 2 patients from the same family, who had the same GNAS variant (p.P115S, p.V340M), and developed brain calcification.
PMID 35600030 reports a patient with a rare GNAS variant who developed bilateral basal ganglia calcification.
PMID 20444925 reports 2 patients from the same family who developed brain calcification. The patients had broad epigenetic defects at the GNAS gene and a deletion that exclusively affects exons encoding the antisense transcript (delAS3-4). The deletion is suspected to partially influence the imprinting of some GNAS loci.
Sources: Expert list
Brain Calcification v1.51 GNA11 Yetong Chen gene: GNA11 was added
gene: GNA11 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: GNA11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GNA11 were set to 27334330
Phenotypes for gene: GNA11 were set to Hypocalcemia, autosomal dominant 2, MIM# 615361
Review for gene: GNA11 was set to RED
Added comment: PMID 27334330 reports 4 patients with the same GNA11 variant (c.1018G>A), who are from the same family, developed intracranial calcifications.
Sources: Expert list
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.132 ANXA11 Bryony Thompson Marked gene: ANXA11 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.132 ANXA11 Bryony Thompson Gene: anxa11 has been classified as Amber List (Moderate Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.132 ANXA11 Bryony Thompson Classified gene: ANXA11 as Amber List (moderate evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.132 ANXA11 Bryony Thompson Gene: anxa11 has been classified as Amber List (Moderate Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.131 BICD2 Bryony Thompson Marked gene: BICD2 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.131 BICD2 Bryony Thompson Gene: bicd2 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.131 BICD2 Bryony Thompson Classified gene: BICD2 as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.131 BICD2 Bryony Thompson Gene: bicd2 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.130 GFPT1 Bryony Thompson Marked gene: GFPT1 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.130 GFPT1 Bryony Thompson Gene: gfpt1 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.130 GFPT1 Bryony Thompson Classified gene: GFPT1 as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.130 GFPT1 Bryony Thompson Gene: gfpt1 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.129 HNRNPA1 Bryony Thompson Marked gene: HNRNPA1 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.129 HNRNPA1 Bryony Thompson Gene: hnrnpa1 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.129 HNRNPA1 Bryony Thompson Classified gene: HNRNPA1 as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.129 HNRNPA1 Bryony Thompson Gene: hnrnpa1 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.128 HNRNPA2B1 Bryony Thompson Marked gene: HNRNPA2B1 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.128 HNRNPA2B1 Bryony Thompson Gene: hnrnpa2b1 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.128 HNRNPA2B1 Bryony Thompson Classified gene: HNRNPA2B1 as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.128 HNRNPA2B1 Bryony Thompson Gene: hnrnpa2b1 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.127 LDB3 Bryony Thompson Marked gene: LDB3 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.127 LDB3 Bryony Thompson Gene: ldb3 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.127 LDB3 Bryony Thompson Classified gene: LDB3 as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.127 LDB3 Bryony Thompson Gene: ldb3 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.126 PABPN1 Bryony Thompson Marked gene: PABPN1 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.126 PABPN1 Bryony Thompson Gene: pabpn1 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.126 PABPN1 Bryony Thompson Classified gene: PABPN1 as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.126 PABPN1 Bryony Thompson Gene: pabpn1 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.125 SMPX Bryony Thompson Marked gene: SMPX as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.125 SMPX Bryony Thompson Gene: smpx has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.125 SMPX Bryony Thompson Classified gene: SMPX as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.125 SMPX Bryony Thompson Gene: smpx has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.124 SQSTM1 Bryony Thompson Marked gene: SQSTM1 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.124 SQSTM1 Bryony Thompson Gene: sqstm1 has been classified as Amber List (Moderate Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.124 SQSTM1 Bryony Thompson Classified gene: SQSTM1 as Amber List (moderate evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.124 SQSTM1 Bryony Thompson Gene: sqstm1 has been classified as Amber List (Moderate Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.123 TIA1 Bryony Thompson Marked gene: TIA1 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.123 TIA1 Bryony Thompson Gene: tia1 has been classified as Amber List (Moderate Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.123 TIA1 Bryony Thompson Publications for gene: TIA1 were set to 23401021; 23401021
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.122 TIA1 Bryony Thompson Classified gene: TIA1 as Amber List (moderate evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.122 TIA1 Bryony Thompson Gene: tia1 has been classified as Amber List (Moderate Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.121 TMEM43 Bryony Thompson Marked gene: TMEM43 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.121 TMEM43 Bryony Thompson Gene: tmem43 has been classified as Amber List (Moderate Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.121 TMEM43 Bryony Thompson Classified gene: TMEM43 as Amber List (moderate evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.121 TMEM43 Bryony Thompson Gene: tmem43 has been classified as Amber List (Moderate Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.120 DMD Bryony Thompson Marked gene: DMD as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.120 DMD Bryony Thompson Gene: dmd has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.120 DMD Bryony Thompson Publications for gene: DMD were set to
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.119 DAG1 Bryony Thompson Marked gene: DAG1 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.119 DAG1 Bryony Thompson Gene: dag1 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.119 DAG1 Bryony Thompson Publications for gene: DAG1 were set to
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.118 COL6A3 Bryony Thompson Marked gene: COL6A3 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.118 COL6A3 Bryony Thompson Gene: col6a3 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.118 COL6A3 Bryony Thompson Phenotypes for gene: COL6A3 were changed from Bethlem myopathy 1 158810 to Bethlem myopathy 1 MIM#158810; Ullrich congenital muscular dystrophy 1 MIM#254090
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.117 COL6A3 Bryony Thompson Publications for gene: COL6A3 were set to
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.116 COL6A3 Bryony Thompson Mode of inheritance for gene: COL6A3 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Severe Combined Immunodeficiency v1.1 POLD3 Peter McNaughton gene: POLD3 was added
gene: POLD3 was added to Severe Combined Immunodeficiency (absent T present B cells). Sources: Literature
Mode of inheritance for gene: POLD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLD3 were set to PMID: 37030525
Phenotypes for gene: POLD3 were set to Severe combined immunodeficiency
Review for gene: POLD3 was set to AMBER
Added comment: Homozygous mutation in POLD3 (NM_006591.3: c.29T>C; p.Ile10Thr) in the offspring of a consanguineous Lebanese family with syndromic T -B +NK- SCID, including neurodevelopmental delay and profound hearing loss.
Sources: Literature
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.115 COL6A2 Bryony Thompson Marked gene: COL6A2 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.115 COL6A2 Bryony Thompson Gene: col6a2 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.115 COL6A2 Bryony Thompson Phenotypes for gene: COL6A2 were changed from Bethlem myopathy 1 158810 to Bethlem myopathy 1 MIM#158810; Ullrich congenital muscular dystrophy 1 MIM#254090
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.114 COL6A2 Bryony Thompson Publications for gene: COL6A2 were set to
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.113 COL6A2 Bryony Thompson Mode of inheritance for gene: COL6A2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.112 COL6A1 Bryony Thompson Marked gene: COL6A1 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.112 COL6A1 Bryony Thompson Gene: col6a1 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.112 COL6A1 Bryony Thompson Phenotypes for gene: COL6A1 were changed from Bethlem myopathy 1 158810 to Bethlem myopathy MIM#158810; Ullrich congenital muscular dystrophy MIM#254090
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.111 COL6A1 Bryony Thompson Mode of inheritance for gene: COL6A1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.110 COL6A1 Bryony Thompson Publications for gene: COL6A1 were set to
Rhabdomyolysis and Metabolic Myopathy v0.167 DGUOK Bryony Thompson Classified gene: DGUOK as Green List (high evidence)
Rhabdomyolysis and Metabolic Myopathy v0.167 DGUOK Bryony Thompson Gene: dguok has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.166 DGUOK Bryony Thompson Phenotypes for gene: DGUOK were changed from Rhabdomyolisis; lower limb weakness to Mitochondrial DNA depletion syndrome 3 (hepatocerebral type), MIM# 251880; Portal hypertension, noncirrhotic, 1, MIM# 617068; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4, MIM# 617070
Rhabdomyolysis and Metabolic Myopathy v0.165 DGUOK Bryony Thompson Publications for gene: DGUOK were set to 23043144
Rhabdomyolysis and Metabolic Myopathy v0.164 SUCLA2 Bryony Thompson Publications for gene: SUCLA2 were set to
Rhabdomyolysis and Metabolic Myopathy v0.163 SUCLA2 Bryony Thompson Deleted their review
Rhabdomyolysis and Metabolic Myopathy v0.163 SUCLA2 Bryony Thompson commented on gene: SUCLA2
Rhabdomyolysis and Metabolic Myopathy v0.163 SUCLA2 Bryony Thompson Deleted their review
Rhabdomyolysis and Metabolic Myopathy v0.163 SUCLA2 Bryony Thompson Classified gene: SUCLA2 as Green List (high evidence)
Rhabdomyolysis and Metabolic Myopathy v0.163 SUCLA2 Bryony Thompson Gene: sucla2 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.162 SUCLA2 Bryony Thompson Deleted their comment
Rhabdomyolysis and Metabolic Myopathy v0.162 SLC25A20 Bryony Thompson Deleted their review
Rhabdomyolysis and Metabolic Myopathy v0.162 SLC25A20 Bryony Thompson commented on gene: SLC25A20
Rhabdomyolysis and Metabolic Myopathy v0.162 SLC25A20 Bryony Thompson Classified gene: SLC25A20 as Green List (high evidence)
Rhabdomyolysis and Metabolic Myopathy v0.162 SLC25A20 Bryony Thompson Gene: slc25a20 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.161 SLC25A20 Bryony Thompson Deleted their review
Rhabdomyolysis and Metabolic Myopathy v0.161 SLC25A20 Bryony Thompson Deleted their comment
Rhabdomyolysis and Metabolic Myopathy v0.161 PUS1 Bryony Thompson Marked gene: PUS1 as ready
Rhabdomyolysis and Metabolic Myopathy v0.161 PUS1 Bryony Thompson Gene: pus1 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.161 PUS1 Bryony Thompson Classified gene: PUS1 as Green List (high evidence)
Rhabdomyolysis and Metabolic Myopathy v0.161 PUS1 Bryony Thompson Gene: pus1 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.160 OPA1 Bryony Thompson Marked gene: OPA1 as ready
Rhabdomyolysis and Metabolic Myopathy v0.160 OPA1 Bryony Thompson Gene: opa1 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.160 OPA1 Bryony Thompson Classified gene: OPA1 as Green List (high evidence)
Rhabdomyolysis and Metabolic Myopathy v0.160 OPA1 Bryony Thompson Gene: opa1 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.159 MGME1 Bryony Thompson Marked gene: MGME1 as ready
Rhabdomyolysis and Metabolic Myopathy v0.159 MGME1 Bryony Thompson Gene: mgme1 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.159 MGME1 Bryony Thompson Classified gene: MGME1 as Green List (high evidence)
Rhabdomyolysis and Metabolic Myopathy v0.159 MGME1 Bryony Thompson Gene: mgme1 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.158 FLAD1 Bryony Thompson Marked gene: FLAD1 as ready
Rhabdomyolysis and Metabolic Myopathy v0.158 FLAD1 Bryony Thompson Gene: flad1 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.158 FLAD1 Bryony Thompson Classified gene: FLAD1 as Green List (high evidence)
Rhabdomyolysis and Metabolic Myopathy v0.158 FLAD1 Bryony Thompson Gene: flad1 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.157 SLC22A5 Bryony Thompson Marked gene: SLC22A5 as ready
Rhabdomyolysis and Metabolic Myopathy v0.157 SLC22A5 Bryony Thompson Gene: slc22a5 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.157 SLC22A5 Bryony Thompson Publications for gene: SLC22A5 were set to
Rhabdomyolysis and Metabolic Myopathy v0.156 RYR1 Bryony Thompson Marked gene: RYR1 as ready
Rhabdomyolysis and Metabolic Myopathy v0.156 RYR1 Bryony Thompson Gene: ryr1 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.156 RYR1 Bryony Thompson Publications for gene: RYR1 were set to
Rhabdomyolysis and Metabolic Myopathy v0.155 RRM2B Bryony Thompson Marked gene: RRM2B as ready
Rhabdomyolysis and Metabolic Myopathy v0.155 RRM2B Bryony Thompson Gene: rrm2b has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.155 RRM2B Bryony Thompson Publications for gene: RRM2B were set to
Rhabdomyolysis and Metabolic Myopathy v0.154 RBCK1 Bryony Thompson Marked gene: RBCK1 as ready
Rhabdomyolysis and Metabolic Myopathy v0.154 RBCK1 Bryony Thompson Gene: rbck1 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.154 RBCK1 Bryony Thompson Publications for gene: RBCK1 were set to
Rhabdomyolysis and Metabolic Myopathy v0.153 PYGM Bryony Thompson Marked gene: PYGM as ready
Rhabdomyolysis and Metabolic Myopathy v0.153 PYGM Bryony Thompson Gene: pygm has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.153 PYGM Bryony Thompson Publications for gene: PYGM were set to
Rhabdomyolysis and Metabolic Myopathy v0.152 POLG2 Bryony Thompson Marked gene: POLG2 as ready
Rhabdomyolysis and Metabolic Myopathy v0.152 POLG2 Bryony Thompson Gene: polg2 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.152 POLG2 Bryony Thompson Phenotypes for gene: POLG2 were changed from Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 610131 to Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, MIM# 610131
Rhabdomyolysis and Metabolic Myopathy v0.151 POLG2 Bryony Thompson Publications for gene: POLG2 were set to
Rhabdomyolysis and Metabolic Myopathy v0.150 POLG Bryony Thompson Marked gene: POLG as ready
Rhabdomyolysis and Metabolic Myopathy v0.150 POLG Bryony Thompson Gene: polg has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.150 POLG Bryony Thompson Publications for gene: POLG were set to
Rhabdomyolysis and Metabolic Myopathy v0.149 PHKA1 Bryony Thompson Marked gene: PHKA1 as ready
Rhabdomyolysis and Metabolic Myopathy v0.149 PHKA1 Bryony Thompson Gene: phka1 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.149 PHKA1 Bryony Thompson Phenotypes for gene: PHKA1 were changed from Muscle glycogenosis 300559 to Muscle glycogenosis, MIM# 300559
Rhabdomyolysis and Metabolic Myopathy v0.148 PHKA1 Bryony Thompson Publications for gene: PHKA1 were set to
Rhabdomyolysis and Metabolic Myopathy v0.147 PGK1 Bryony Thompson Marked gene: PGK1 as ready
Rhabdomyolysis and Metabolic Myopathy v0.147 PGK1 Bryony Thompson Gene: pgk1 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.147 PGK1 Bryony Thompson Publications for gene: PGK1 were set to 6933565; 1547346; 7577653; 9512313
Rhabdomyolysis and Metabolic Myopathy v0.146 PGK1 Bryony Thompson Marked gene: PGK1 as ready
Rhabdomyolysis and Metabolic Myopathy v0.146 PGK1 Bryony Thompson Gene: pgk1 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.146 PGK1 Bryony Thompson Publications for gene: PGK1 were set to
Rhabdomyolysis and Metabolic Myopathy v0.145 PGAM2 Bryony Thompson Marked gene: PGAM2 as ready
Rhabdomyolysis and Metabolic Myopathy v0.145 PGAM2 Bryony Thompson Gene: pgam2 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.145 PGAM2 Bryony Thompson Phenotypes for gene: PGAM2 were changed from Glycogen storage disease X 261670 to Glycogen storage disease X, MIM# 261670
Rhabdomyolysis and Metabolic Myopathy v0.144 PGAM2 Bryony Thompson Publications for gene: PGAM2 were set to
Rhabdomyolysis and Metabolic Myopathy v0.143 GBE1 Bryony Thompson Marked gene: GBE1 as ready
Rhabdomyolysis and Metabolic Myopathy v0.143 GBE1 Bryony Thompson Gene: gbe1 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.143 GBE1 Bryony Thompson Phenotypes for gene: GBE1 were changed from Glycogen storage disease IV 232500 to Glycogen storage disease IV, MIM# 232500; Polyglucosan body disease, adult form MIM#263570
Rhabdomyolysis and Metabolic Myopathy v0.142 GBE1 Bryony Thompson Publications for gene: GBE1 were set to 8613547
Rhabdomyolysis and Metabolic Myopathy v0.141 GBE1 Bryony Thompson Publications for gene: GBE1 were set to
Rhabdomyolysis and Metabolic Myopathy v0.140 GAA Bryony Thompson Marked gene: GAA as ready
Rhabdomyolysis and Metabolic Myopathy v0.140 GAA Bryony Thompson Gene: gaa has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.140 GAA Bryony Thompson Phenotypes for gene: GAA were changed from Glycogen storage disease II 232300 to Glycogen storage disease II (MIM#232300)
Rhabdomyolysis and Metabolic Myopathy v0.139 GAA Bryony Thompson Publications for gene: GAA were set to
Rhabdomyolysis and Metabolic Myopathy v0.138 FKRP Bryony Thompson Marked gene: FKRP as ready
Rhabdomyolysis and Metabolic Myopathy v0.138 FKRP Bryony Thompson Gene: fkrp has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.138 FKRP Bryony Thompson Publications for gene: FKRP were set to
Rhabdomyolysis and Metabolic Myopathy v0.137 DYSF Bryony Thompson Marked gene: DYSF as ready
Rhabdomyolysis and Metabolic Myopathy v0.137 DYSF Bryony Thompson Gene: dysf has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.137 DYSF Bryony Thompson Publications for gene: DYSF were set to
Rhabdomyolysis and Metabolic Myopathy v0.136 PFKM Bryony Thompson Marked gene: PFKM as ready
Rhabdomyolysis and Metabolic Myopathy v0.136 PFKM Bryony Thompson Gene: pfkm has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.136 PFKM Bryony Thompson Phenotypes for gene: PFKM were changed from Glycogen storage disease VII 232800 to Glycogen storage disease VII, MIM# 232800
Rhabdomyolysis and Metabolic Myopathy v0.135 PFKM Bryony Thompson Publications for gene: PFKM were set to
Rhabdomyolysis and Metabolic Myopathy v0.134 LDHA Bryony Thompson Marked gene: LDHA as ready
Rhabdomyolysis and Metabolic Myopathy v0.134 LDHA Bryony Thompson Gene: ldha has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.134 LDHA Bryony Thompson Phenotypes for gene: LDHA were changed from Glycogen storage disease XI 612933 to Glycogen storage disease XI, MIM# 612933
Rhabdomyolysis and Metabolic Myopathy v0.133 LDHA Bryony Thompson Publications for gene: LDHA were set to
Rhabdomyolysis and Metabolic Myopathy v0.132 LAMP2 Bryony Thompson Marked gene: LAMP2 as ready
Rhabdomyolysis and Metabolic Myopathy v0.132 LAMP2 Bryony Thompson Gene: lamp2 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.132 LAMP2 Bryony Thompson Phenotypes for gene: LAMP2 were changed from Danon disease 300257 to Danon disease, MIM# 300257; MONDO:0010281
Rhabdomyolysis and Metabolic Myopathy v0.131 ISCU Bryony Thompson Marked gene: ISCU as ready
Rhabdomyolysis and Metabolic Myopathy v0.131 ISCU Bryony Thompson Gene: iscu has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.131 ISCU Bryony Thompson Phenotypes for gene: ISCU were changed from Myopathy with lactic acidosis, hereditary 255125 to Myopathy with lactic acidosis, hereditary, MIM# 255125
Rhabdomyolysis and Metabolic Myopathy v0.130 ISCU Bryony Thompson Publications for gene: ISCU were set to
Rhabdomyolysis and Metabolic Myopathy v0.129 HADHB Bryony Thompson Marked gene: HADHB as ready
Rhabdomyolysis and Metabolic Myopathy v0.129 HADHB Bryony Thompson Gene: hadhb has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.129 HADHB Bryony Thompson Phenotypes for gene: HADHB were changed from Trifunctional protein deficiency 609015 to Trifunctional protein deficiency MIM#609015
Rhabdomyolysis and Metabolic Myopathy v0.128 HADHB Bryony Thompson Publications for gene: HADHB were set to
Rhabdomyolysis and Metabolic Myopathy v0.127 HADHA Bryony Thompson Marked gene: HADHA as ready
Rhabdomyolysis and Metabolic Myopathy v0.127 HADHA Bryony Thompson Gene: hadha has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.127 HADHA Bryony Thompson Phenotypes for gene: HADHA were changed from Trifunctional protein deficiency 609015 to LCHAD deficiency MIM#609016; Trifunctional protein deficiency MIM#609015
Rhabdomyolysis and Metabolic Myopathy v0.126 HADHA Bryony Thompson Publications for gene: HADHA were set to
Rhabdomyolysis and Metabolic Myopathy v0.125 TMEM126B Bryony Thompson Marked gene: TMEM126B as ready
Rhabdomyolysis and Metabolic Myopathy v0.125 TMEM126B Bryony Thompson Gene: tmem126b has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.125 TMEM126B Bryony Thompson Classified gene: TMEM126B as Green List (high evidence)
Rhabdomyolysis and Metabolic Myopathy v0.125 TMEM126B Bryony Thompson Gene: tmem126b has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.124 DMD Bryony Thompson Marked gene: DMD as ready
Rhabdomyolysis and Metabolic Myopathy v0.124 DMD Bryony Thompson Gene: dmd has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.124 DMD Bryony Thompson Publications for gene: DMD were set to
Rhabdomyolysis and Metabolic Myopathy v0.123 DMD Bryony Thompson Classified gene: DMD as Green List (high evidence)
Rhabdomyolysis and Metabolic Myopathy v0.123 DMD Bryony Thompson Added comment: Comment on list classification: The phenotype spectrum includes asymptomatic increase in serum concentration of creatine phosphokinase (CK) and muscle cramps with myoglobinuria.
Rhabdomyolysis and Metabolic Myopathy v0.123 DMD Bryony Thompson Gene: dmd has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.122 DMD Bryony Thompson Mode of inheritance for gene: DMD was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Rhabdomyolysis and Metabolic Myopathy v0.121 CPT2 Bryony Thompson Marked gene: CPT2 as ready
Rhabdomyolysis and Metabolic Myopathy v0.121 CPT2 Bryony Thompson Gene: cpt2 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.121 CPT2 Bryony Thompson edited their review of gene: CPT2: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and Metabolic Myopathy v0.121 CAV3 Bryony Thompson Marked gene: CAV3 as ready
Rhabdomyolysis and Metabolic Myopathy v0.121 CAV3 Bryony Thompson Gene: cav3 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.121 ANO5 Bryony Thompson Marked gene: ANO5 as ready
Rhabdomyolysis and Metabolic Myopathy v0.121 ANO5 Bryony Thompson Gene: ano5 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.121 ANO5 Bryony Thompson Publications for gene: ANO5 were set to
Rhabdomyolysis and Metabolic Myopathy v0.120 ANO5 Bryony Thompson Classified gene: ANO5 as Green List (high evidence)
Rhabdomyolysis and Metabolic Myopathy v0.120 ANO5 Bryony Thompson Added comment: Comment on list classification: The phenotype can range from asymptomatic hyperCKemia and exercise-induced myalgia to proximal and/or distal muscle weakness
Rhabdomyolysis and Metabolic Myopathy v0.120 ANO5 Bryony Thompson Gene: ano5 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.119 CACNA1S Bryony Thompson Marked gene: CACNA1S as ready
Rhabdomyolysis and Metabolic Myopathy v0.119 CACNA1S Bryony Thompson Gene: cacna1s has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.119 CACNA1S Bryony Thompson Classified gene: CACNA1S as Green List (high evidence)
Rhabdomyolysis and Metabolic Myopathy v0.119 CACNA1S Bryony Thompson Added comment: Comment on list classification: Second most common cause of malignant hyperthermia susceptibility after RYR1, but it is still a rare cause.
Rhabdomyolysis and Metabolic Myopathy v0.119 CACNA1S Bryony Thompson Gene: cacna1s has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.118 CACNA1S Bryony Thompson Mode of pathogenicity for gene: CACNA1S was changed from to Other
Rhabdomyolysis and Metabolic Myopathy v0.117 CACNA1S Bryony Thompson Publications for gene: CACNA1S were set to 20301325
Rhabdomyolysis and Metabolic Myopathy v0.116 CACNA1S Bryony Thompson Publications for gene: CACNA1S were set to
Rhabdomyolysis and Metabolic Myopathy v0.115 AGL Bryony Thompson Marked gene: AGL as ready
Rhabdomyolysis and Metabolic Myopathy v0.115 AGL Bryony Thompson Gene: agl has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.115 AGL Bryony Thompson Publications for gene: AGL were set to
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.108 VPS13A Bryony Thompson Marked gene: VPS13A as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.108 VPS13A Bryony Thompson Gene: vps13a has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.108 VPS13A Bryony Thompson Classified gene: VPS13A as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.108 VPS13A Bryony Thompson Gene: vps13a has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.107 VPS13A Bryony Thompson gene: VPS13A was added
gene: VPS13A was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Literature
Mode of inheritance for gene: VPS13A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS13A were set to 33652783; 20301561
Phenotypes for gene: VPS13A were set to chorea-acanthocytosis MONDO:0008695
Review for gene: VPS13A was set to GREEN
gene: VPS13A was marked as current diagnostic
Added comment: Well-established gene-disease association. A feature of the condition can be progressive distal muscle wasting and weakness that can be subclinical (only creatine kinase [CK] elevation). Myopathic changes can be detected on electromyography (as well as chronic denervation).
Sources: Literature
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.106 VMA21 Bryony Thompson Classified gene: VMA21 as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.106 VMA21 Bryony Thompson Gene: vma21 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.105 TMEM43 Bryony Thompson gene: TMEM43 was added
gene: TMEM43 was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Literature
Mode of inheritance for gene: TMEM43 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMEM43 were set to 21391237; 30311943
Phenotypes for gene: TMEM43 were set to Emery-Dreifuss muscular dystrophy 7, autosomal dominant MONDO:0013677
Rhabdomyolysis and Metabolic Myopathy v0.112 TMEM126B Bryony Thompson gene: TMEM126B was added
gene: TMEM126B was added to Rhabdomyolysis and Metabolic Myopathy. Sources: Expert list
Mode of inheritance for gene: TMEM126B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM126B were set to 27374774; 27374773
Phenotypes for gene: TMEM126B were set to mitochondrial complex 1 deficiency, nuclear type 29 MONDO:0032633
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.104 TIA1 Bryony Thompson gene: TIA1 was added
gene: TIA1 was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Literature
Mode of inheritance for gene: TIA1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TIA1 were set to 23401021; 23401021
Phenotypes for gene: TIA1 were set to distal myopathy, Welander type MONDO:0011466
Mode of pathogenicity for gene: TIA1 was set to Other
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.103 STIM1 Bryony Thompson Classified gene: STIM1 as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.103 STIM1 Bryony Thompson Gene: stim1 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.102 PYROXD1 Bryony Thompson Classified gene: PYROXD1 as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.102 PYROXD1 Bryony Thompson Gene: pyroxd1 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.101 SQSTM1 Bryony Thompson gene: SQSTM1 was added
gene: SQSTM1 was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Literature
Mode of inheritance for gene: SQSTM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SQSTM1 were set to 29599744; 26208961; 29457785
Phenotypes for gene: SQSTM1 were set to myopathy, distal, with rimmed vacuoles MONDO:0014945; multisystem proteinopathy
Mode of pathogenicity for gene: SQSTM1 was set to Other
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.100 SMPX Bryony Thompson gene: SMPX was added
gene: SMPX was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Literature
Mode of inheritance for gene: SMPX was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SMPX were set to 33974137
Phenotypes for gene: SMPX were set to Myopathy, distal, 7, adult-onset, X-linked, MIM# 301075
Mode of pathogenicity for gene: SMPX was set to Other
Rhabdomyolysis and Metabolic Myopathy v0.111 PUS1 Bryony Thompson gene: PUS1 was added
gene: PUS1 was added to Rhabdomyolysis and Metabolic Myopathy. Sources: Expert Review
Mode of inheritance for gene: PUS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PUS1 were set to 25227147; 17056637; 15108122; 32287105; 31641589; 28832011
Phenotypes for gene: PUS1 were set to myopathy, lactic acidosis, and sideroblastic anemia 1 MONDO:0024553
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.99 ORAI1 Bryony Thompson Classified gene: ORAI1 as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.99 ORAI1 Bryony Thompson Gene: orai1 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.98 PABPN1 Bryony Thompson gene: PABPN1 was added
gene: PABPN1 was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Other
Mode of inheritance for gene: PABPN1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PABPN1 were set to 19080757; 33805441; 16648376
Phenotypes for gene: PABPN1 were set to oculopharyngeal muscular dystrophy MONDO:0008116
Added comment: Included for overlapping phenotype
Sources: Other
Rhabdomyolysis and Metabolic Myopathy v0.110 OPA1 Bryony Thompson gene: OPA1 was added
gene: OPA1 was added to Rhabdomyolysis and Metabolic Myopathy. Sources: Literature
Mode of inheritance for gene: OPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: OPA1 were set to 30165240; 20301426
Phenotypes for gene: OPA1 were set to optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy MONDO:0007429
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.97 MYOT Bryony Thompson Classified gene: MYOT as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.97 MYOT Bryony Thompson Gene: myot has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.96 MYOT Bryony Thompson Publications for gene: MYOT were set to 30055862; 21336781; 15947064
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.95 MYH7 Bryony Thompson Classified gene: MYH7 as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.95 MYH7 Bryony Thompson Gene: myh7 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.109 MGME1 Bryony Thompson gene: MGME1 was added
gene: MGME1 was added to Rhabdomyolysis and Metabolic Myopathy. Sources: Other
Mode of inheritance for gene: MGME1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MGME1 were set to 23313956; 29572490; 28711739
Phenotypes for gene: MGME1 were set to mitochondrial DNA depletion syndrome 11 MONDO:0014039
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.94 MATR3 Bryony Thompson Marked gene: MATR3 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.94 MATR3 Bryony Thompson Gene: matr3 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.94 MATR3 Bryony Thompson Classified gene: MATR3 as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.94 MATR3 Bryony Thompson Gene: matr3 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.93 MATR3 Bryony Thompson gene: MATR3 was added
gene: MATR3 was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Literature
Mode of inheritance for gene: MATR3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MATR3 were set to 19344878; 34659085; 25154462; 31056746
Phenotypes for gene: MATR3 were set to distal myopathy with vocal cord weakness MONDO:0018951
Mode of pathogenicity for gene: MATR3 was set to Other
Review for gene: MATR3 was set to GREEN
gene: MATR3 was marked as current diagnostic
Added comment: At least 13 families with distal myopathy with vocal cord and pharyngeal weakness reported with the same recurrent missense variant p.Ser85Cys, which has been shown to arise by independent mutational events in multiple populations. A mouse model of the variant recapitulated the multisystem proteinopathy phenotype which includes myopathy. The mechanism of disease is toxic gain of function
Sources: Literature
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.92 LDB3 Bryony Thompson gene: LDB3 was added
gene: LDB3 was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Literature
Mode of inheritance for gene: LDB3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LDB3 were set to 24668811; 27546599; 25911362
Phenotypes for gene: LDB3 were set to myofibrillar myopathy 4 MONDO:0012277
Mode of pathogenicity for gene: LDB3 was set to Other
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.91 HNRNPA2B1 Bryony Thompson gene: HNRNPA2B1 was added
gene: HNRNPA2B1 was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Literature
Mode of inheritance for gene: HNRNPA2B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPA2B1 were set to 23455423; 30279180; 29358076; 26744327; 23635965; 35484142
Phenotypes for gene: HNRNPA2B1 were set to inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 MONDO:0014178; oculopharyngeal muscular dystrophy, MONDO:0008116
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.90 HNRNPA1 Bryony Thompson gene: HNRNPA1 was added
gene: HNRNPA1 was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Literature
Mode of inheritance for gene: HNRNPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPA1 were set to 23455423; 27066560
Phenotypes for gene: HNRNPA1 were set to inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 3 MONDO:0014179
Mode of pathogenicity for gene: HNRNPA1 was set to Other
Added comment: Protein aggregation is expected to be the mechanism of disease. Most individuals with IBMPFD have limb-girdle weakness
Sources: Literature
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.89 GNE Bryony Thompson Publications for gene: GNE were set to 22883483
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.88 GNE Bryony Thompson Classified gene: GNE as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.88 GNE Bryony Thompson Added comment: Comment on list classification: Distal myopathy
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.88 GNE Bryony Thompson Gene: gne has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.87 GFPT1 Bryony Thompson gene: GFPT1 was added
gene: GFPT1 was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Expert list
Mode of inheritance for gene: GFPT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GFPT1 were set to 28712002; 29905857; 31449669
Phenotypes for gene: GFPT1 were set to Myasthenia, congenital, 12, with tubular aggregates MIM#610542; Limb-girdle congenital myasthenic syndrome
Rhabdomyolysis and Metabolic Myopathy v0.108 FLAD1 Bryony Thompson gene: FLAD1 was added
gene: FLAD1 was added to Rhabdomyolysis and Metabolic Myopathy. Sources: Expert list
Mode of inheritance for gene: FLAD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLAD1 were set to 34454814; 34718578; 31392824; 30982706; 30311138; 30427553; 28433476; 27259049; 25058219
Phenotypes for gene: FLAD1 were set to Lipid storage myopathy due to flavin adenine dinucleotide synthetase deficiency MIM#255100
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.86 CAV3 Bryony Thompson Classified gene: CAV3 as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.86 CAV3 Bryony Thompson Gene: cav3 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.85 DNAJB4 Bryony Thompson Marked gene: DNAJB4 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.85 DNAJB4 Bryony Thompson Gene: dnajb4 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.85 DNAJB4 Bryony Thompson Classified gene: DNAJB4 as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.85 DNAJB4 Bryony Thompson Gene: dnajb4 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.84 DNAJB4 Bryony Thompson gene: DNAJB4 was added
gene: DNAJB4 was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Literature
Mode of inheritance for gene: DNAJB4 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DNAJB4 were set to 36512060; 36264506
Phenotypes for gene: DNAJB4 were set to distal myopathy MONDO:0018949; Myopathy, MONDO:0005336, DNAJB4-related
Review for gene: DNAJB4 was set to GREEN
Added comment: Emerging evidence of 2 different disease mechanisms: monoallelic distal myopathy may be caused by toxic gain of function and biallelic loss of function with variable onset myopathy with respiratory failure. There is more evidence for the biallelic myopathy with 3 families.
PMID: 36512060 - A single family with distal myopathy segregating a heterozygous missense variant (c.270T>A p.F90L). In vitro functional assays suggest a toxic gain of function mechanism of disease for p.F90L. Both Dnajb4F90L knock-in and Dnafjb4 knockout mice developed muscle weakness
PMID: 36264506 - 4 individuals from 3 unrelated families with myopathy with early respiratory failure with homozygous variants (c.856A > T; p.Lys286Ter, c.74G > A; p.Arg25Gln, c.785 T > C; p.Leu262Ser). DNAJB4 knockout mice had muscle weakness and fibre atrophy with prominent diaphragm involvement and kyphosis, muscle and myotubes had myofibrillar disorganization and accumulated Z-disc proteins and protein chaperones.
Sources: Literature
Mendeliome v1.807 DNAJB4 Bryony Thompson reviewed gene: DNAJB4: Rating: AMBER; Mode of pathogenicity: Other; Publications: 36512060; Phenotypes: distal myopathy MONDO:0018949; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.807 TSPAN7 Ain Roesley reviewed gene: TSPAN7: Rating: AMBER; Mode of pathogenicity: None; Publications: 26350204, 36625203; Phenotypes: Intellectual developmental disorder, X-linked 58, MIM #300210, MONDO:0010266; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.83 DES Bryony Thompson Classified gene: DES as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.83 DES Bryony Thompson Added comment: Comment on list classification: Myofibrillar myopathy is characterized by slowly progressive muscle weakness, from distal to proximal lower extremities
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.83 DES Bryony Thompson Gene: des has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.82 DES Bryony Thompson Classified gene: DES as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.82 DES Bryony Thompson Gene: des has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.81 BICD2 Bryony Thompson gene: BICD2 was added
gene: BICD2 was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Expert list
Mode of inheritance for gene: BICD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BICD2 were set to 27784775; 28635954; 31561939; 29306765
Phenotypes for gene: BICD2 were set to distal myopathy MONDO:0018949
Rhabdomyolysis and Metabolic Myopathy v0.107 ATP2A1 Bryony Thompson Classified gene: ATP2A1 as Green List (high evidence)
Rhabdomyolysis and Metabolic Myopathy v0.107 ATP2A1 Bryony Thompson Gene: atp2a1 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.106 ATP2A1 Bryony Thompson Deleted their review
Rhabdomyolysis and Metabolic Myopathy v0.106 ATP2A1 Bryony Thompson commented on gene: ATP2A1
Rhabdomyolysis and Metabolic Myopathy v0.106 ATP2A1 Bryony Thompson Deleted their review
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.80 ANXA11 Bryony Thompson gene: ANXA11 was added
gene: ANXA11 was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Literature
Mode of inheritance for gene: ANXA11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANXA11 were set to 34048612
Phenotypes for gene: ANXA11 were set to Inclusion body myopathy and brain white matter abnormalities, MIM# 619733
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.79 ADSSL1 Bryony Thompson Marked gene: ADSSL1 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.79 ADSSL1 Bryony Thompson Gene: adssl1 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.79 ADSSL1 Bryony Thompson Classified gene: ADSSL1 as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.79 ADSSL1 Bryony Thompson Gene: adssl1 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.78 ADSSL1 Bryony Thompson gene: ADSSL1 was added
gene: ADSSL1 was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Literature
Mode of inheritance for gene: ADSSL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADSSL1 were set to 26506222; 28268051; 34635388; 32646962
Phenotypes for gene: ADSSL1 were set to adenylosuccinate synthetase-like 1-related distal myopathy MONDO:0018834
Review for gene: ADSSL1 was set to GREEN
gene: ADSSL1 was marked as current diagnostic
Added comment: Over 60 families reported mainly in Japan and Korea.
PMID: 26506222 - 4 individuals with adolescent-onset distal myopathy in 2 unrelated Korean families cosegregating compound heterozygous variants (p.D304N and p.I350fs). In vitro assays demonstrated reduced enzyme activity and cell viability and supporting zebrafish model.
PMID: 28268051 - 4 unrelated Korean distal myopathy cases with biallelic variants
PMID: 34635388 - Turkish individual with distal myopathy and homozygous variant (c.989G>A, p.Ala300Thr) and Indian individual with proximal muscle weakness and homozygous variant (c.910G>A, p.Asp304Asn)
PMID: 32646962 - 63 patients from 59 Japanese families with biallelic variants of ADSSL1. Most displayed variable muscle symptoms including in the proximal and/or distal leg muscles. Nemaline bodies in addition to increased lipid droplets and myofibrillar disorganization were commonly observed in all patients, suggesting that the disease may be classified as nemaline myopathy
Sources: Literature
Rhabdomyolysis and Metabolic Myopathy v0.106 Bryony Thompson Panel name changed from Rhabdomyolysis to Rhabdomyolysis and Metabolic Myopathy
HPO terms changed from Rhabdomyolysis, HP:0003201 to Rhabdomyolysis, HP:0003201;Exercise intolerance, HP:0003546;Metabolic myopathy, MONDO:0020123
List of related panels changed from Rhabdomyolysis; HP:0003201 to Rhabdomyolysis; HP:0003201;Exercise intolerance; HP:0003546;Metabolic myopathy; MONDO:0020123
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.77 ACTN2 Bryony Thompson Marked gene: ACTN2 as ready
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.77 ACTN2 Bryony Thompson Gene: actn2 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.77 ACTN2 Bryony Thompson Classified gene: ACTN2 as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.77 ACTN2 Bryony Thompson Gene: actn2 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.76 ACTN2 Bryony Thompson gene: ACTN2 was added
gene: ACTN2 was added to Limb-Girdle Muscular Dystrophy and Distal Myopathy. Sources: Literature
Mode of inheritance for gene: ACTN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACTN2 were set to 30900782; 34170073; 36116040; 34471957; 34386585
Phenotypes for gene: ACTN2 were set to Myopathy, distal, 6, adult onset MIM#618655
Mode of pathogenicity for gene: ACTN2 was set to Other
Review for gene: ACTN2 was set to GREEN
gene: ACTN2 was marked as current diagnostic
Added comment: At least 8 families segregating variants with dominant distal myopathy and 1 variant reported with recessive inheritance. Some functional evidence suggesting protein aggregation is the mechanism of disease
4 fams - PMID: 30900782 - 3 Spanish families segregating c.1459T>C p.(Cys487Arg) with distal myopathy & 1 Swedish family segregated c.392T>C p.(Leu131Pro)
1 fam - PMID: 34170073 - a frameshift c.2504delT, p. Phe835Serfs*66 resulting in C-terminal extension segregating with distal myopathy in a Chinese family. The proband was diagnosed with distal myopathy with multi‐minicores on muscle biopsy. In vitro assays demonstrated p. Phe835Serfs*66 and p. Leu131Pro resulted in protein aggregation, whereas p.C487R and p.L727R were similar to WT
1 fam - PMID: 36116040 - 2 individuals with distal myopathy in a Spanish family with the splice site variant c.1840‐2A>T, shown with RNA studies to lead to an in-frame deletion (r.1840_1878del p.(Val614_Gln626del)).
0 - PMID: 34471957 - 3 apparently unrelated Japanese probands with distal myopathy with the same homozygous missense - c.1439A>G p.(Asn480Ser). The variant appears to be associated with a recessive inheritance pattern but there is a suggestion of semidominance in one of the families. In vitro assays demonstrate the variant does not interfere with protein dimerisation and cellular localisation.
2 fams - PMID: 34386585 - c.2567del p.Pro856Argfs*45 and c.2558del p.Glu853Glyfs*48 resulting in C-terminal elongation identified in 3 individuals with distal myopathy from 2 families.
Sources: Literature
Disorders of immune dysregulation v0.168 LIG4 Peter McNaughton gene: LIG4 was added
gene: LIG4 was added to Disorders of immune dysregulation. Sources: Literature
Mode of inheritance for gene: LIG4 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: LIG4 were set to PMID: 37004747
Phenotypes for gene: LIG4 were set to Immune dysregulation
Mode of pathogenicity for gene: LIG4 was set to Other
Review for gene: LIG4 was set to GREEN
Added comment: 2 variants (p.R580Q, p.A842D) in unrelated patients associated with a dominantly inherited
familial immune-dysregulation consisting of autoimmune cytopenias, lymphoproliferation, agammaglobulinemia and adaptive immune cell infiltration into nonlymphoid organ. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient.
Sources: Literature
Combined Immunodeficiency v1.34 LIG4 Peter McNaughton reviewed gene: LIG4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37004747; Phenotypes: Combined immune deficiency; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.74 Bryony Thompson Panel name changed from Limb Girdle Muscular Dystrophy to Limb-Girdle Muscular Dystrophy and Distal Myopathy
HPO terms changed from Limb-girdle muscular dystrophy, MONDO:0016971; Proximal muscle weakness, HP:0003701 to Limb-girdle muscular dystrophy, MONDO:0016971; Proximal muscle weakness, HP:0003701; Distal myopathy MONDO:0018949
List of related panels changed from Limb-girdle muscular dystrophy; MONDO:0016971;Proximal muscle weakness; HP:0003701 to Limb-girdle muscular dystrophy; MONDO:0016971; Proximal muscle weakness; HP:0003701; Distal myopathy MONDO:0018949
Rhabdomyolysis and Metabolic Myopathy v0.105 PRKAG2 Bryony Thompson Publications for gene: PRKAG2 were set to
Rhabdomyolysis and Metabolic Myopathy v0.104 PRKAG2 Bryony Thompson Classified gene: PRKAG2 as Green List (high evidence)
Rhabdomyolysis and Metabolic Myopathy v0.104 PRKAG2 Bryony Thompson Gene: prkag2 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.103 PRKAG2 Bryony Thompson reviewed gene: PRKAG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15766830, 31049239; Phenotypes: Cardiomyopathy, hypertrophic 6 MIM#600858, Glycogen storage disease of heart, lethal congenital MIM#261740, Wolff-Parkinson-White syndrome MIM#194200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Rhabdomyolysis and Metabolic Myopathy v0.103 PRKAG2 Bryony Thompson Deleted their review
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.73 POGLUT1 Bryony Thompson Publications for gene: POGLUT1 were set to 27807076; 29034878
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.72 POGLUT1 Bryony Thompson Classified gene: POGLUT1 as Green List (high evidence)
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.72 POGLUT1 Bryony Thompson Gene: poglut1 has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v0.71 POGLUT1 Bryony Thompson reviewed gene: POGLUT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27807076, 31897643; Phenotypes: autosomal recessive limb-girdle muscular dystrophy type 2R1 MONDO:0014977; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fatty Acid Oxidation Defects v1.12 FLAD1 Bryony Thompson Publications for gene: FLAD1 were set to 25058219; 27259049; 16643857; 20060505
Fatty Acid Oxidation Defects v1.11 FLAD1 Bryony Thompson Classified gene: FLAD1 as Green List (high evidence)
Fatty Acid Oxidation Defects v1.11 FLAD1 Bryony Thompson Added comment: Comment on list classification: ClinGen FAOD GCEP upgraded the classification of the gene-disease association to DEFINITIVE on 16/12/2020, adding new evidence from the following publications PMIDs: 30061063, 30982706, 30311138, 31392824, 30427553
Fatty Acid Oxidation Defects v1.11 FLAD1 Bryony Thompson Gene: flad1 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.103 DNA2 Bryony Thompson Publications for gene: DNA2 were set to 31636600
Rhabdomyolysis and Metabolic Myopathy v0.102 DNA2 Bryony Thompson Classified gene: DNA2 as Green List (high evidence)
Rhabdomyolysis and Metabolic Myopathy v0.102 DNA2 Bryony Thompson Added comment: Comment on list classification: AD PEO phenotype includes mitochondrial myopathy, which can present with rhabdomyolysis and exercise intolerance
Rhabdomyolysis and Metabolic Myopathy v0.102 DNA2 Bryony Thompson Gene: dna2 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.101 DNA2 Bryony Thompson commented on gene: DNA2
Rhabdomyolysis and Metabolic Myopathy v0.101 DNA2 Bryony Thompson Deleted their review
Rhabdomyolysis and Metabolic Myopathy v0.101 CHCHD10 Bryony Thompson Marked gene: CHCHD10 as ready
Rhabdomyolysis and Metabolic Myopathy v0.101 CHCHD10 Bryony Thompson Gene: chchd10 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.101 CHCHD10 Bryony Thompson Classified gene: CHCHD10 as Green List (high evidence)
Rhabdomyolysis and Metabolic Myopathy v0.101 CHCHD10 Bryony Thompson Gene: chchd10 has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.100 CHCHD10 Bryony Thompson gene: CHCHD10 was added
gene: CHCHD10 was added to Rhabdomyolysis. Sources: Literature
Mode of inheritance for gene: CHCHD10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHCHD10 were set to 30874923; 29112723; 25193783; 24934289
Phenotypes for gene: CHCHD10 were set to autosomal dominant mitochondrial myopathy with exercise intolerance MONDO:0014532
Mode of pathogenicity for gene: CHCHD10 was set to Other
Review for gene: CHCHD10 was set to GREEN
gene: CHCHD10 was marked as current diagnostic
Added comment: There are 2 families reported with mitochondrial myopathy phenotype and supporting functional assays and a knock-in mouse model
1 fam - PMID: 24934289 - c.176C>T; p.Ser59Leu segregates with mitochondrial myopathy (confirmed by muscle biopsy) with either isolated or associated symptoms including ataxia, dementia and ALS-like presentation in a large French family. Functional assays demonstrated the variant induces mitochondrial fragmentation.
1 fam - PMID: 25193783 - c.43C>A, p.Arg15Ser & c.172G>C, p.Gly58Arg in cis segregates with mitochondrial myopathy in members presenting with exercise intolerance and a proximal myopathy in a large Puerto Rican family. Functional assays demonstrated the Gly58Arg variant induced mitochondrial fragmentation.
0 - PMID: 29519717 - c.286C>A, p.Pro96Thr identified homozygous in an Italian mitochondrial myopathy case. However, this is a common variant in the African/African American population in gnomAD v2.1 (MAF=0.20, 336 homozygotes) and would be classified as benign.
Fxnl - PMID: 29112723 - Chchd10 knockout mice are viable, and have no gross phenotypes, no bioenergetic defects or ultrastructural mitochondrial abnormalities in the brain, heart or skeletal muscle. Cells expressing CHCHD10 S59L or R15L mutants, but not WT, had impaired mitochondrial energy metabolism. Suggested toxic gain of function mechanism of disease
Animal model - PMID: 30874923 - knock-in CHCHD10 S59L/+ mouse model demonstrates mitochondrial myopathy with mtDNA instability
Sources: Literature
Rhabdomyolysis and Metabolic Myopathy v0.99 C1QBP Bryony Thompson Marked gene: C1QBP as ready
Rhabdomyolysis and Metabolic Myopathy v0.99 C1QBP Bryony Thompson Gene: c1qbp has been classified as Green List (High Evidence).
Rhabdomyolysis and Metabolic Myopathy v0.99 C1QBP Bryony Thompson Phenotypes for gene: C1QBP were changed from to Progressive external opthalmoplegia; mitochondrial myopathy
Rhabdomyolysis and Metabolic Myopathy v0.98 C1QBP Bryony Thompson Publications for gene: C1QBP were set to
Rhabdomyolysis and Metabolic Myopathy v0.97 C1QBP Bryony Thompson Classified gene: C1QBP as Green List (high evidence)
Rhabdomyolysis and Metabolic Myopathy v0.97 C1QBP Bryony Thompson Added comment: Comment on list classification: Exercise intolerance is a presenting feature
Rhabdomyolysis and Metabolic Myopathy v0.97 C1QBP Bryony Thompson Gene: c1qbp has been classified as Green List (High Evidence).
Mendeliome v1.807 KDM5A Achchuthan Shanmugasundram gene: KDM5A was added
gene: KDM5A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KDM5A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: KDM5A were set to 21937992; 33350388
Phenotypes for gene: KDM5A were set to autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071
Review for gene: KDM5A was set to GREEN
Added comment: PMID:21937992 reported a family with recessive missense KDM5A variant presenting with an undefined developmental disorder characterised with intellectual disability and facial dysmorphisms.

PMID:33350388 reported nine patients from seven unrelated families identified with variants in KDM5A, of which three unrelated patients harboured heterozygous variants, while six patients from four unrelated families had homozygous variants. These patients presented with autism spectrum disorder (ASD) and a spectrum of neurodevelopmental phenotypes including intellectual disability, lack of speech, developmental delay and motor impairment.

In addition, loss of KDM5A has resulted in repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis in mice.

This gene has already been associated with phenotype in Gene2Phenotype (biallelic inheritance with 'limited' rating), but not in OMIM.
Sources: Literature
Brain Calcification v1.51 GLA Yetong Chen gene: GLA was added
gene: GLA was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: GLA was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: GLA were set to 32734340; 24372060; 30532363
Phenotypes for gene: GLA were set to Fabry disease, MIM# 301500
Review for gene: GLA was set to AMBER
Added comment: PMID 17224688 suggests Fabry disease should not be considered an X-linked recessive disorder since women carrying heterozygous GLA variants may experience significant life-threatening conditions.
The association between brain calcification and Fabry disease is well-established. However, no cases with GLA variants that developed brain calcification are reported in the literature.
Sources: Expert list
Stickler Syndrome v1.8 COL11A1 Elena Savva Publications for gene: COL11A1 were set to
Stickler Syndrome v1.7 COL11A1 Elena Savva Mode of inheritance for gene: COL11A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Stickler Syndrome v1.6 COL11A1 Elena Savva reviewed gene: COL11A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32578940; Phenotypes: Stickler syndrome, type II, MIM# 604841, MONDO:0011493; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Brain Calcification v1.51 GJA1 Yetong Chen edited their review of gene: GJA1: Changed rating: GREEN
Brain Calcification v1.51 GJA1 Yetong Chen gene: GJA1 was added
gene: GJA1 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: GJA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GJA1 were set to 26444782; 31023660; 31240666
Phenotypes for gene: GJA1 were set to Oculodentodigital dysplasia, MIM# 164200
Review for gene: GJA1 was set to RED
Added comment: PMID 26444782 reports a patient with a heterozygous missense GJA1 variant who developed bilateral calcifications of the basal ganglia and mild hydrocephalus.
PMID 31023660 reports 2 patients with missense GJA1 variants who developed brain calcifications. Patients 4 and 7 had unilateral and bilateral calcifications, respectively.
PMID 31240666 reports a patient with a homozygous GJA1 variant who developed bilateral calcification of the basal ganglia, thalamus and deep white matter.
Sources: Expert list
Brain Calcification v1.51 GCM2 Yetong Chen gene: GCM2 was added
gene: GCM2 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: GCM2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: GCM2 were set to 32642802; 19940031; 36405867; 18583467
Phenotypes for gene: GCM2 were set to Hypoparathyroidism, familial isolated 2, MIM# 618883
Review for gene: GCM2 was set to GREEN
Added comment: PMID 19940031 reports 11 patients with GCM2 variants who developed basal ganglia calcification. In the pedigrees of 5 families, some individuals with an R110W variant were affected while some with an R110W variant were nonaffected.
PMID 36405867 reports a patient with a GCM2 variant who developed bilateral basal ganglia calcification.
PMID 18583467 reports 2 patients from the same family who had the same GCM2 variant and developed basal ganglia calcification.
Sources: Expert list
Congenital diaphragmatic hernia v1.12 Bryony Thompson Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease
Growth failure v1.63 Bryony Thompson Panel types changed to Victorian Clinical Genetics Services; Genetic Health Queensland; Royal Melbourne Hospital; Rare Disease
Brain Calcification v1.51 GATA3 Yetong Chen gene: GATA3 was added
gene: GATA3 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: GATA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GATA3 were set to 32642802; 19248180; 26268891; 16912130; 15337474
Phenotypes for gene: GATA3 were set to Hypoparathyroidism, sensorineural deafness, and renal dysplasia, MIM# 146255
Review for gene: GATA3 was set to GREEN
Added comment: PMID 19248180 reports a patient with a GATA3 variant who developed basal ganglia calcification.
PMID 26268891 reports a patient with a GATA3 variant who developed multiple intracranial calcifications.
PMID 16912130 reports a patient with a GATA3 variant who developed basal ganglia calcification.
PMID 15337474 reports a patient with a chromosome 10p deletion, where the GATA3 gene is located, who developed basal ganglia calcification.
Sources: Expert list
Brain Calcification v1.51 GALC Yetong Chen reviewed gene: GALC: Rating: GREEN; Mode of pathogenicity: None; Publications: 22150413, 20135576; Phenotypes: Krabbe disease, MIM# 245200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v0.33 ROBO1 Zornitza Stark Phenotypes for gene: ROBO1 were changed from pituitary stalk interruption syndrome; pituitary anomalies; pituitary hormone deficiency to Pituitary hormone deficiency, combined or isolated, 8, MIM# 620303
Pituitary hormone deficiency v0.32 ROBO1 Zornitza Stark reviewed gene: ROBO1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pituitary hormone deficiency, combined or isolated, 8, MIM# 620303; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5204 ROBO1 Zornitza Stark Phenotypes for gene: ROBO1 were changed from intellectual disability, MONDO:0001071 to Neurooculorenal syndrome, MIM# 620305
Intellectual disability syndromic and non-syndromic v0.5203 ROBO1 Zornitza Stark reviewed gene: ROBO1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurooculorenal syndrome, MIM# 620305; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital anomalies of the kidney and urinary tract (CAKUT) v0.129 ROBO1 Zornitza Stark Phenotypes for gene: ROBO1 were changed from Syndromic disease, MONDO:0002254; CAKUT to Neurooculorenal syndrome, MIM# 620305
Congenital anomalies of the kidney and urinary tract (CAKUT) v0.128 ROBO1 Zornitza Stark edited their review of gene: ROBO1: Changed phenotypes: Neurooculorenal syndrome, MIM# 620305
Mendeliome v1.807 ROBO1 Zornitza Stark Phenotypes for gene: ROBO1 were changed from Congenital heart disease; Pituitary anomalies; Nystagmus 8, congenital, autosomal recessive, MIM# 257400; intellectual disability, MONDO:0001071 to Pituitary hormone deficiency, combined or isolated, 8, MIM# 620303; Nystagmus 8, congenital, autosomal recessive, MIM# 257400; Neurooculorenal syndrome, MIM# 620305
Mendeliome v1.806 ROBO1 Zornitza Stark edited their review of gene: ROBO1: Changed phenotypes: Pituitary hormone deficiency, combined or isolated, 8, MIM# 620303, Nystagmus 8, congenital, autosomal recessive, MIM# 257400, Neurooculorenal syndrome, MIM# 620305
Mendeliome v1.806 ROBO1 Zornitza Stark Publications for gene: ROBO1 were set to 28592524; 30530901; 30692597; 33270637; 28402530; 33270637; 28402530; 35348658
Mendeliome v1.805 ROBO1 Zornitza Stark edited their review of gene: ROBO1: Changed publications: 28286008, 30692597, 35227688, 35348658, 28592524, 30530901, 33270637, 28402530
Mendeliome v1.805 ROBO1 Zornitza Stark Phenotypes for gene: ROBO1 were changed from Congenital heart disease; Pituitary anomalies to Congenital heart disease; Pituitary anomalies; Nystagmus 8, congenital, autosomal recessive, MIM# 257400; intellectual disability, MONDO:0001071
Mendeliome v1.804 ROBO1 Zornitza Stark Publications for gene: ROBO1 were set to 28592524; 30530901; 30692597; 33270637; 28402530
Mendeliome v1.803 ROBO1 Zornitza Stark edited their review of gene: ROBO1: Added comment: Association with ID: GREEN for bi-allelic variants:

PMID:28286008 reported a boy with compound heterozygous variants that was presented with developmental delay in 13 months and had severe intellectual disability and hyperactivity at nine years of age. He was nonverbal and wheelchair dependent because of spastic diplegia and ataxia.

PMID:30692597 reported a five year old boy identified with a homozygous ROBO1 variant who had combined pituitary hormone deficiency, psychomotor developmental delay, severe intellectual disability, sensorineural hearing loss, strabismus and characteristic facial features.

PMID:35227688 reported eight patients including the boy reported in PMID:30692597. Of the other seven patients, three were presented with intellectual disability. Of these three patients, two harboured compound heterozygous and one harboured homozygous variants.

PMID:35348658 reported a patient identified with monoallelic de novo variant (p.D422G) who presented with early-onset epileptic encephalopathy and had severe developmental delay.; Changed phenotypes: Congenital heart disease, Pituitary anomalies, Nystagmus 8, congenital, autosomal recessive, MIM# 257400, intellectual disability, MONDO:0001071
Congenital nystagmus v1.18 ROBO1 Zornitza Stark Marked gene: ROBO1 as ready
Congenital nystagmus v1.18 ROBO1 Zornitza Stark Gene: robo1 has been classified as Red List (Low Evidence).
Congenital nystagmus v1.18 ROBO1 Zornitza Stark Classified gene: ROBO1 as Red List (low evidence)
Congenital nystagmus v1.18 ROBO1 Zornitza Stark Gene: robo1 has been classified as Red List (Low Evidence).
Mendeliome v1.803 ROBO1 Zornitza Stark changed review comment from: PMID 35348658: three male siblings from the same family with nystagmus with a homozygous missense variant p.Ser1522Leu.; to: PMID 35348658: three male siblings from the same family with nystagmus with a homozygous missense variant p.Ser1522Leu. This association is RED.
Mendeliome v1.803 ROBO1 Zornitza Stark edited their review of gene: ROBO1: Added comment: PMID 35348658: three male siblings from the same family with nystagmus with a homozygous missense variant p.Ser1522Leu.; Changed publications: 28592524, 30530901, 30692597, 33270637, 28402530, 35348658; Changed phenotypes: Congenital heart disease, Pituitary anomalies, Nystagmus 8, congenital, autosomal recessive, MIM# 257400
Congenital nystagmus v1.17 ROBO1 Zornitza Stark reviewed gene: ROBO1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Nystagmus 8, congenital, autosomal recessive, MIM# 257400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5203 ROBO1 Zornitza Stark Marked gene: ROBO1 as ready
Intellectual disability syndromic and non-syndromic v0.5203 ROBO1 Zornitza Stark Gene: robo1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5203 ROBO1 Zornitza Stark Classified gene: ROBO1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5203 ROBO1 Zornitza Stark Gene: robo1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5202 CAMSAP1 Zornitza Stark Phenotypes for gene: CAMSAP1 were changed from lissencephaly spectrum disorders (MONDO:0018838), CAMSAP1-related to Cortical dysplasia, complex, with other brain malformations 12, MIM# 620316
Intellectual disability syndromic and non-syndromic v0.5201 CAMSAP1 Zornitza Stark reviewed gene: CAMSAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cortical dysplasia, complex, with other brain malformations 12, MIM# 620316; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Callosome v0.488 CAMSAP1 Zornitza Stark Phenotypes for gene: CAMSAP1 were changed from lissencephaly spectrum disorders (MONDO:0018838), CAMSAP1-related to Cortical dysplasia, complex, with other brain malformations 12, MIM# 620316
Callosome v0.487 CAMSAP1 Zornitza Stark reviewed gene: CAMSAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cortical dysplasia, complex, with other brain malformations 12, MIM# 620316; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1840 CAMSAP1 Zornitza Stark Phenotypes for gene: CAMSAP1 were changed from lissencephaly spectrum disorders (MONDO:0018838), CAMSAP1-related to Cortical dysplasia, complex, with other brain malformations 12, MIM# 620316
Genetic Epilepsy v0.1839 CAMSAP1 Zornitza Stark reviewed gene: CAMSAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cortical dysplasia, complex, with other brain malformations 12, MIM# 620316; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Microcephaly v1.202 CAMSAP1 Zornitza Stark Phenotypes for gene: CAMSAP1 were changed from lissencephaly spectrum disorders (MONDO:0018838), CAMSAP1-related to Cortical dysplasia, complex, with other brain malformations 12, MIM# 620316
Microcephaly v1.201 CAMSAP1 Zornitza Stark reviewed gene: CAMSAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cortical dysplasia, complex, with other brain malformations 12, MIM# 620316; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.803 CAMSAP1 Zornitza Stark Phenotypes for gene: CAMSAP1 were changed from lissencephaly spectrum disorders (MONDO:0018838), CAMSAP1-related to Cortical dysplasia, complex, with other brain malformations 12, MIM# 620316
Mendeliome v1.802 CAMSAP1 Zornitza Stark reviewed gene: CAMSAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cortical dysplasia, complex, with other brain malformations 12, MIM# 620316; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Lissencephaly and Band Heterotopia v1.15 CAMSAP1 Zornitza Stark Phenotypes for gene: CAMSAP1 were changed from lissencephaly spectrum disorders (MONDO:0018838), CAMSAP1-related to Cortical dysplasia, complex, with other brain malformations 12, MIM# 620316
Lissencephaly and Band Heterotopia v1.14 CAMSAP1 Zornitza Stark reviewed gene: CAMSAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cortical dysplasia, complex, with other brain malformations 12, MIM# 620316; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.802 RYR3 Zornitza Stark Phenotypes for gene: RYR3 were changed from Congenital myopathy 20, MIM# 620310 to Congenital myopathy 20, MIM# 620310; developmental and epileptic encephalopathy (MONDO:0100062)
Mendeliome v1.801 RYR3 Zornitza Stark Publications for gene: RYR3 were set to 29498452; 32451403; 31230720
Mendeliome v1.800 RYR3 Zornitza Stark Mode of inheritance for gene: RYR3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.799 RYR3 Zornitza Stark Phenotypes for gene: RYR3 were changed from Nemaline myopathy; fetal akinesia; arthrogryposis to Congenital myopathy 20, MIM# 620310
Mendeliome v1.798 RYR3 Zornitza Stark edited their review of gene: RYR3: Changed phenotypes: Congenital myopathy 20, MIM# 620310
Craniosynostosis v1.47 BCL11B Calder Hamill gene: BCL11B was added
gene: BCL11B was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: BCL11B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BCL11B were set to 36980886; 34900871
Phenotypes for gene: BCL11B were set to Craniosynostosis
Penetrance for gene: BCL11B were set to Incomplete
Review for gene: BCL11B was set to GREEN
Added comment: The potential gene disease association between BCL11B and craniosynostosis was a topic in Tooze, R.S.; Calpena, E.; Weber, A.; Wilson, L.C.; Twigg, S.R.F.; Wilkie, A.O.M. Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels. Genes 2023, 14, 615. https://doi.org/10.3390/ genes14030615

Summary of evidence:
>There are seven families with variants in BCL11B and confirmed craniosynostosis
>There are two green reviews in UK Panel App

>A de novo substitution was described in BCL11B (c.7C>A; p.(Arg3Ser)) - further mouse model data
Goos, J.A.C.; Vogel, W.K.; Mlcochova, H.; Millard, C.J.; Esfandiari, E.; Selman, W.H.; Calpena, E.; Koelling, N.; Carpenter, E.L.; Swagemakers, S.M.A.; et al. A de novo substitution in BCL11B leads to loss of interaction with transcriptional complexes and craniosynostosis. Hum. Mol. Genet. 2019, 28, 2501–2513.

> a de novo frameshift variant in BCL11B, identified by whole-exome sequencing: c.2346_2361del; p.(Gly783Alafs*24)
Zhao, X.; Wu, B.; Chen, H.; Zhang, P.; Qian, Y.; Peng, X.; Dong, X.; Wang, Y.; Li, G.; Dong, C.; et al. Case report: A novel truncating variant of BCL11B associated with rare feature of craniosynostosis and global developmental delay. Front. Pediatr. 2022, 10, 982361

> A de novo loss of function variant has been described in a patient with developmental delay and craniosynostosis: c.2439_2452dup; p.(His818Argfs*31)
Eto, K.; Machida, O.; Yanagishita, T.; Shimojima Yamamoto, K.; Chiba, K.; Aihara, Y.; Hasegawa, Y.; Nagata, M.; Ishihara, Y.; Miyashita, Y.; et al. Novel BCL11B truncation variant in a patient with developmental delay, distinctive features, and early craniosynostosis. Hum. Genome Var. 2022, 9, 43

The following evidence first noted from review by Helen Lord in UK PanelApp:
PMID 34900871 Gaillard et al, 2021, reported 4 patients with BCL11B variants
Patient A: c.2000G>A p.(Gly667Glu) het left sided congernital diaphragmatic hernia (CDH) and progressive sagittal synostosis. Maternally inherited.
Patient B: c.1744G>A p.(Gly582Ser) het sagittal and bilambdoid synostosis. Paternally inherited.
Patient C: c.2018C>G p.(Pro673Arg) het left unicoronal synostosis. Maternally inherited.
Patient D: c.1265C>T p.(Pro422Leu) het sagittal synostosis. Maternally inherited.
Parentally inherited in some instances suggesting incomplete penetrance
Sources: Literature
Craniosynostosis v1.47 NFIA Calder Hamill gene: NFIA was added
gene: NFIA was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: NFIA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NFIA were set to 36980886
Phenotypes for gene: NFIA were set to Craniosynostosis
Penetrance for gene: NFIA were set to Incomplete
Review for gene: NFIA was set to AMBER
Added comment: A gene which has growing evidence in its association with craniosynostosis, most recently subject to review in in Tooze, R.S.; Calpena, E.; Weber, A.; Wilson, L.C.; Twigg, S.R.F.; Wilkie, A.O.M. Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels. Genes 2023, 14, 615. https://doi.org/10.3390/ genes14030615
> Four patients with craniosynostosis in independent families reported in the four papers below.
>> deletion of 7765kb including this entire gene - craniosynostosis in chromosome 1p32-p31 deletion syndrome (Yoon 2019)
>> del 1p32.3p31.2, g.53675707_66644963del- 13Mb del including the NFIA gene. (Tonne 2021)

> Recently given green gene status in UK Panel App (2023)

1. Yoon, J.G.; Hahn, H.M.; Choi, S.; Kim, S.J.; Aum, S.; Yu, J.W.; Park, E.K.; Shim, K.W.; Lee, M.G.; Kim, Y.O. Molecular Diagnosis of Craniosynostosis Using Targeted Next-Generation Sequencing. Neurosurgery 2020, 87, 294–302. [
2. Tønne, E.; Due-Tønnessen, B.J.; Mero, I.L.; Wiig, U.S.; Kulseth, M.A.; Vigeland, M.D.; Sheng, Y.; von der Lippe, C.; Tveten, K.; Meling, T.R.; et al. Benefits of clinical criteria and high-throughput sequencing for diagnosing children with syndromic craniosynostosis. Eur. J. Hum. Genet. 2021, 29, 920–929.
3. Chen, J.; Zhang, P.; Peng, M.; Liu, B.; Wang, X.; Du, S.; Lu, Y.; Mu, X.; Lu, Y.; Wang, S.; et al. An additional whole-exome sequencing study in 102 panel-undiagnosed patients: A retrospective study in a Chinese craniosynostosis cohort. Front. Genet. 2022, 13, 967688.
4. Tønne, E.; Due-Tønnessen, B.J.; Vigeland, M.D.; Amundsen, S.S.; Ribarska, T.; Asten, P.M.; Sheng, Y.; Helseth, E.; Gilfillan, G.D.; Mero, I.L.; et al. Whole-exome sequencing in syndromic craniosynostosis increases diagnostic yield and identifies candidate genes in osteogenic signaling pathways. Am. J. Med. Genet. A 2022, 188, 1464–1475. [CrossRef] [PubMed]

Note also the additional case report:
Bayat, Allana; Kirchhoff, Mariab; Madsen, Camilla G.d; Roos, Laurab; Kreiborg, Svenc,e. Familial craniofacial abnormality and polymicrogyria associated with a microdeletion affecting the NFIA gene. Clinical Dysmorphology 26(3):p 148-153, July 2017. | DOI: 10.1097/MCD.0000000000000182

Have not provided a high evidence review out of caution that some of the reported mutations have been microdeletions
Sources: Literature
Craniosynostosis v1.47 PRRX1 Calder Hamill gene: PRRX1 was added
gene: PRRX1 was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: PRRX1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRRX1 were set to 36980886
Phenotypes for gene: PRRX1 were set to Craniosynostosis
Penetrance for gene: PRRX1 were set to Incomplete
Mode of pathogenicity for gene: PRRX1 was set to Other
Review for gene: PRRX1 was set to GREEN
Added comment: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, predicting loss of function variants or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent
(Tooze, R.S.; Calpena, E.; Weber, A.; Wilson, L.C.; Twigg, S.R.F.; Wilkie, A.O.M. Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels. Genes 2023, 14, 615. https://doi.org/10.3390/ genes14030615)

Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development.
(Wilk, K.; Yeh, S.A.; Mortensen, L.J.; Ghaffarigarakani, S.; Lombardo, C.M.; Bassir, S.H.; Aldawood, Z.A.; Lin, C.P.; Intini, G. Postnatal Calvarial Skeletal Stem Cells Expressing PRX1 Reside Exclusively in the Calvarial Sutures and Are Required for Bone Regeneration. Stem Cell Rep. 2017, 8, 933–946.)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture.
(Farmer, D.T.; Mlcochova, H.; Zhou, Y.; Koelling, N.; Wang, G.; Ashley, N.; Bugacov, H.; Chen, H.J.; Parvez, R.; Tseng, K.C.; et al. The developing mouse coronal suture at single-cell resolution. Nat. Commun. 2021, 12, 4797)
Sources: Literature
Brain Calcification v1.51 FARSB Yetong Chen reviewed gene: FARSB: Rating: GREEN; Mode of pathogenicity: None; Publications: 29979980, 19161147, 30014610; Phenotypes: Rajab interstitial lung disease with brain calcifications 1, MIM# 613658; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.51 FARSA Yetong Chen changed review comment from: PMID 31355908 reports a patient with compound heterozygous variants of FARSA who developed brain calcification.
PMID 30014610 reports 5 patients with homozygous variants of FARSA who developed brain calcification. The 5 individuals are from a large consanguineous family. Co-segregation of phenotype and FARSA variant is confirmed. 3 deceased individuals were affected by brain calcification; however, their genotypes are not indicated in the pedigree while the author state that all affected individuals carried the same FARSA variant. The genotypes of the 3 individuals are unsure, so they are not counted.; to: An additional case is reported.
PMID 31355908 reports a patient with compound heterozygous variants of FARSA who developed brain calcification.
Brain Calcification v1.51 FOLR1 Yetong Chen gene: FOLR1 was added
gene: FOLR1 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: FOLR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FOLR1 were set to 24556562; 27378809
Review for gene: FOLR1 was set to RED
Added comment: Limited evidence supports the causal role of the FOLR1 gene in brain calcification since there are only 2 patients reported.
PMID 24556562 reports a patient with a homozygous variant of FOLR1 (c.610C>T, p.Arg204) who had bilateral calcification within the basal ganglia.
PMID 27378809 reports a patient with a homozygous variant of FOLR1 (c.562C.G, p.Leu188Val) who had brain calcification.
Sources: Expert list
Brain Calcification v1.51 FAM20C Yetong Chen gene: FAM20C was added
gene: FAM20C was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: FAM20C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM20C were set to 27862258; 20825432
Phenotypes for gene: FAM20C were set to Raine syndrome, MIM# 259775
Review for gene: FAM20C was set to RED
Added comment: PMID 27862258 reports 2 patients with compounded FAM20C variants, who were from the same family, developed brain calcification. Co-segregation of brain calcification and the genotype of compounded FAM20C variants is reported.
PMID 20825432 reports 2 patients with a homozygous FAM20C variant, who were from the same family, developed brain calcification. Co-segregation of brain calcification and the genotype of homozygous FAM20C variants is reported.
Although co-segregation of phenotypes and genotypes is seen, the 4 individuals are related so more evidence is required.
Sources: Expert list
Brain Calcification v1.51 FARSA Yetong Chen reviewed gene: FARSA: Rating: GREEN; Mode of pathogenicity: None; Publications: 31355908, 30014610; Phenotypes: Rajab interstitial lung disease with brain calcifications 2, MIM# 619013; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5201 YWHAE Yetong Chen gene: YWHAE was added
gene: YWHAE was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: YWHAE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: YWHAE were set to 36999555
Phenotypes for gene: YWHAE were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: YWHAE was set to GREEN
Added comment: PMID 36999555 reports 6 patients with YWHAE variants (1 intragenic deletion and 5 large deletions encompassing YWHEA but not PAFAH1B1) who have mild to severe intellectual disability.
Sources: Literature
Callosome v0.487 YWHAE Yetong Chen edited their review of gene: YWHAE: Changed publications: 36999555, 20452996, 19584063, 20599530, 28542865, 29458882
Callosome v0.487 YWHAE Yetong Chen gene: YWHAE was added
gene: YWHAE was added to Callosome. Sources: Literature
Mode of inheritance for gene: YWHAE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: YWHAE were set to 36999555; 20452996; 19584063; 20599530
Phenotypes for gene: YWHAE were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: YWHAE was set to GREEN
Added comment: PMID 36999555 reports 10 patients, including 8 new individuals and 2 follow-up individuals with heterozygous YWHAE variants (3 splice site variants, 2 intragenic deletions and 10 large deletions encompassing YWHEA but not PAFAH1B1), who developed neurodevelopmental disease with brain abnormalities. The paper also references 5 patients from the following publications:
PMID 20452996 reports a patient with a YWHAE variant (deletion encompassing YWHEA but not PAFAH1B1) who had neurodevelopmental disease with brain abnormalities and developmental delay.
PMID 19584063 reports a patient with a YWHAE variant (deletion encompassing YWHEA but not PAHAF1B1) who had brain abnormalities and developmental delay. (Patients 2-5 with YWHAE deletions also presented developmental delay and brain abnormalities.)
PMID 20599530 reports a patient with a YWHAE variant (deletion encompassing YWHEA but not PAHAF1B1) who had brain abnormalities and developmental delay.
PMID 28542865 reports a patient with a YWHAE variant (intragenic deletion) who had myoclonic epilepsy and dysgraphia and learning disability related to mathematics. CT scan noted a Chiari Malformation Type I (CM), thin corpus callosum, cavum septum pellucidum and cavum vergae, but the patient's general and neurological exams were normal.
PMID 29458882 reports a fetus with a YWHAE variant (deletion encompassing YWHEA but not PAHAF1B1) who had facial dysmorphisms. The parents decided to terminate the pregnancy so detailed information regarding brain CT and development is not available. Although the authors concluded that the fetus did not have brain abnormalities, PMID 36999555 concludes that this patient had microcephaly (the last supplementary table).
Sources: Literature
Mendeliome v1.798 LYN Zornitza Stark Phenotypes for gene: LYN were changed from to Vasculitis, MONDO:0018882, LYN-related
Mendeliome v1.797 LYN Zornitza Stark Publications for gene: LYN were set to
Mendeliome v1.796 LYN Zornitza Stark Mode of inheritance for gene: LYN was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.795 LYN Zornitza Stark Classified gene: LYN as Green List (high evidence)
Mendeliome v1.795 LYN Zornitza Stark Gene: lyn has been classified as Green List (High Evidence).
Mendeliome v1.794 LYN Zornitza Stark reviewed gene: LYN: Rating: GREEN; Mode of pathogenicity: None; Publications: 36932076, 36122175; Phenotypes: Vasculitis, MONDO:0018882, LYN-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Syndromic Retinopathy v0.198 CLCN2 Zornitza Stark Marked gene: CLCN2 as ready
Syndromic Retinopathy v0.198 CLCN2 Zornitza Stark Gene: clcn2 has been classified as Green List (High Evidence).
Syndromic Retinopathy v0.198 CLCN2 Zornitza Stark Classified gene: CLCN2 as Green List (high evidence)
Syndromic Retinopathy v0.198 CLCN2 Zornitza Stark Gene: clcn2 has been classified as Green List (High Evidence).
Mendeliome v1.794 MAP3K3 Zornitza Stark Marked gene: MAP3K3 as ready
Mendeliome v1.794 MAP3K3 Zornitza Stark Gene: map3k3 has been classified as Green List (High Evidence).
Mendeliome v1.794 MAP3K3 Zornitza Stark Classified gene: MAP3K3 as Green List (high evidence)
Mendeliome v1.794 MAP3K3 Zornitza Stark Gene: map3k3 has been classified as Green List (High Evidence).
Mendeliome v1.793 MAP3K3 Zornitza Stark gene: MAP3K3 was added
gene: MAP3K3 was added to Mendeliome. Sources: Literature
somatic tags were added to gene: MAP3K3.
Mode of inheritance for gene: MAP3K3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP3K3 were set to 33729480; 35355835; 33891857; 36995941; 10700190; 25728774
Phenotypes for gene: MAP3K3 were set to Cerebral malformation, MONDO:0016054, MAP3K3-related
Mode of pathogenicity for gene: MAP3K3 was set to Other
Review for gene: MAP3K3 was set to GREEN
Added comment: Recurrent somatic missense variant (p.I441M) identified in sporadic cases of cerebral and spinal cavernous malformation. Recent publication demonstrates that this missense variant can drive CCM formation (in vitro and in vivo studies).
Sources: Literature
Vascular Malformations_Somatic v1.10 MAP3K3 Zornitza Stark Phenotypes for gene: MAP3K3 were changed from Verrucous venous malformation to Verrucous venous malformation; Cerebral malformation, MONDO:0016054, MAP3K3-related
Vascular Malformations_Somatic v1.9 MAP3K3 Zornitza Stark Publications for gene: MAP3K3 were set to 10700190; 25728774
Mendeliome v1.792 VWA8 Zornitza Stark Marked gene: VWA8 as ready
Mendeliome v1.792 VWA8 Zornitza Stark Gene: vwa8 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.792 VWA8 Zornitza Stark Classified gene: VWA8 as Amber List (moderate evidence)
Mendeliome v1.792 VWA8 Zornitza Stark Gene: vwa8 has been classified as Amber List (Moderate Evidence).
Growth failure v1.62 CRIPT Zornitza Stark Phenotypes for gene: CRIPT were changed from Short stature with microcephaly and distinctive facies (MIM#615789) to Short stature with microcephaly and distinctive facies (MIM#615789); Rothmund-Thomson syndrome MONDO:0010002
Growth failure v1.61 CRIPT Zornitza Stark Publications for gene: CRIPT were set to 24389050; 27250922
Growth failure v1.60 CRIPT Zornitza Stark Classified gene: CRIPT as Green List (high evidence)
Growth failure v1.60 CRIPT Zornitza Stark Gene: cript has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5201 CRIPT Zornitza Stark Marked gene: CRIPT as ready
Intellectual disability syndromic and non-syndromic v0.5201 CRIPT Zornitza Stark Gene: cript has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5201 CRIPT Zornitza Stark Classified gene: CRIPT as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5201 CRIPT Zornitza Stark Gene: cript has been classified as Green List (High Evidence).
Microcephaly v1.201 CRIPT Zornitza Stark Phenotypes for gene: CRIPT were changed from Short stature with microcephaly and distinctive facies (MIM#615789) to Short stature with microcephaly and distinctive facies (MIM#615789); Rothmund-Thomson syndrome MONDO:0010002
Microcephaly v1.200 CRIPT Zornitza Stark Publications for gene: CRIPT were set to 24389050; 27250922
Microcephaly v1.199 CRIPT Zornitza Stark Classified gene: CRIPT as Green List (high evidence)
Microcephaly v1.199 CRIPT Zornitza Stark Gene: cript has been classified as Green List (High Evidence).
Incidentalome v0.230 Zornitza Stark removed gene:ACTC1 from the panel
Mendeliome v1.791 MKL2 Zornitza Stark Marked gene: MKL2 as ready
Mendeliome v1.791 MKL2 Zornitza Stark Gene: mkl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.791 MKL2 Zornitza Stark Classified gene: MKL2 as Amber List (moderate evidence)
Mendeliome v1.791 MKL2 Zornitza Stark Gene: mkl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5200 MKL2 Zornitza Stark Marked gene: MKL2 as ready
Intellectual disability syndromic and non-syndromic v0.5200 MKL2 Zornitza Stark Gene: mkl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.790 ACTC1 Zornitza Stark Marked gene: ACTC1 as ready
Mendeliome v1.790 ACTC1 Zornitza Stark Gene: actc1 has been classified as Green List (High Evidence).
Mendeliome v1.790 ACTC1 Zornitza Stark Classified gene: ACTC1 as Green List (high evidence)
Mendeliome v1.790 ACTC1 Zornitza Stark Gene: actc1 has been classified as Green List (High Evidence).
Mendeliome v1.789 ACTC1 Zornitza Stark reviewed gene: ACTC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrial septal defect 5 MIM#612794, Cardiomyopathy, dilated, 1R MIM#613424, Cardiomyopathy, hypertrophic, 11 MIM#612098, ACTC1 related distal arthrogryposis MONDO:0019942; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.279 ACTC1 Zornitza Stark Publications for gene: ACTC1 were set to 17947298; 31430208
Congenital Heart Defect v0.278 ACTC1 Zornitza Stark Classified gene: ACTC1 as Green List (high evidence)
Congenital Heart Defect v0.278 ACTC1 Zornitza Stark Gene: actc1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5200 RNH1 Zornitza Stark Phenotypes for gene: RNH1 were changed from RNH1-related disorder to Neurodevelopmental disorder, MONDO:0700092, RNH1-related
Intellectual disability syndromic and non-syndromic v0.5199 RNH1 Zornitza Stark reviewed gene: RNH1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, RNH1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Regression v0.525 RNH1 Zornitza Stark Phenotypes for gene: RNH1 were changed from RNH1-related disorder to Neurodevelopmental disorder, MONDO:0700092, RNH1-related
Regression v0.524 RNH1 Zornitza Stark reviewed gene: RNH1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, RNH1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v0.1839 RNH1 Zornitza Stark Phenotypes for gene: RNH1 were changed from RNH1-related disorder to Neurodevelopmental disorder, MONDO:0700092, RNH1-related
Genetic Epilepsy v0.1838 RNH1 Zornitza Stark reviewed gene: RNH1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, RNH1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.789 RNH1 Zornitza Stark Phenotypes for gene: RNH1 were changed from RNH1-related disorder to Neurodevelopmental disorder, MONDO:0700092, RNH1-related
Mendeliome v1.788 RNH1 Zornitza Stark reviewed gene: RNH1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, RNH1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cataract v0.352 RNH1 Zornitza Stark Phenotypes for gene: RNH1 were changed from RNH1-related disease to Neurodevelopmental disorder, MONDO:0700092, RNH1-related
Cataract v0.351 RNH1 Zornitza Stark reviewed gene: RNH1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, RNH1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.788 POLR1A Zornitza Stark Phenotypes for gene: POLR1A were changed from Acrofacial dysostosis, Cincinnati type, (MIM#616462); Leukodystrophy to Acrofacial dysostosis, Cincinnati type, (MIM#616462); Leukodystrophy MONDO:0019046, POLR1A-related
Mendeliome v1.787 POLR1A Zornitza Stark Publications for gene: POLR1A were set to 25913037; 28051070
Mendeliome v1.786 POLR1A Zornitza Stark Mode of inheritance for gene: POLR1A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.785 POLR1A Zornitza Stark commented on gene: POLR1A: Evidence for association of bi-allelic variants with leukodystrophy is moderate.
Mendeliome v1.785 POLR1A Zornitza Stark edited their review of gene: POLR1A: Changed rating: GREEN; Changed phenotypes: Leukodystrophy MONDO:0019046, POLR1A-related, Acrofacial dysostosis, Cincinnati type, (MIM#616462); Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.99 FILIP1 Zornitza Stark Marked gene: FILIP1 as ready
Fetal anomalies v1.99 FILIP1 Zornitza Stark Gene: filip1 has been classified as Green List (High Evidence).
Fetal anomalies v1.99 FILIP1 Zornitza Stark Classified gene: FILIP1 as Green List (high evidence)
Fetal anomalies v1.99 FILIP1 Zornitza Stark Gene: filip1 has been classified as Green List (High Evidence).
Fetal anomalies v1.98 FILIP1 Zornitza Stark Phenotypes for gene: FILIP1 were changed from Arthrogryposis multiplex congenita MONDO:0015168 to Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 related
Microcephaly v1.198 FILIP1 Zornitza Stark Marked gene: FILIP1 as ready
Microcephaly v1.198 FILIP1 Zornitza Stark Gene: filip1 has been classified as Green List (High Evidence).
Microcephaly v1.198 FILIP1 Zornitza Stark Phenotypes for gene: FILIP1 were changed from Arthrogryposis multiplex congenita MONDO:0015168 to Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 related
Microcephaly v1.197 FILIP1 Zornitza Stark Classified gene: FILIP1 as Green List (high evidence)
Microcephaly v1.197 FILIP1 Zornitza Stark Gene: filip1 has been classified as Green List (High Evidence).
Mendeliome v1.785 FILIP1 Zornitza Stark Marked gene: FILIP1 as ready
Mendeliome v1.785 FILIP1 Zornitza Stark Gene: filip1 has been classified as Green List (High Evidence).
Mendeliome v1.785 FILIP1 Zornitza Stark Phenotypes for gene: FILIP1 were changed from Arthrogryposis multiplex congenita MONDO:0015168 to Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 related
Mendeliome v1.784 FILIP1 Zornitza Stark Classified gene: FILIP1 as Green List (high evidence)
Mendeliome v1.784 FILIP1 Zornitza Stark Gene: filip1 has been classified as Green List (High Evidence).
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.310 TP63 Zornitza Stark Phenotypes for gene: TP63 were changed from Premature ovarian insufficiency; Limb-mammary syndrome MIM#603543; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 MIM#604292 to Premature ovarian failure-21, MIM#620311; Limb-mammary syndrome MIM#603543; Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 MIM#604292
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.309 TP63 Zornitza Stark reviewed gene: TP63: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Premature ovarian failure-21, MIM#620311; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rhabdomyolysis and Metabolic Myopathy v0.93 C1QBP Bryony Thompson gene: C1QBP was added
gene: C1QBP was added to Rhabdomyolysis. Sources: Literature
Mode of inheritance for gene: C1QBP was set to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.783 BIN1 Bryony Thompson Publications for gene: BIN1 were set to 17676042
Mendeliome v1.782 BIN1 Bryony Thompson Added comment: Comment on mode of inheritance: ClinGen Definititive for semidominant for centronuclear myopathy by the Congenital myopathy GCEP - Classification - 04/27/2020
Mendeliome v1.782 BIN1 Bryony Thompson Mode of inheritance for gene: BIN1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.781 VWA8 Dean Phelan gene: VWA8 was added
gene: VWA8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VWA8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VWA8 were set to PMID: 37012052
Phenotypes for gene: VWA8 were set to Retinitis pigmentosa (MONDO:0019200), VWA8-related
Review for gene: VWA8 was set to AMBER
Added comment: PMID: 37012052
- Single family with 11 affected patients, 9 - 87y, all presented initial symptoms of night blindness, visual field defects and reduced visual acuity later, macular changes, including macular degeneration and dystrophy. A heterozygous two-loci variant in VWA8 c.3070G>A;c.4558C>T (p.Gly1024Arg; p.Arg1520Ter) was identified and segregated with disease. Expression studies showed reduced protein expression. Zebrafish knockout model displayed an RP phenotype.
Sources: Literature
Mendeliome v1.781 MKL2 Dean Phelan gene: MKL2 was added
gene: MKL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MKL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MKL2 were set to PMID: 37013900
Phenotypes for gene: MKL2 were set to Neurodevelopmental disorder (MONDO:0700092), MKL2-related
Mode of pathogenicity for gene: MKL2 was set to Other
Review for gene: MKL2 was set to AMBER
Added comment: PMID: 37013900
- de novo missense variants in MKL2 (now known as MRTFB) were identified in two patients with mild dysmorphic features, intellectual disability, global developmental delay, speech apraxia, and impulse control issues. Functional studies in a Drosophila model suggest a gain of function disease mechanism.
Sources: Literature
Mitochondrial disease v0.864 SLC25A36 Bryony Thompson Marked gene: SLC25A36 as ready
Mitochondrial disease v0.864 SLC25A36 Bryony Thompson Gene: slc25a36 has been classified as Green List (High Evidence).
Mitochondrial disease v0.864 SLC25A36 Bryony Thompson Classified gene: SLC25A36 as Green List (high evidence)
Mitochondrial disease v0.864 SLC25A36 Bryony Thompson Gene: slc25a36 has been classified as Green List (High Evidence).
Mitochondrial disease v0.863 PPCS Bryony Thompson Publications for gene: PPCS were set to 29754768
Mitochondrial disease v0.863 PPCS Bryony Thompson Classified gene: PPCS as Green List (high evidence)
Mitochondrial disease v0.863 PPCS Bryony Thompson Gene: ppcs has been classified as Green List (High Evidence).
Mitochondrial disease v0.862 ATP5E Bryony Thompson Publications for gene: ATP5E were set to 20566710; 27626380; 20026007
Mitochondrial disease v0.861 ATP5E Bryony Thompson Classified gene: ATP5E as Green List (high evidence)
Mitochondrial disease v0.861 ATP5E Bryony Thompson Gene: atp5e has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1838 RNH1 Seb Lunke Marked gene: RNH1 as ready
Genetic Epilepsy v0.1838 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Regression v0.524 RNH1 Seb Lunke Marked gene: RNH1 as ready
Regression v0.524 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5199 RNH1 Seb Lunke Marked gene: RNH1 as ready
Intellectual disability syndromic and non-syndromic v0.5199 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5199 RNH1 Seb Lunke Classified gene: RNH1 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.5199 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1838 RNH1 Seb Lunke Classified gene: RNH1 as Red List (low evidence)
Genetic Epilepsy v0.1838 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Regression v0.524 RNH1 Seb Lunke Classified gene: RNH1 as Red List (low evidence)
Regression v0.524 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Mendeliome v1.781 RNH1 Seb Lunke Marked gene: RNH1 as ready
Mendeliome v1.781 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Mendeliome v1.781 RNH1 Seb Lunke Classified gene: RNH1 as Red List (low evidence)
Mendeliome v1.781 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Fetal anomalies v1.97 ESAM Seb Lunke Marked gene: ESAM as ready
Fetal anomalies v1.97 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Fetal anomalies v1.97 ESAM Seb Lunke Classified gene: ESAM as Green List (high evidence)
Fetal anomalies v1.97 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1837 ESAM Seb Lunke Marked gene: ESAM as ready
Genetic Epilepsy v0.1837 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Mendeliome v1.780 ESAM Seb Lunke Marked gene: ESAM as ready
Mendeliome v1.780 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Brain Calcification v1.51 ESAM Seb Lunke Marked gene: ESAM as ready
Brain Calcification v1.51 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1837 ESAM Seb Lunke Classified gene: ESAM as Green List (high evidence)
Genetic Epilepsy v0.1837 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Brain Calcification v1.51 ESAM Seb Lunke Classified gene: ESAM as Green List (high evidence)
Brain Calcification v1.51 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Mendeliome v1.780 ESAM Seb Lunke Classified gene: ESAM as Green List (high evidence)
Mendeliome v1.780 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5198 CRIPT Karina Sandoval commented on gene: CRIPT: PMID: 37013901 identified 6 individuals with Rothmund-Thomson syndrome characterised by poikiloderma, sparse hair, small stature, skeletal defects, cancer, cataracts, resembling features of premature aging. Two new variants identified and 4 were already published. 5 were hom, 1 was chet, all with different variants.
All CRIPT individuals fulfilled the diagnostic criteria for RTS, and additionally had neurodevelopmental delay and seizures.

CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors,

c.132del p.(Ala45Glyfs*82), hom
c.227G>A, p.(Cys76Tyr), hom
c.133_134insGG,p.(Ala45Glyfs*82),hom
c.141del p.(Phe47Leufs*84), hom
c.8G>A p.(Cys3Tyr), 1,331 bp del exon 1, chet
c.7_8del; p.(Cys3Argfs*4), hom
Intellectual disability syndromic and non-syndromic v0.5198 CRIPT Karina Sandoval gene: CRIPT was added
gene: CRIPT was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CRIPT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CRIPT were set to PMID: 37013901
Phenotypes for gene: CRIPT were set to Short stature with microcephaly and distinctive facies (MIM#615789) : Rothmund-Thomson syndrome MONDO:0010002
Review for gene: CRIPT was set to GREEN
Added comment: Sources: Literature
Growth failure v1.59 CRIPT Karina Sandoval reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37013901; Phenotypes: Short stature with microcephaly and distinctive facies (MIM#615789), Rothmund-Thomson syndrome MONDO:0010002; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5198 MKL2 Zornitza Stark Classified gene: MKL2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5198 MKL2 Zornitza Stark Gene: mkl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.779 CRIPT Zornitza Stark Phenotypes for gene: CRIPT were changed from Short stature with microcephaly and distinctive facies (MIM#615789) to Short stature with microcephaly and distinctive facies (MIM#615789); Rothmund-Thomson syndrome MONDO:0010002
Mendeliome v1.778 CRIPT Zornitza Stark Classified gene: CRIPT as Green List (high evidence)
Mendeliome v1.778 CRIPT Zornitza Stark Gene: cript has been classified as Green List (High Evidence).
Fetal anomalies v1.96 CRIPT Zornitza Stark Phenotypes for gene: CRIPT were changed from Short stature with microcephaly and distinctive facies, 615789 to Short stature with microcephaly and distinctive facies (MIM#615789); Rothmund-Thomson syndrome MONDO:0010002
Fetal anomalies v1.95 CRIPT Zornitza Stark Publications for gene: CRIPT were set to 24389050; 27250922
Fetal anomalies v1.94 CRIPT Zornitza Stark Classified gene: CRIPT as Green List (high evidence)
Fetal anomalies v1.94 CRIPT Zornitza Stark Gene: cript has been classified as Green List (High Evidence).
Microcephaly v1.196 CRIPT Karina Sandoval reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37013901; Phenotypes: Short stature with microcephaly and distinctive facies (MIM#615789), Rothmund-Thomson syndrome MONDO:0010002; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinitis pigmentosa v0.132 CEP162 Zornitza Stark Marked gene: CEP162 as ready
Retinitis pigmentosa v0.132 CEP162 Zornitza Stark Gene: cep162 has been classified as Amber List (Moderate Evidence).
Retinitis pigmentosa v0.132 CEP162 Zornitza Stark Marked gene: CEP162 as ready
Retinitis pigmentosa v0.132 CEP162 Zornitza Stark Gene: cep162 has been classified as Amber List (Moderate Evidence).
Retinitis pigmentosa v0.132 CEP162 Zornitza Stark Classified gene: CEP162 as Amber List (moderate evidence)
Retinitis pigmentosa v0.132 CEP162 Zornitza Stark Gene: cep162 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.777 CEP162 Zornitza Stark Marked gene: CEP162 as ready
Mendeliome v1.777 CEP162 Zornitza Stark Gene: cep162 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.777 CEP162 Zornitza Stark Classified gene: CEP162 as Amber List (moderate evidence)
Mendeliome v1.777 CEP162 Zornitza Stark Gene: cep162 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.93 CRIPT Karina Sandoval reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37013901; Phenotypes: Short stature with microcephaly and distinctive facies (MIM#615789), Rothmund-Thomson syndrome MONDO:0010002; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.776 CRIPT Karina Sandoval changed review comment from: PMID: 37013901 identified 6 individuals with Rothmund-Thomson syndrome, two new identified and 4 were already published. 5 were hom, 1 was chet, all with different variants. Additionally all presented with neuro dev delay and seizures.

CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors,

c.132del p.(Ala45Glyfs*82), hom
c.227G>A, p.(Cys76Tyr), hom
c.133_134insGG,p.(Ala45Glyfs*82),hom
c.141del p.(Phe47Leufs*84), hom
c.8G>A p.(Cys3Tyr), 1,331 bp del exon 1, chet
c.7_8del; p.(Cys3Argfs*4), hom; to: PMID: 37013901 identified 6 individuals with Rothmund-Thomson syndrome characterised by poikiloderma, sparse hair, small stature, skeletal defects, cancer, cataracts, resembling features of premature aging. Two new variants identified and 4 were already published. 5 were hom, 1 was chet, all with different variants.
All CRIPT individuals fulfilled the diagnostic criteria for RTS, and additionally had neurodevelopmental delay and seizures.

CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors,

c.132del p.(Ala45Glyfs*82), hom
c.227G>A, p.(Cys76Tyr), hom
c.133_134insGG,p.(Ala45Glyfs*82),hom
c.141del p.(Phe47Leufs*84), hom
c.8G>A p.(Cys3Tyr), 1,331 bp del exon 1, chet
c.7_8del; p.(Cys3Argfs*4), hom
Fetal anomalies v1.93 ACTC1 Lilian Downie reviewed gene: ACTC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36945405; Phenotypes: Atrial septal defect 5 MIM#612794, Cardiomyopathy, dilated, 1R MIM#613424, Cardiomyopathy, hypertrophic, 11 MIM#612098, ACTC1 related distal arthrogryposis MONDO:0019942; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.776 CEP162 Paul De Fazio gene: CEP162 was added
gene: CEP162 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CEP162 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP162 were set to 36862503
Phenotypes for gene: CEP162 were set to Retinitis pigmentosa MONDO:0019200, CEP162-related
Penetrance for gene: CEP162 were set to unknown
Review for gene: CEP162 was set to AMBER
gene: CEP162 was marked as current diagnostic
Added comment: 2 patients from reportedly unrelated consanguineous Moroccan families with the same homozygous frameshift variant reported with late-onset retinal degeneration. Patient 1 was diagnosed with RP at age 60, patient 2 at age 69. Both reported loss of visual acuity in the years prior.

Immunoblotting of cell lysates from patient fibroblasts showed that some mutant transcript escaped NMD. Functional testing showed that the truncated protein could bind microtubules but was unable to associate with centrioles or its interaction partner CEP290. Patient fibroblasts were shown to have delayed ciliation.

Mutant protein was unable to rescue loss of cilia in CEP162 knockdown mice supporting that the mutant protein does not retain any ciliary function, however additional data supported that the truncated protein was able to bind microtubules and function normally during neuroretinal development. The authors suggest this likely underlies the late-onset RP in both patients.

Rated Amber because only a single variant has been reported in patients who may or may not be related (same ethnic background).
Sources: Literature
Arthrogryposis v0.395 ACTC1 Zornitza Stark Marked gene: ACTC1 as ready
Arthrogryposis v0.395 ACTC1 Zornitza Stark Gene: actc1 has been classified as Green List (High Evidence).
Mendeliome v1.776 ACTC1 Lilian Downie gene: ACTC1 was added
gene: ACTC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ACTC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACTC1 were set to PMID: 36945405
Phenotypes for gene: ACTC1 were set to Atrial septal defect 5 MIM#612794; Cardiomyopathy, dilated, 1R MIM#613424; Cardiomyopathy, hypertrophic, 11 MIM#612098; ACTC1 related distal arthrogryposis MONDO:0019942
Review for gene: ACTC1 was set to GREEN
Added comment: ClinGen definitive association with HCM, moderate for DCM
5 new families (8 individuals) with a distral arthrogryposis phenotype (PMID: 36945405)
multiple congenital contractures, neck pterygia, scoliosis, and congenital heart defects/cardiomyopathy
facial features: microretrognathia, ptosis, downslanting palpebral fissures, low-set ears, and a long nasal bridge
All missense variants
Sources: Literature
Syndromic Retinopathy v0.197 CLCN2 Michelle Torres gene: CLCN2 was added
gene: CLCN2 was added to Syndromic Retinopathy. Sources: Literature
Mode of inheritance for gene: CLCN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLCN2 were set to 36964785
Phenotypes for gene: CLCN2 were set to Leukoencephalopathy with ataxia MIM# 615651
Review for gene: CLCN2 was set to GREEN
Added comment: The homozygous R753X was detected in a Chinese individual from a consanguineous family with leukodystrophy with ataxia (LKPAT) (described in a previous paper) as well as severe bilateral retinal degeneration with loss of photoreceptor and RPE.

Four additional patients with LKPAT (described elsewhere) have been reported with homozygous variants and ocular features (Table 1).

Transfection to HEK293T cells showed that R753X reduced channel activity compared to wild-type.

Additionally, patient iPSC-derived RPE cells carrying the R753X exhibited dysfunctional ClC-2 chloride channels and outer segment phagocytosis. These functions were rescued following the repair of the CLCN2 mutation using the CRISPR-Cas9 system. NB: No significant difference was observed in the R753X mRNA expression levels between the control and patient hiPSC-RPE cells (suggesting NMD escape).
Sources: Literature
Arthrogryposis v0.395 ACTC1 Zornitza Stark Classified gene: ACTC1 as Green List (high evidence)
Arthrogryposis v0.395 ACTC1 Zornitza Stark Gene: actc1 has been classified as Green List (High Evidence).
Vascular Malformations_Somatic v1.8 MAP3K3 Naomi Baker reviewed gene: MAP3K3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33729480, 35355835, 33891857, 36995941; Phenotypes: Cerebral malformation, MONDO:0016054, MAP3K3-related; Mode of inheritance: Other
Mendeliome v1.776 CRIPT Karina Sandoval reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37013901; Phenotypes: Short stature with microcephaly and distinctive facies (MIM#615789), Rothmund-Thomson syndrome MONDO:0010002; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinitis pigmentosa v0.131 CEP162 Paul De Fazio gene: CEP162 was added
gene: CEP162 was added to Retinitis pigmentosa_Autosomal Recessive/X-linked. Sources: Literature
Mode of inheritance for gene: CEP162 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP162 were set to 36862503
Phenotypes for gene: CEP162 were set to Retinitis pigmentosa MONDO:0019200, CEP162-related
Penetrance for gene: CEP162 were set to unknown
Review for gene: CEP162 was set to AMBER
gene: CEP162 was marked as current diagnostic
Added comment: 2 patients from reportedly unrelated consanguineous Moroccan families with the same homozygous frameshift variant reported with late-onset retinal degeneration. Patient 1 was diagnosed with RP at age 60, patient 2 at age 69. Both reported loss of visual acuity in the years prior.

Immunoblotting of cell lysates from patient fibroblasts showed that some mutant transcript escaped NMD. Functional testing showed that the truncated protein could bind microtubules but was unable to associate with centrioles or its interaction partner CEP290. Patient fibroblasts were shown to have delayed ciliation.

Mutant protein was unable to rescue loss of cilia in CEP162 knockdown mice supporting that the mutant protein does not retain any ciliary function, however additional data supported that the truncated protein was able to bind microtubules and function normally during neuroretinal development. The authors suggest this likely underlies the late-onset RP in both patients.

Rated Amber because only a single variant has been reported in patients who may or may not be related (same ethnic background).
Sources: Literature
Hereditary Spastic Paraplegia v1.58 SNAPC4 Zornitza Stark Marked gene: SNAPC4 as ready
Hereditary Spastic Paraplegia v1.58 SNAPC4 Zornitza Stark Gene: snapc4 has been classified as Green List (High Evidence).
Mendeliome v1.776 DOCK11 Seb Lunke Marked gene: DOCK11 as ready
Mendeliome v1.776 DOCK11 Seb Lunke Gene: dock11 has been classified as Green List (High Evidence).
Mendeliome v1.776 DOCK11 Seb Lunke Classified gene: DOCK11 as Green List (high evidence)
Mendeliome v1.776 DOCK11 Seb Lunke Gene: dock11 has been classified as Green List (High Evidence).
Hereditary Spastic Paraplegia v1.58 SNAPC4 Zornitza Stark Classified gene: SNAPC4 as Green List (high evidence)
Hereditary Spastic Paraplegia v1.58 SNAPC4 Zornitza Stark Gene: snapc4 has been classified as Green List (High Evidence).
Fetal anomalies v1.93 ESAM Chern Lim gene: ESAM was added
gene: ESAM was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to 36996813
Phenotypes for gene: ESAM were set to Neurodevelopmental disorder (MONDO#0700092), ESAM-related
Review for gene: ESAM was set to GREEN
gene: ESAM was marked as current diagnostic
Added comment: PMID 36996813
- Thirteen affected individuals, including four fetuses, from eight unrelated families, with homozygous loss-of-function-type variants in ESAM – 2 of the variants are frameshifts, 1x nonsense, 1x canonical splice.
- Affected individuals have profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses.
- One of the frameshift variant c.115del (p.Arg39Glyfs*33), was detected in six individuals from four unrelated families from the same geographic region in Turkey (southeastern Anatolia), suggesting a founder effect.
- The c.451+1G>A variant was detected in three individuals from two independent families with the same ethnic origin (Arab Bedouin)
Sources: Literature
Mendeliome v1.775 POLR1A Lucy Spencer reviewed gene: POLR1A: Rating: AMBER; Mode of pathogenicity: None; Publications: 28051070, 36917474; Phenotypes: Leukodystrophy MONDO:0019046, POLR1A-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.50 ESAM Chern Lim gene: ESAM was added
gene: ESAM was added to Brain Calcification. Sources: Literature
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to 36996813
Phenotypes for gene: ESAM were set to Neurodevelopmental disorder (MONDO#0700092), ESAM-related
Review for gene: ESAM was set to GREEN
gene: ESAM was marked as current diagnostic
Added comment: PMID 36996813
- Thirteen affected individuals, including four fetuses, from eight unrelated families, with homozygous loss-of-function-type variants in ESAM – 2 of the variants are frameshifts, 1x nonsense, 1x canonical splice.
- Affected individuals have profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses.
- One of the frameshift variant c.115del (p.Arg39Glyfs*33), was detected in six individuals from four unrelated families from the same geographic region in Turkey (southeastern Anatolia), suggesting a founder effect.
- The c.451+1G>A variant was detected in three individuals from two independent families with the same ethnic origin (Arab Bedouin)
Sources: Literature
Disorders of immune dysregulation v0.168 DOCK11 Seb Lunke Marked gene: DOCK11 as ready
Disorders of immune dysregulation v0.168 DOCK11 Seb Lunke Gene: dock11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5197 SNAPC4 Zornitza Stark Marked gene: SNAPC4 as ready
Intellectual disability syndromic and non-syndromic v0.5197 SNAPC4 Zornitza Stark Gene: snapc4 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v0.168 DOCK11 Seb Lunke Classified gene: DOCK11 as Green List (high evidence)
Disorders of immune dysregulation v0.168 DOCK11 Seb Lunke Gene: dock11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5197 SNAPC4 Zornitza Stark Classified gene: SNAPC4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5197 SNAPC4 Zornitza Stark Gene: snapc4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1836 ESAM Chern Lim gene: ESAM was added
gene: ESAM was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to 36996813
Phenotypes for gene: ESAM were set to Neurodevelopmental disorder (MONDO#0700092), ESAM-related
Review for gene: ESAM was set to GREEN
gene: ESAM was marked as current diagnostic
Added comment: PMID 36996813
- Thirteen affected individuals, including four fetuses, from eight unrelated families, with homozygous loss-of-function-type variants in ESAM – 2 of the variants are frameshifts, 1x nonsense, 1x canonical splice.
- Affected individuals have profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses.
- One of the frameshift variant c.115del (p.Arg39Glyfs*33), was detected in six individuals from four unrelated families from the same geographic region in Turkey (southeastern Anatolia), suggesting a founder effect.
- The c.451+1G>A variant was detected in three individuals from two independent families with the same ethnic origin (Arab Bedouin)
Sources: Literature
Microcephaly v1.196 SNAPC4 Zornitza Stark Marked gene: SNAPC4 as ready
Microcephaly v1.196 SNAPC4 Zornitza Stark Gene: snapc4 has been classified as Green List (High Evidence).
Microcephaly v1.196 SNAPC4 Zornitza Stark Classified gene: SNAPC4 as Green List (high evidence)
Microcephaly v1.196 SNAPC4 Zornitza Stark Gene: snapc4 has been classified as Green List (High Evidence).
Mendeliome v1.775 ESAM Chern Lim gene: ESAM was added
gene: ESAM was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to 36996813
Phenotypes for gene: ESAM were set to Neurodevelopmental disorder (MONDO#0700092), ESAM-related
Review for gene: ESAM was set to GREEN
gene: ESAM was marked as current diagnostic
Added comment: PMID 36996813
- Thirteen affected individuals, including four fetuses, from eight unrelated families, with homozygous loss-of-function-type variants in ESAM – 2 of the variants are frameshifts, 1x nonsense, 1x canonical splice.
- Affected individuals have profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses.
- One of the frameshift variant c.115del (p.Arg39Glyfs*33), was detected in six individuals from four unrelated families from the same geographic region in Turkey (southeastern Anatolia), suggesting a founder effect.
- The c.451+1G>A variant was detected in three individuals from two independent families with the same ethnic origin (Arab Bedouin)
Sources: Literature
Mendeliome v1.775 SNAPC4 Zornitza Stark Marked gene: SNAPC4 as ready
Mendeliome v1.775 SNAPC4 Zornitza Stark Gene: snapc4 has been classified as Green List (High Evidence).
Mendeliome v1.775 SNAPC4 Zornitza Stark Classified gene: SNAPC4 as Green List (high evidence)
Mendeliome v1.775 SNAPC4 Zornitza Stark Gene: snapc4 has been classified as Green List (High Evidence).
Mendeliome v1.774 SNAPC4 Ee Ming Wong changed review comment from: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature; to: - Ten individuals from eight families with neurodevelopmental disorder found to be biallelic for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Hereditary Spastic Paraplegia v1.57 SNAPC4 Ee Ming Wong changed review comment from: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature; to: - Ten individuals from eight families with neurodevelopmental disorder found to be biallelic for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Mendeliome v1.774 DOCK11 Lucy Spencer gene: DOCK11 was added
gene: DOCK11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DOCK11 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DOCK11 were set to 36952639
Phenotypes for gene: DOCK11 were set to autoimmune disease MONDO:0007179, DOCK11-related
Review for gene: DOCK11 was set to GREEN
Added comment: 8 male patients from 7 unrelated families all with hemizygous DOCK11 missense variants. 6 mothers were tested and found to carry the same missense. Early onset autoimmuniy with cytopenia, systemic lupus erythematosus, and skin and digestive manifestations. Patients platelets had abnormal morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B lymphoblastoid cell lines (B-LCL) of patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. A DOCK11 knock-down recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells (MDDC) and primary activated T cells from healthy controls.

6 of the variants are either absent or have only 1 het in gnomad v2, but one of them has 2 hemis and 1 het. The patient with this variant R1885C does seem to be more mild.
Sources: Literature
Microcephaly v1.195 SNAPC4 Ee Ming Wong changed review comment from: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature; to: - Ten individuals from eight families with neurodevelopmental disorder found to be biallelic for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5196 SNAPC4 Ee Ming Wong changed review comment from: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature; to: - Ten individuals from eight families with neurodevelopmental disorder found to be biallelic for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Arthrogryposis v0.394 ACTC1 Lilian Downie gene: ACTC1 was added
gene: ACTC1 was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: ACTC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACTC1 were set to PMID: 36945405
Phenotypes for gene: ACTC1 were set to MONDO:0019942 ACTC1 related distal arthrogrypsis
Penetrance for gene: ACTC1 were set to Incomplete
Review for gene: ACTC1 was set to GREEN
Added comment: 5 new families (8 individuals) with a distral arthrogryposis phenotype:
multiple congenital contractures, neck pterygia, scoliosis, and congenital heart defects/cardiomyopathy, short stature
All missense variants
One variant p.Arg185Trp previously reported in patient with cardiac phenotype only
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5196 ESAM Seb Lunke Marked gene: ESAM as ready
Intellectual disability syndromic and non-syndromic v0.5196 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5196 ESAM Seb Lunke Classified gene: ESAM as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5196 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5195 RNH1 Krithika Murali edited their review of gene: RNH1: Changed rating: RED
Intellectual disability syndromic and non-syndromic v0.5195 SNAPC4 Ee Ming Wong gene: SNAPC4 was added
gene: SNAPC4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SNAPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPC4 were set to 36965478
Phenotypes for gene: SNAPC4 were set to Neurodevelopmental disorder (MONDO#0700092), SNAPC4-related
Review for gene: SNAPC4 was set to GREEN
gene: SNAPC4 was marked as current diagnostic
Added comment: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Regression v0.523 RNH1 Krithika Murali edited their review of gene: RNH1: Changed rating: RED
Genetic Epilepsy v0.1836 RNH1 Krithika Murali edited their review of gene: RNH1: Changed rating: RED
Arthrogryposis v0.394 FILIP1 Zornitza Stark Marked gene: FILIP1 as ready
Arthrogryposis v0.394 FILIP1 Zornitza Stark Gene: filip1 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v0.167 DOCK11 Lucy Spencer gene: DOCK11 was added
gene: DOCK11 was added to Disorders of immune dysregulation. Sources: Literature
Mode of inheritance for gene: DOCK11 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DOCK11 were set to 36952639
Phenotypes for gene: DOCK11 were set to autoimmune disease MONDO:0007179, DOCK11-related
Review for gene: DOCK11 was set to GREEN
Added comment: 8 male patients from 7 unrelated families all with hemizygous DOCK11 missense variants. 6 mothers were tested and found to carry the same missense. Early onset autoimmuniy with cytopenia, systemic lupus erythematosus, and skin and digestive manifestations. Patients platelets had abnormal morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B lymphoblastoid cell lines (B-LCL) of patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. A DOCK11 knock-down recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells (MDDC) and primary activated T cells from healthy controls.

6 of the variants are either absent or have only 1 het in gnomad v2, but one of them has 2 hemis and 1 het. The patient with this variant R1885C does seem to be more mild.
Sources: Literature
Cataract v0.351 RNH1 Seb Lunke Marked gene: RNH1 as ready
Cataract v0.351 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Cataract v0.351 RNH1 Seb Lunke Classified gene: RNH1 as Red List (low evidence)
Cataract v0.351 RNH1 Seb Lunke Added comment: Comment on list classification: One consanguineous family only
Cataract v0.351 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Mendeliome v1.774 RNH1 Krithika Murali edited their review of gene: RNH1: Changed rating: RED
Arthrogryposis v0.394 FILIP1 Zornitza Stark Phenotypes for gene: FILIP1 were changed from Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 to Arthrogryposis multiplex congenita MONDO:0015168, FILIP1-related
Fetal anomalies v1.93 FILIP1 Paul De Fazio edited their review of gene: FILIP1: Changed phenotypes: Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 related
Microcephaly v1.195 FILIP1 Paul De Fazio edited their review of gene: FILIP1: Changed phenotypes: Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 related
Leukodystrophy v0.285 POLR1A Zornitza Stark Marked gene: POLR1A as ready
Leukodystrophy v0.285 POLR1A Zornitza Stark Gene: polr1a has been classified as Amber List (Moderate Evidence).
Mendeliome v1.774 FILIP1 Paul De Fazio edited their review of gene: FILIP1: Changed phenotypes: Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 related
Arthrogryposis v0.394 FILIP1 Zornitza Stark Phenotypes for gene: FILIP1 were changed from Arthrogryposis multiplex congenita MONDO:0015168 to Arthrogryposis multiplex congenita MONDO:0015168, FILIP1
Intellectual disability syndromic and non-syndromic v0.5195 MKL2 Dean Phelan gene: MKL2 was added
gene: MKL2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MKL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MKL2 were set to PMID: 37013900
Phenotypes for gene: MKL2 were set to Neurodevelopmental disorder (MONDO:0700092), MKL2-related
Mode of pathogenicity for gene: MKL2 was set to Other
Review for gene: MKL2 was set to AMBER
Added comment: PMID: 37013900
- de novo missense variants in MKL2 (now known as MRTFB) were identified in two patients with mild dysmorphic features, intellectual disability, global developmental delay, speech apraxia, and impulse control issues. Functional studies in a Drosophila model suggest a gain of function disease mechanism.
Sources: Literature
Microcephaly v1.195 SNAPC4 Ee Ming Wong gene: SNAPC4 was added
gene: SNAPC4 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: SNAPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPC4 were set to 36965478
Phenotypes for gene: SNAPC4 were set to Neurodevelopmental disorder (MONDO#0700092), SNAPC4-related
Review for gene: SNAPC4 was set to GREEN
gene: SNAPC4 was marked as current diagnostic
Added comment: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Fetal anomalies v1.93 FILIP1 Paul De Fazio gene: FILIP1 was added
gene: FILIP1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FILIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FILIP1 were set to 36943452
Phenotypes for gene: FILIP1 were set to Arthrogryposis multiplex congenita MONDO:0015168
Penetrance for gene: FILIP1 were set to unknown
Review for gene: FILIP1 was set to GREEN
gene: FILIP1 was marked as current diagnostic
Added comment: 3 families, all consanguineous, reported with 3 different homozygous loss of function variants (2x NMD-predicted nonsense, 1x intragenic deletion of exons 3-6 of 6). In one family, the variant segregated in 3 affected siblings.

Phenotypes consist of congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly (-1.5 to -4 SD), and facial dysmorphism.
Sources: Literature
Leukodystrophy v0.285 POLR1A Zornitza Stark Phenotypes for gene: POLR1A were changed from ataxia; psychomotor retardation; cerebellar and cerebral atrophy; leukodystrophy to Leukodystrophy MONDO:0019046, POLR1A related
Leukodystrophy v0.284 POLR1A Zornitza Stark Publications for gene: POLR1A were set to 28051070
Leukodystrophy v0.283 POLR1A Zornitza Stark Classified gene: POLR1A as Amber List (moderate evidence)
Leukodystrophy v0.283 POLR1A Zornitza Stark Gene: polr1a has been classified as Amber List (Moderate Evidence).
Mendeliome v1.774 RNH1 Krithika Murali changed review comment from: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature; to: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis. No antenatal features reported.
Sources: Literature
Hereditary Spastic Paraplegia v1.57 SNAPC4 Ee Ming Wong gene: SNAPC4 was added
gene: SNAPC4 was added to Hereditary Spastic Paraplegia - paediatric. Sources: Literature
Mode of inheritance for gene: SNAPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPC4 were set to 36965478
Phenotypes for gene: SNAPC4 were set to Neurodevelopmental disorder (MONDO#0700092), SNAPC4-related
Review for gene: SNAPC4 was set to GREEN
gene: SNAPC4 was marked as current diagnostic
Added comment: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Arthrogryposis v0.393 FILIP1 Zornitza Stark Classified gene: FILIP1 as Green List (high evidence)
Arthrogryposis v0.393 FILIP1 Zornitza Stark Gene: filip1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.277 ACTC1 Lilian Downie reviewed gene: ACTC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36945405; Phenotypes: Atrial septal defect 5 MIM#612794; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.774 SNAPC4 Ee Ming Wong gene: SNAPC4 was added
gene: SNAPC4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SNAPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPC4 were set to 36965478
Phenotypes for gene: SNAPC4 were set to Neurodevelopmental disorder (MONDO#0700092), SNAPC4-related
Review for gene: SNAPC4 was set to GREEN
gene: SNAPC4 was marked as current diagnostic
Added comment: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Mendeliome v1.774 DAAM2 Zornitza Stark Phenotypes for gene: DAAM2 were changed from Nephrotic syndrome, type 24, MIM# 619263; steroid-resistant nephrotic syndrome (SRNS) to Nephrotic syndrome, type 24, MIM# 619263; steroid-resistant nephrotic syndrome (SRNS); Androgen insensitivity syndrome, MONDO:0019154, DAAM2-related
Mendeliome v1.773 RNH1 Krithika Murali gene: RNH1 was added
gene: RNH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNH1 were set to PMID: 36935417
Phenotypes for gene: RNH1 were set to RNH1-related disorder
Review for gene: RNH1 was set to AMBER
Added comment: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature
Mendeliome v1.773 DAAM2 Zornitza Stark Publications for gene: DAAM2 were set to 33232676
Mendeliome v1.772 DAAM2 Zornitza Stark Mode of inheritance for gene: DAAM2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.771 DAAM2 Zornitza Stark edited their review of gene: DAAM2: Added comment: AIS: 6 unrelated individuals with extensive functional data.; Changed publications: 33232676, 36972684; Changed phenotypes: Nephrotic syndrome, type 24, MIM# 619263, Steroid-resistant nephrotic syndrome (SRNS), Androgen insensitivity syndrome, MONDO:0019154, DAAM2-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Differences of Sex Development v0.274 DAAM2 Zornitza Stark Marked gene: DAAM2 as ready
Differences of Sex Development v0.274 DAAM2 Zornitza Stark Gene: daam2 has been classified as Green List (High Evidence).
Differences of Sex Development v0.274 DAAM2 Zornitza Stark Classified gene: DAAM2 as Green List (high evidence)
Differences of Sex Development v0.274 DAAM2 Zornitza Stark Gene: daam2 has been classified as Green List (High Evidence).
Cataract v0.350 RNH1 Krithika Murali changed review comment from: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, regression in the context of infection and seizures. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature; to: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, regression in the context of infection and seizures. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature
Differences of Sex Development v0.273 DAAM2 Zornitza Stark gene: DAAM2 was added
gene: DAAM2 was added to Differences of Sex Development. Sources: Literature
Mode of inheritance for gene: DAAM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DAAM2 were set to 36972684
Phenotypes for gene: DAAM2 were set to Androgen insensitivity syndrome, MONDO:0019154, DAAM2-related
Review for gene: DAAM2 was set to GREEN
Added comment: 6 unrelated individuals with extensive functional data.
Sources: Literature
Genetic Epilepsy v0.1836 RNH1 Krithika Murali gene: RNH1 was added
gene: RNH1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: RNH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNH1 were set to PMID: 36935417
Phenotypes for gene: RNH1 were set to RNH1-related disorder
Review for gene: RNH1 was set to AMBER
Added comment: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature
Mendeliome v1.771 MB Elena Savva Classified gene: MB as Green List (high evidence)
Mendeliome v1.771 MB Elena Savva Gene: mb has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5195 RNH1 Krithika Murali gene: RNH1 was added
gene: RNH1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RNH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNH1 were set to PMID: 36935417
Phenotypes for gene: RNH1 were set to RNH1-related disorder
Review for gene: RNH1 was set to AMBER
Added comment: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature
Mendeliome v1.770 MB Elena Savva Classified gene: MB as Green List (high evidence)
Mendeliome v1.770 MB Elena Savva Gene: mb has been classified as Green List (High Evidence).
Mendeliome v1.769 MB Elena Savva Marked gene: MB as ready
Mendeliome v1.769 MB Elena Savva Gene: mb has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5195 ESAM Chern Lim gene: ESAM was added
gene: ESAM was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to 36996813
Phenotypes for gene: ESAM were set to Neurodevelopmental disorder (MONDO#0700092), ESAM-related
Review for gene: ESAM was set to GREEN
gene: ESAM was marked as current diagnostic
Added comment: PMID 36996813:
- Thirteen affected individuals, including four fetuses, from eight unrelated families, with homozygous loss-of-function-type variants in ESAM – 2 of the variants are frameshifts, 1x nonsense, 1x canonical splice.
- Affected individuals have profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses.
- One of the frameshift variant c.115del (p.Arg39Glyfs*33), was detected in six individuals from four unrelated families from the same geographic region in Turkey (southeastern Anatolia), suggesting a founder effect.
- The c.451+1G>A variant was detected in three individuals from two independent families with the same ethnic origin (Arab Bedouin)
Sources: Literature
Regression v0.523 RNH1 Krithika Murali gene: RNH1 was added
gene: RNH1 was added to Regression. Sources: Literature
Mode of inheritance for gene: RNH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNH1 were set to PMID: 36935417
Phenotypes for gene: RNH1 were set to RNH1-related disorder
Review for gene: RNH1 was set to AMBER
Added comment: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature
Mendeliome v1.769 MB Elena Savva gene: MB was added
gene: MB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MB were set to 35527200; 30918256
Phenotypes for gene: MB were set to Myopathy, sarcoplasmic body MIM#620286
Mode of pathogenicity for gene: MB was set to Other
Review for gene: MB was set to GREEN
Added comment: PMID: 30918256:
- Recurrent c.292C>T (p.His98Tyr) in fourteen members of six European families with AD progressive myopathy.
- Mutant myoglobin has altered O2 binding, exhibits a faster heme dissociation rate and has a lower reduction potential compared to wild-type myoglobin.
- GOF hypothesised
- 2/3 of myoglobin knockout mice die in utero, 1/3 live to adulthood with little sign of functional effects, likely due to multiple compensatory mechanisms.

PMID: 35527200:
- single adult patient with myoglobinopathy
- same recurring p.His98Tyr variant
Sources: Literature
Cataract v0.350 RNH1 Krithika Murali gene: RNH1 was added
gene: RNH1 was added to Cataract. Sources: Literature
Mode of inheritance for gene: RNH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNH1 were set to PMID: 36935417
Phenotypes for gene: RNH1 were set to RNH1-related disease
Review for gene: RNH1 was set to AMBER
Added comment: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, regression in the context of infection and seizures. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature
Leukodystrophy v0.282 POLR1A Lucy Spencer reviewed gene: POLR1A: Rating: AMBER; Mode of pathogenicity: None; Publications: 36917474; Phenotypes: Leukodystrophy MONDO:0019046, POLR1A related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.768 FILIP1 Paul De Fazio gene: FILIP1 was added
gene: FILIP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FILIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FILIP1 were set to 36943452
Phenotypes for gene: FILIP1 were set to Arthrogryposis multiplex congenita MONDO:0015168
Penetrance for gene: FILIP1 were set to unknown
Review for gene: FILIP1 was set to GREEN
gene: FILIP1 was marked as current diagnostic
Added comment: 3 families, all consanguineous, reported with 3 different homozygous loss of function variants (2x NMD-predicted nonsense, 1x intragenic deletion of exons 3-6 of 6). In one family, the variant segregated in 3 affected siblings.

Phenotypes consist of congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly (-1.5 to -4 SD), and facial dysmorphism.
Sources: Literature
Microcephaly v1.195 FILIP1 Paul De Fazio gene: FILIP1 was added
gene: FILIP1 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: FILIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FILIP1 were set to 36943452
Phenotypes for gene: FILIP1 were set to Arthrogryposis multiplex congenita MONDO:0015168
Penetrance for gene: FILIP1 were set to unknown
Review for gene: FILIP1 was set to GREEN
gene: FILIP1 was marked as current diagnostic
Added comment: 3 families, all consanguineous, reported with 3 different homozygous loss of function variants (2x NMD-predicted nonsense, 1x intragenic deletion of exons 3-6 of 6). In one family, the variant segregated in 3 affected siblings.

Phenotypes consist of congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly (-1.5 to -4 SD), and facial dysmorphism.
Sources: Literature
Skeletal dysplasia v0.232 PKDCC Zornitza Stark Phenotypes for gene: PKDCC were changed from Rhizomelia; dysmorphism to Rhizomelic limb shortening with dysmorphic features, MIM# 618821
Skeletal dysplasia v0.231 PKDCC Zornitza Stark Publications for gene: PKDCC were set to 30478137; 19097194
Skeletal dysplasia v0.230 PKDCC Zornitza Stark Classified gene: PKDCC as Green List (high evidence)
Skeletal dysplasia v0.230 PKDCC Zornitza Stark Gene: pkdcc has been classified as Green List (High Evidence).
Arthrogryposis v0.392 FILIP1 Paul De Fazio gene: FILIP1 was added
gene: FILIP1 was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: FILIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FILIP1 were set to 36943452
Phenotypes for gene: FILIP1 were set to Arthrogryposis multiplex congenita MONDO:0015168
Penetrance for gene: FILIP1 were set to unknown
Review for gene: FILIP1 was set to GREEN
gene: FILIP1 was marked as current diagnostic
Added comment: 3 families, all consanguineous, reported with 3 different homozygous loss of function variants (2x NMD-predicted nonsense, 1x intragenic deletion of exons 3-6 of 6). In one family, the variant segregated in 3 affected siblings.

Phenotypes consist of congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly (-1.5 to -4 SD), and facial dysmorphism.
Sources: Literature
Skeletal dysplasia v0.229 PKDCC Zornitza Stark edited their review of gene: PKDCC: Changed rating: GREEN; Changed publications: 30478137, 19097194, 36896672; Changed phenotypes: Rhizomelic limb shortening with dysmorphic features, MIM# 618821
Mendeliome v1.768 PKDCC Zornitza Stark Phenotypes for gene: PKDCC were changed from Dysmorphism; shortening of extremities to Rhizomelic limb shortening with dysmorphic features, MIM# 618821
Mendeliome v1.767 PKDCC Zornitza Stark Publications for gene: PKDCC were set to PMID:30478137; 19097194
Mendeliome v1.766 PKDCC Zornitza Stark Classified gene: PKDCC as Green List (high evidence)
Mendeliome v1.766 PKDCC Zornitza Stark Gene: pkdcc has been classified as Green List (High Evidence).
Mendeliome v1.765 PKDCC Zornitza Stark reviewed gene: PKDCC: Rating: GREEN; Mode of pathogenicity: None; Publications: 36896672; Phenotypes: Rhizomelic limb shortening with dysmorphic features 618821; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.765 NPPA Chern Lim changed review comment from: PMID: 36303204:
- 1x Brugada patient with heterozygous R107X (NMD-predicted, 5 hets in gnomADv3), regarded as ACMG-LP.

PMID: 19646991:
- NPPA S64R missense in one fam with familial AF, heterozygous in two affected family members but was absent in unaffected family members and their controls. This variant has 195 hets in gnomADv3.

PMID: 23275345:
- Segregation of the homozygous p.R150Q mutation of the NPPA gene with the phenotype in the 6 families with autosomal recessive AD cardiomyopathy (ADCM). This variant has no homozygotes in gnomAD.

ClinGen gene curation: for autosomal recessive DCM - No Known Disease Relationship (09/04/2020).; to: PMID: 36303204:
- 1x Brugada patient with heterozygous R107X (NMD-predicted, 5 hets in gnomADv3), regarded as ACMG-LP.

PMID: 19646991:
- NPPA S64R missense in one fam with familial AF, heterozygous in two affected family members but was absent in unaffected family members and their controls. This variant has >200 hets in gnomADv3.

PMID: 23275345:
- Segregation of the homozygous p.R150Q mutation of the NPPA gene with the phenotype in the 6 families with autosomal recessive AD cardiomyopathy (ADCM). This variant has no homozygotes in gnomAD.

ClinGen gene curation: for autosomal recessive DCM - No Known Disease Relationship (09/04/2020).
Cardiomyopathy_Paediatric v0.157 PPCS Bryony Thompson Marked gene: PPCS as ready
Cardiomyopathy_Paediatric v0.157 PPCS Bryony Thompson Gene: ppcs has been classified as Green List (High Evidence).
Cardiomyopathy_Paediatric v0.157 PPCS Bryony Thompson reviewed gene: PPCS: Rating: GREEN; Mode of pathogenicity: None; Publications: 35616428, 29754768; Phenotypes: Cardiomyopathy, dilated, 2C, MIM# 618189; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.765 PPCS Bryony Thompson Publications for gene: PPCS were set to 29754768
Dilated Cardiomyopathy v1.16 PPCS Bryony Thompson Classified gene: PPCS as Red List (low evidence)
Dilated Cardiomyopathy v1.16 PPCS Bryony Thompson Added comment: Comment on list classification: This gene is associated with early-onset DCM and is not suitable for this panel which contains genes associated with adolescent and adult-onset DCM
Dilated Cardiomyopathy v1.16 PPCS Bryony Thompson Gene: ppcs has been classified as Red List (Low Evidence).
Mendeliome v1.764 PPCS Bryony Thompson Classified gene: PPCS as Green List (high evidence)
Mendeliome v1.764 PPCS Bryony Thompson Gene: ppcs has been classified as Green List (High Evidence).
Mendeliome v1.763 PPCS Bryony Thompson reviewed gene: PPCS: Rating: GREEN; Mode of pathogenicity: None; Publications: 35616428, 29754768; Phenotypes: Cardiomyopathy, dilated, 2C, MIM# 618189; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.763 PPCDC Bryony Thompson Marked gene: PPCDC as ready
Mendeliome v1.763 PPCDC Bryony Thompson Gene: ppcdc has been classified as Red List (Low Evidence).
Mendeliome v1.763 PPCDC Bryony Thompson gene: PPCDC was added
gene: PPCDC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPCDC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPCDC were set to 36564894
Phenotypes for gene: PPCDC were set to dilated cardiomyopathy MONDO:0005021
Review for gene: PPCDC was set to RED
Added comment: Single family reported with two siblings with a fatal cardiac phenotype including dilated cardiomyopathy with biallelic variants p.Thr53Pro and p.Ala95Val. Patient-derived fibroblasts showed an absence of PPCDC protein, and nearly 50% reductions in CoA levels. The cells showed clear energy deficiency problems, with defects in mitochondrial respiration, and mostly glycolytic ATP synthesis. Functional studies performed in yeast suggest these mutations to be functionally relevant.
Sources: Literature
Mendeliome v1.762 ELOC Bryony Thompson Marked gene: ELOC as ready
Mendeliome v1.762 ELOC Bryony Thompson Gene: eloc has been classified as Red List (Low Evidence).
Mendeliome v1.762 ELOC Bryony Thompson Classified gene: ELOC as Red List (low evidence)
Mendeliome v1.762 ELOC Bryony Thompson Gene: eloc has been classified as Red List (Low Evidence).
Mendeliome v1.761 EPHA10 Bryony Thompson Marked gene: EPHA10 as ready
Mendeliome v1.761 EPHA10 Bryony Thompson Gene: epha10 has been classified as Red List (Low Evidence).
Mendeliome v1.761 EPHA10 Bryony Thompson Classified gene: EPHA10 as Red List (low evidence)
Mendeliome v1.761 EPHA10 Bryony Thompson Gene: epha10 has been classified as Red List (Low Evidence).
Mendeliome v1.760 RNF212B Bryony Thompson Marked gene: RNF212B as ready
Mendeliome v1.760 RNF212B Bryony Thompson Gene: rnf212b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.760 RNF212B Bryony Thompson Classified gene: RNF212B as Amber List (moderate evidence)
Mendeliome v1.760 RNF212B Bryony Thompson Gene: rnf212b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.759 SLC25A36 Bryony Thompson Marked gene: SLC25A36 as ready
Mendeliome v1.759 SLC25A36 Bryony Thompson Gene: slc25a36 has been classified as Green List (High Evidence).
Mendeliome v1.759 SLC25A36 Bryony Thompson Classified gene: SLC25A36 as Green List (high evidence)
Mendeliome v1.759 SLC25A36 Bryony Thompson Gene: slc25a36 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5195 NCAPG2 Zornitza Stark Classified gene: NCAPG2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5195 NCAPG2 Zornitza Stark Gene: ncapg2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5195 NCAPG2 Zornitza Stark Classified gene: NCAPG2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5195 NCAPG2 Zornitza Stark Gene: ncapg2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5194 NCAPG2 Zornitza Stark reviewed gene: NCAPG2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Khan-Khan-Katsanis syndrome, MIM# 618460; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.758 NCAPG2 Zornitza Stark Classified gene: NCAPG2 as Amber List (moderate evidence)
Mendeliome v1.758 NCAPG2 Zornitza Stark Gene: ncapg2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.757 NCAPG2 Zornitza Stark changed review comment from: Two families and functional evidence (zebrafish model).
Sources: Literature; to: Two families and functional evidence (zebrafish model). Rated as LIMITED by ClinGen; one of the families had a homozygous missense variant. Internal case identified by VCGS but dual diagnosis.
Sources: Literature
Mendeliome v1.757 NCAPG2 Zornitza Stark edited their review of gene: NCAPG2: Changed rating: AMBER; Changed phenotypes: Khan-Khan-Katsanis syndrome, MIM# 618460
Mendeliome v1.757 NPPA Chern Lim reviewed gene: NPPA: Rating: AMBER; Mode of pathogenicity: None; Publications: 36303204, 19646991, 23275345; Phenotypes: Atrial fibrillation, familial, 6 (MIM#612201), AD, Atrial standstill 2 (MIM#615745), AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Atrial Fibrillation v1.1 NPPA Chern Lim reviewed gene: NPPA: Rating: AMBER; Mode of pathogenicity: None; Publications: 36303204, 19646991, 23275345; Phenotypes: Atrial fibrillation, familial, 6 (MIM#612201), AD, Atrial standstill 2 (MIM#615745), AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Incidentalome v0.229 UBQLN2 Sangavi Sivagnanasundram reviewed gene: UBQLN2: Rating: AMBER; Mode of pathogenicity: None; Publications: 21857683, 31319884, 26152284, 25388785; Phenotypes: Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia (MONDO: 0010459, MIM#300857); Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Holoprosencephaly and septo-optic dysplasia v1.8 STIL Chirag Patel Classified gene: STIL as Green List (high evidence)
Holoprosencephaly and septo-optic dysplasia v1.8 STIL Chirag Patel Gene: stil has been classified as Green List (High Evidence).
Holoprosencephaly and septo-optic dysplasia v1.7 STIL Chirag Patel reviewed gene: STIL: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25658757; Phenotypes: Holoprosencephaly and microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult Cardiac SuperPanel v1.0 Bryony Thompson Added Panel Adult Cardiac SuperPanel
Set list of related panels to Cardiomyopathy; HP:0001638; Abnormality of the myocardium; HP:0001637; Arrhythmia; HP:0011675
Set child panels to: Dilated Cardiomyopathy; Short QT syndrome; Atrial Fibrillation; Sick sinus syndrome; Hypertrophic cardiomyopathy_HCM; Arrhythmogenic Cardiomyopathy; Long QT Syndrome; Brugada syndrome; Catecholaminergic Polymorphic Ventricular Tachycardia; Ventricular Fibrillation
Set panel types to: Royal Melbourne Hospital; Rare Disease
Incidentalome v0.229 TARDBP Sangavi Sivagnanasundram reviewed gene: TARDBP: Rating: GREEN; Mode of pathogenicity: Other; Publications: 18309045, 19609911; Phenotypes: Amyotrophic lateral sclerosis 10, with or without FTD, Frontotemporal lobar degeneration, TARDBP-related (MIM#612069, MONDO: 0012790); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.229 SORL1 Sangavi Sivagnanasundram reviewed gene: SORL1: Rating: RED; Mode of pathogenicity: Other; Publications: 17564960; Phenotypes: ; Mode of inheritance: Unknown
Incidentalome v0.229 SNCAIP Sangavi Sivagnanasundram reviewed gene: SNCAIP: Rating: RED; Mode of pathogenicity: None; Publications: 18366718; Phenotypes: ; Mode of inheritance: Unknown
Mosaic skin disorders v1.6 PORCN Sangavi Sivagnanasundram gene: PORCN was added
gene: PORCN was added to Mosaic skin disorders. Sources: NHS GMS
Mode of inheritance for gene: PORCN was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: PORCN were set to 17546030; 19309688
Phenotypes for gene: PORCN were set to Focal dermal hypoplasia (MONDO:0010592; MIM#305600)
Mode of pathogenicity for gene: PORCN was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: PORCN was set to GREEN
Added comment: Well established gene associated with Focal Dermal Hypoplasia (FDH). Predominantly reported in females (male lethality).

PMID: 19309688 - 24 unrelated patients (21 female and 3 male) with focal dermal hypoplasia (FDH) were studied. A variety of variants (nonsense, splice site and missense) were identified while 3 cases with skewed X inactivation had microdeletions eliminating PORCN. The 3 male cases were shown to be a result of postzygotic mosaicism which was also identified in 2 female cases.

PMID: 17546030 - 10 of 15 confirmed with FDH were analysed and heterozygous (missense, nonsense, indels) mutations causative of FDH was identified. In 9 cases, variants weren't detected in parental samples. A mildy affected father of 1 case showed somatic mosaicism for this variant while they identified de novo mosaic mutations in 3 male FDH cases but not in their parents.
Sources: NHS GMS
Mosaic skin disorders v1.6 BRAF Sangavi Sivagnanasundram gene: BRAF was added
gene: BRAF was added to Mosaic skin disorders. Sources: NHS GMS
Mode of inheritance for gene: BRAF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BRAF were set to 31111470
Phenotypes for gene: BRAF were set to Melanocytic naevus syndrome (MONDO:0044792; MIM#137550)
Mode of pathogenicity for gene: BRAF was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Added comment: More than 3 unrelated cases with tissue specific mosaic variants.

7 cases with congenital melanocytic naevi (CMN) identified a BRAF missense mutation (p.V600E) from naevus biopsies.
Sanger sequencing of mutant BRAF (p.V600E) naevus cultured cells showed confirmed heterozygosity with an increase in somatic load compared to those extracted directly from whole tissue from CMN.
Expression of the BRAF variant protein in all naevus cells was identified using immunohistochemistry.
Sources: NHS GMS
Mendeliome v1.757 RNF212B Sangavi Sivagnanasundram gene: RNF212B was added
gene: RNF212B was added to Mendeliome. Sources: Other
Mode of inheritance for gene: RNF212B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF212B were set to https://doi.org/10.1016/j.xhgg.2023.100189
Phenotypes for gene: RNF212B were set to Infertility disorder, MONDO:0005047
Review for gene: RNF212B was set to AMBER
Added comment: Homozygous nonsense mutation (R150X) causative of oligoasthenotheratozoospermia (OAT) identified in three unrelated individuals (two of Jewish decent from the same consanguineous family).

Drosophila ZIP3/RNF212 related gene paralogs (vilya, narya, nenya) showed loss of function in the RNF212B protein and promoted formation of DNA double-stand breaks. The mutant was shown to result in a reduction in fertility in the Drosophila paralogs.

Note: RNF212B is reported to be exclusively expressed in the testes only compared to RNF212 which is reported in both the testes and ovaries.
Sources: Other
Mosaic skin disorders v1.6 CSPP1 Bryony Thompson Marked gene: CSPP1 as ready
Mosaic skin disorders v1.6 CSPP1 Bryony Thompson Gene: cspp1 has been classified as Red List (Low Evidence).
Mosaic skin disorders v1.6 GJA1 Bryony Thompson Marked gene: GJA1 as ready
Mosaic skin disorders v1.6 GJA1 Bryony Thompson Gene: gja1 has been classified as Red List (Low Evidence).
Mosaic skin disorders v1.6 GJA1 Bryony Thompson Classified gene: GJA1 as Red List (low evidence)
Mosaic skin disorders v1.6 GJA1 Bryony Thompson Gene: gja1 has been classified as Red List (Low Evidence).
Mosaic skin disorders v1.5 CSPP1 Bryony Thompson Classified gene: CSPP1 as Red List (low evidence)
Mosaic skin disorders v1.5 CSPP1 Bryony Thompson Gene: cspp1 has been classified as Red List (Low Evidence).
Mosaic skin disorders v1.4 CARD14 Bryony Thompson Publications for gene: CARD14 were set to
Mosaic skin disorders v1.3 CARD14 Bryony Thompson Mode of pathogenicity for gene: CARD14 was changed from to Other
Mosaic skin disorders v1.2 CARD14 Bryony Thompson Classified gene: CARD14 as Amber List (moderate evidence)
Mosaic skin disorders v1.2 CARD14 Bryony Thompson Added comment: Comment on list classification: Now published data, but only 2 cases
Mosaic skin disorders v1.2 CARD14 Bryony Thompson Gene: card14 has been classified as Amber List (Moderate Evidence).
Brain Calcification v1.50 FAM111A Zornitza Stark Marked gene: FAM111A as ready
Brain Calcification v1.50 FAM111A Zornitza Stark Gene: fam111a has been classified as Green List (High Evidence).
Brain Calcification v1.50 FAM111A Zornitza Stark Classified gene: FAM111A as Green List (high evidence)
Brain Calcification v1.50 FAM111A Zornitza Stark Gene: fam111a has been classified as Green List (High Evidence).
Brain Calcification v1.49 ERCC8 Zornitza Stark Publications for gene: ERCC8 were set to 26204423
Brain Calcification v1.48 ERCC6 Zornitza Stark Publications for gene: ERCC6 were set to
Brain Calcification v1.47 ERCC5 Zornitza Stark Marked gene: ERCC5 as ready
Brain Calcification v1.47 ERCC5 Zornitza Stark Gene: ercc5 has been classified as Red List (Low Evidence).
Brain Calcification v1.47 ERCC5 Zornitza Stark Classified gene: ERCC5 as Red List (low evidence)
Brain Calcification v1.47 ERCC5 Zornitza Stark Gene: ercc5 has been classified as Red List (Low Evidence).
Brain Calcification v1.46 ERCC3 Zornitza Stark Marked gene: ERCC3 as ready
Brain Calcification v1.46 ERCC3 Zornitza Stark Gene: ercc3 has been classified as Red List (Low Evidence).
Brain Calcification v1.46 ERCC3 Zornitza Stark Phenotypes for gene: ERCC3 were changed from to Xeroderma pigmentosum, group B, MIM# 610651
Brain Calcification v1.45 ECM1 Zornitza Stark Marked gene: ECM1 as ready
Brain Calcification v1.45 ECM1 Zornitza Stark Gene: ecm1 has been classified as Green List (High Evidence).
Brain Calcification v1.45 ERCC3 Zornitza Stark Classified gene: ERCC3 as Red List (low evidence)
Brain Calcification v1.45 ERCC3 Zornitza Stark Gene: ercc3 has been classified as Red List (Low Evidence).
Brain Calcification v1.44 ECM1 Zornitza Stark Classified gene: ECM1 as Green List (high evidence)
Brain Calcification v1.44 ECM1 Zornitza Stark Gene: ecm1 has been classified as Green List (High Evidence).
Brain Calcification v1.43 FAM111A Yetong Chen gene: FAM111A was added
gene: FAM111A was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: FAM111A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FAM111A were set to 32734340; 23996431; 35205306
Phenotypes for gene: FAM111A were set to Kenny-Caffey syndrome, type 2, MIM# 127000
Review for gene: FAM111A was set to GREEN
Added comment: PMID 32734340 reports 3 unrelated patients with FAM111A variants who developed calcification in the basal ganglia. Co-segregation is supported by pedigrees that contain parents and unaffected siblings.
PMID 35205306 reports a patient with a novel FAM111A variant who developed calcification in the basal ganglia and the thalamic region. The FAM111A variant caused Osteocraniostenosis (OCS, OMIM #602361), which is an allelic disorder sharing some common features with Kenny-Caffey syndrome.
Sources: Expert list
Brain Calcification v1.43 ERCC8 Yetong Chen reviewed gene: ERCC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 17092472, 20522568; Phenotypes: Cockayne syndrome, type A, MIM# 216400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.43 ERCC6 Yetong Chen reviewed gene: ERCC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 17092472, 20522568; Phenotypes: Cockayne syndrome, type B, MIM# 133540; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.43 ERCC5 Yetong Chen gene: ERCC5 was added
gene: ERCC5 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: ERCC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC5 were set to 20301571; 26884178
Phenotypes for gene: ERCC5 were set to Xeroderma pigmentosum, group G; Cockayne syndrome, MIM# 278780
Review for gene: ERCC5 was set to RED
Added comment: PMID 26884178 reports 2 siblings with the same ERCC5 variant who developed bilateral globus pallidus and posterior periventricular white matter calcification.
Sources: Expert list
Heterotaxy v1.30 Bryony Thompson Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease
Brain Calcification v1.43 ERCC3 Yetong Chen edited their review of gene: ERCC3: Changed phenotypes: Xeroderma pigmentosum, group B, MIM# 610651
Brain Calcification v1.43 ERCC3 Yetong Chen gene: ERCC3 was added
gene: ERCC3 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: ERCC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC3 were set to 16947863; 20301571
Review for gene: ERCC3 was set to RED
Added comment: PMID 20301571 reports 2 unrelated patients with ERCC3 variants who developed brain calcification.
Sources: Expert list
Brain Calcification v1.43 ECM1 Yetong Chen edited their review of gene: ECM1: Changed rating: GREEN
Brain Calcification v1.43 ECM1 Yetong Chen gene: ECM1 was added
gene: ECM1 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: ECM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ECM1 were set to 27398129; 26336196; 12603844
Phenotypes for gene: ECM1 were set to Urbach-Wiethe disease, MIM# 247100
Review for gene: ECM1 was set to AMBER
Added comment: Although reported cases with ECM1 status are limited, Urbach-Wiethe disease is commonly associated with brain calcification.
PMID 27398129 reports a patient with calcifications in both the hippocampi and amygdala. The patient was confirmed to have Urbach-Wiethe syndrome by skin biopsy. However, the paper does not explicitly mention whether genetic testing of the ECM1 gene or genomics testing was done for the patient.

PMID 26336196 reports 2 siblings diagnosed to have Urbach-Wiethe syndrome who developed bilateral basal ganglia calcification. The method of diagnosis and patients' ECM1 status is not mentioned.

PMID 12603844 reports unrelated 3 patients with ECM1 variants who developed temporal lobe calcification.
Sources: Expert list
Mendeliome v1.757 RYR3 Chern Lim reviewed gene: RYR3: Rating: AMBER; Mode of pathogenicity: None; Publications: 25262651; Phenotypes: developmental and epileptic encephalopathy (MONDO:0100062); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Incidentalome v0.229 PSEN2 Sangavi Sivagnanasundram changed review comment from: Well established rare cause of Alzheimer Disease.

PMID: 10652366: In vitro functional assay shows that a mutation in the PSEN2 gene causes an effect to the endoproteolytic processing of the transmembrane protein thus a loss of function to the transmembrane protein.

PMID: 7638622: (Article refers to gene in previously terminology of STM2)
N141I founder mutation was identified in 20 individuals from 5 Volgan German families.
The point mutation is present in the conserved human and mouse homolog (S182).

PMID: 12925374: A spanish individual identified with a T430M mutation (a common variant reported in the Latino/Admixed American population but at a low frequency [PopMax AF 0.01%]).; to: Well established rare cause of Alzheimer Disease.

PMID: 10652366: In vitro functional assay shows that a mutation in the PSEN2 gene causes an effect to the endoproteolytic processing of the transmembrane protein thus a loss of function to the transmembrane protein.

PMID: 7638622: (Article refers to gene in previously terminology of STM2)
N141I founder mutation was identified in 20 individuals from 5 Volgan German families.
The point mutation is present in the conserved human and mouse homolog (S182).

PMID: 12925374: A spanish individual identified with a T430M mutation (a common variant reported in the Latino/Admixed American population but at a low frequency [PopMax AF 0.01%]).
Incidentalome v0.229 PSEN2 Sangavi Sivagnanasundram reviewed gene: PSEN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 10652366, 7638622, 7651536, 12925374; Phenotypes: Alzheimer Disease type 4 (MONDO:0011743, MIM#606889); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.229 PSEN1 Sangavi Sivagnanasundram reviewed gene: PSEN1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 20301340, 7596406, 16033913; Phenotypes: Alzheimer disease, type 3 (MONDO:0011913, MIM#607822); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.93 CRIPT Suliman Khan edited their review of gene: CRIPT: Changed rating: AMBER
Mosaic skin disorders v1.1 GJA1 Sangavi Sivagnanasundram gene: GJA1 was added
gene: GJA1 was added to Mosaic skin disorders. Sources: Other
Mode of inheritance for gene: GJA1 was set to Unknown
Publications for gene: GJA1 were set to 27890787
Phenotypes for gene: GJA1 were set to Inflammatory linear verrucous epidermal naevus (ILVEN)
Mode of pathogenicity for gene: GJA1 was set to Other
Review for gene: GJA1 was set to RED
Added comment: Only published in one article.
Somatic mutation p.A44V identified in one individual with ILVEN.
Sources: Other
Mosaic skin disorders v1.1 CARD14 Sangavi Sivagnanasundram reviewed gene: CARD14: Rating: AMBER; Mode of pathogenicity: Other; Publications: 34116062; Phenotypes: Inflammatory linear verrucous epidermal naevus (ILVEN); Mode of inheritance: None
Mosaic skin disorders v1.1 CSPP1 Sangavi Sivagnanasundram gene: CSPP1 was added
gene: CSPP1 was added to Mosaic skin disorders. Sources: Other
Mode of inheritance for gene: CSPP1 was set to Unknown
Publications for gene: CSPP1 were set to https://doi.org/10.1016/S2096-6911(21)00044-3
Phenotypes for gene: CSPP1 were set to Inflammatory linear verrucous epidermal naevus (ILVEN)
Mode of pathogenicity for gene: CSPP1 was set to Other
Review for gene: CSPP1 was set to RED
Added comment: Only one Chinese journal published relating to ILVEN - not on pubmed
1 somatic heterozygous mutation (R698X) was identified in a 10yr old individual.
Sources: Other
Regression v0.523 SLC31A1 Zornitza Stark Marked gene: SLC31A1 as ready
Regression v0.523 SLC31A1 Zornitza Stark Gene: slc31a1 has been classified as Amber List (Moderate Evidence).
Regression v0.523 SLC31A1 Zornitza Stark Classified gene: SLC31A1 as Amber List (moderate evidence)
Regression v0.523 SLC31A1 Zornitza Stark Gene: slc31a1 has been classified as Amber List (Moderate Evidence).
Regression v0.522 SLC31A1 Zornitza Stark gene: SLC31A1 was added
gene: SLC31A1 was added to Regression. Sources: Expert Review
Mode of inheritance for gene: SLC31A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC31A1 were set to 35913762; 36562171
Phenotypes for gene: SLC31A1 were set to Neurodegeneration and seizures due to copper transport defect, MIM# 620306
Review for gene: SLC31A1 was set to AMBER
Added comment: PMID:36562171
Homozygous c.236T>C; p.(Leu79Pro) identified in a newborn of consanguineous parents. Variant absent from gnomAD. Prenatal ultrasound showed a male fetus with short femoral bones, an apparently enlarged heart-to-thorax ratio, and a wide cisterna magna. The infant was born with pulmonary hypoplasia. At 2 weeks of age, multifocal brain hemorrhages were diagnosed and the infant developed seizures. The infant died at 1 month of age. The Mother had three healthy children while nine pregnancies had been extrauterine gravidities or ended in first or mid-trimester spontaneous abortions.

PMID: 35913762
SLC31A1 is also referred to as CTR1.
Monozygotic twins with hypotonia, global developmental delay, seizures, and rapid brain atrophy, consistent with profound central nervous system copper deficiency. Homozygous for a novel missense variant (p.(Arg95His)) in copper transporter CTR1, both parents heterozygous. A mouse knock-out model of CTR1 deficiency resulted in prenatal lethality.
Sources: Expert Review
Fetal anomalies v1.93 SLC31A1 Zornitza Stark Phenotypes for gene: SLC31A1 were changed from Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092) to Neurodegeneration and seizures due to copper transport defect, MIM# 620306
Fetal anomalies v1.92 SLC31A1 Zornitza Stark reviewed gene: SLC31A1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration and seizures due to copper transport defect, MIM# 620306; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5194 SLC31A1 Zornitza Stark Phenotypes for gene: SLC31A1 were changed from Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092) to Neurodegeneration and seizures due to copper transport defect, MIM# 620306
Intellectual disability syndromic and non-syndromic v0.5193 SLC31A1 Zornitza Stark edited their review of gene: SLC31A1: Changed phenotypes: Neurodegeneration and seizures due to copper transport defect, MIM# 620306
Genetic Epilepsy v0.1836 SLC31A1 Zornitza Stark Phenotypes for gene: SLC31A1 were changed from Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092) to Neurodegeneration and seizures due to copper transport defect, MIM# 620306
Genetic Epilepsy v0.1835 SLC31A1 Zornitza Stark Publications for gene: SLC31A1 were set to PMID: 35913762
Genetic Epilepsy v0.1834 SLC31A1 Zornitza Stark reviewed gene: SLC31A1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration and seizures due to copper transport defect, MIM# 620306; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.757 SLC31A1 Zornitza Stark Phenotypes for gene: SLC31A1 were changed from Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092) to Neurodegeneration and seizures due to copper transport defect, MIM# 620306
Mendeliome v1.756 SLC31A1 Zornitza Stark edited their review of gene: SLC31A1: Changed phenotypes: Neurodegeneration and seizures due to copper transport defect, MIM# 620306
Incidentalome v0.229 SCN1B Sangavi Sivagnanasundram reviewed gene: SCN1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 9697698, 17020904, 12011299; Phenotypes: Generalized epilepsy with febrile seizures plus, type 1 (MONDO:0018214, MIM 604233); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.5193 SCN1B Sangavi Sivagnanasundram Deleted their review
Intellectual disability syndromic and non-syndromic v0.5193 SCN1B Sangavi Sivagnanasundram reviewed gene: SCN1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 9697698, 17020904, 12011299; Phenotypes: Generalized epilepsy with febrile seizures plus, type 1 (MONDO:0018214, MIM 604233); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Incidentalome v0.229 RBM12 Sangavi Sivagnanasundram reviewed gene: RBM12: Rating: AMBER; Mode of pathogenicity: Other; Publications: 28628109, 36711667; Phenotypes: Schizophrenia 19 (MIM#617629); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.229 PCSK9 Zornitza Stark Marked gene: PCSK9 as ready
Incidentalome v0.229 PCSK9 Zornitza Stark Gene: pcsk9 has been classified as Green List (High Evidence).
Incidentalome v0.229 PCSK9 Zornitza Stark Phenotypes for gene: PCSK9 were changed from to Familial Hypercholesterolemia 3 (MONDO:0011369; MIM# 603776); Low-density lipoprotein cholesterol level quantitative trait locus-1 (LDLCQ1; MIM# 603776)
Incidentalome v0.228 PCSK9 Zornitza Stark Publications for gene: PCSK9 were set to
Incidentalome v0.227 PCSK9 Zornitza Stark Mode of inheritance for gene: PCSK9 was changed from Unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Incidentalome v0.226 PCSK9 Zornitza Stark Tag treatable tag was added to gene: PCSK9.
Genomic newborn screening: BabyScreen+ v0.2151 GPR161 Zornitza Stark Marked gene: GPR161 as ready
Genomic newborn screening: BabyScreen+ v0.2151 GPR161 Zornitza Stark Gene: gpr161 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2151 GPR161 Zornitza Stark Classified gene: GPR161 as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.2151 GPR161 Zornitza Stark Gene: gpr161 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2150 GPR161 Zornitza Stark Tag cancer tag was added to gene: GPR161.
Genomic newborn screening: BabyScreen+ v0.2150 CTR9 Zornitza Stark Tag cancer tag was added to gene: CTR9.
Genomic newborn screening: BabyScreen+ v0.2150 CTR9 Zornitza Stark Marked gene: CTR9 as ready
Genomic newborn screening: BabyScreen+ v0.2150 CTR9 Zornitza Stark Gene: ctr9 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2150 CTR9 Zornitza Stark Classified gene: CTR9 as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.2150 CTR9 Zornitza Stark Gene: ctr9 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2149 ALK Zornitza Stark Marked gene: ALK as ready
Genomic newborn screening: BabyScreen+ v0.2149 ALK Zornitza Stark Gene: alk has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2149 ALK Zornitza Stark Tag cancer tag was added to gene: ALK.
Genomic newborn screening: BabyScreen+ v0.2149 ALK Zornitza Stark Classified gene: ALK as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.2149 ALK Zornitza Stark Gene: alk has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2148 SUFU Lilian Downie gene: SUFU was added
gene: SUFU was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SUFU was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SUFU were set to PMID: 29186568
Phenotypes for gene: SUFU were set to {Medulloblastoma} MIM#155255
Penetrance for gene: SUFU were set to Incomplete
Review for gene: SUFU was set to RED
Added comment: Medullobastoma 1st year of life
incomplete penetrance
worse outcomes
no determined screening protocol
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2148 PAX5 Lilian Downie gene: PAX5 was added
gene: PAX5 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: PAX5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PAX5 were set to PMID: 24013638
Phenotypes for gene: PAX5 were set to {Leukemia, acute lymphoblastic, susceptibility to, 3} MIM#615545
Penetrance for gene: PAX5 were set to Incomplete
Review for gene: PAX5 was set to RED
Added comment: Incomplete penetrance
Sources: Expert list
Incidentalome v0.226 PCSK9 Sangavi Sivagnanasundram reviewed gene: PCSK9: Rating: GREEN; Mode of pathogenicity: Other; Publications: 24404629, 18354137, 12730697, 15654334, 16909389; Phenotypes: Familial Hypercholesterolemia 3 (MONDO:0011369, MIM# 603776), Low-density lipoprotein cholesterol level quantitative trait locus-1 (LDLCQ1, MIM# 603776); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2148 GPR161 Lilian Downie gene: GPR161 was added
gene: GPR161 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GPR161 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GPR161 were set to PMID: 31609649
Phenotypes for gene: GPR161 were set to Medulloblastoma predisposition syndrome MIM#155255
Penetrance for gene: GPR161 were set to Incomplete
Review for gene: GPR161 was set to RED
Added comment: Increased risk of medulloblastoma at <3yrs
Also identified in population and healthy parents
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2148 CTR9 Lilian Downie gene: CTR9 was added
gene: CTR9 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: CTR9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CTR9 were set to PMID: 32412586
Phenotypes for gene: CTR9 were set to Wilms tumour predisposition
Penetrance for gene: CTR9 were set to Incomplete
Review for gene: CTR9 was set to RED
Added comment: 9/14 germline variant developed Wilms (in 4 families)
Red due to reduced penetrance
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2148 ALK Lilian Downie gene: ALK was added
gene: ALK was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: ALK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALK were set to PMID: 22071890
Phenotypes for gene: ALK were set to {Neuroblastoma, susceptibility to, 3} MIM#613014
Penetrance for gene: ALK were set to Incomplete
Review for gene: ALK was set to RED
Added comment: Reduced penetrance
Not clear guideline on management if detected
Sources: Expert list
Mendeliome v1.756 HCK Zornitza Stark Phenotypes for gene: HCK were changed from Autoinflammatory syndrome, MONDO:0019751, HCK-related to Autoinflammation with pulmonary and cutaneous vasculitis, MIM#620296
Mendeliome v1.755 HCK Zornitza Stark edited their review of gene: HCK: Changed phenotypes: Autoinflammation with pulmonary and cutaneous vasculitis, MIM#620296
Autoinflammatory Disorders v1.4 HCK Zornitza Stark Phenotypes for gene: HCK were changed from Autoinflammatory syndrome, MONDO:0019751, HCK-related to Autoinflammation with pulmonary and cutaneous vasculitis, MIM#620296
Autoinflammatory Disorders v1.3 HCK Zornitza Stark reviewed gene: HCK: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammation with pulmonary and cutaneous vasculitis, MIM#620296; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.226 PARK7 Sangavi Sivagnanasundram changed review comment from: Note that the gene was renamed from DJ1 to PARK7 (articles and OMIM reference our gene with previous name)

Variants in PARK7 (DJ1) gene are a rare cause of Parkinson Disease and is currently only reported in 3 individuals from 3 unrelated families.

PMID: 11462174; 11835383 – 2 individuals from 2 unrelated families with variants in DJ1 that were causative of Parkinson Disease.

PMID: 16240358 – 3 affected sibs from a consanguineous Italian family; to: Note that the gene was renamed from DJ1 to PARK7 (articles and OMIM reference our gene with previous name)

Variants in PARK7 (DJ1) gene are a rare cause of Parkinson Disease and is currently only reported in 3 individuals from 3 unrelated families.

PMID: 11462174; 11835383 – 2 individuals from 2 unrelated families with variants in DJ1 that were causative of Parkinson Disease.

PMID: 16240358 – 3 affected sibs from a consanguineous Italian family
Incidentalome v0.226 PARK7 Sangavi Sivagnanasundram reviewed gene: PARK7: Rating: AMBER; Mode of pathogenicity: None; Publications: 11462174, 11835383, 16240358, 20301402; Phenotypes: Parkinson Disease (MONDO:0005180, MIM: 606324); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.226 OPTN Sangavi Sivagnanasundram reviewed gene: OPTN: Rating: GREEN; Mode of pathogenicity: None; Publications: 20428114, 31838784, 27493188; Phenotypes: Amyotrophic lateral sclerosis 12 with or without frontotemporal dementia (MONDO: 0013264, MIM#613435); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Brain Calcification v1.43 DENND5A Zornitza Stark Marked gene: DENND5A as ready
Brain Calcification v1.43 DENND5A Zornitza Stark Gene: dennd5a has been classified as Red List (Low Evidence).
Brain Calcification v1.43 AP1S2 Yetong Chen edited their review of gene: AP1S2: Changed publications: 17617514
Brain Calcification v1.43 AP1S2 Yetong Chen changed review comment from: PMID 17617514 reports a linkage study of AP1S2 in 2 unrelated families with multiple generations affected by Fried syndrome. Cosegregation of the phenotype and AP1S2 variants is demonstrated. Two patients from the French family and 3 patients from the Scottish family developed brain calcification.
PMID 19161147 reports 8 individuals from 2 interrelated Omani families who developed brain calcification.; to: PMID 17617514 reports a linkage study of AP1S2 in 2 unrelated families with multiple generations affected by Fried syndrome. Cosegregation of the phenotype and AP1S2 variants is demonstrated. Two patients from the French family and 3 patients from the Scottish family developed brain calcification.
Brain Calcification v1.43 DENND5A Zornitza Stark Classified gene: DENND5A as Red List (low evidence)
Brain Calcification v1.43 DENND5A Zornitza Stark Gene: dennd5a has been classified as Red List (Low Evidence).
Brain Calcification v1.42 CYP2U1 Zornitza Stark Publications for gene: CYP2U1 were set to 23176821
Brain Calcification v1.41 COL4A2 Zornitza Stark Marked gene: COL4A2 as ready
Brain Calcification v1.41 COL4A2 Zornitza Stark Gene: col4a2 has been classified as Red List (Low Evidence).
Brain Calcification v1.41 CTC1 Zornitza Stark Publications for gene: CTC1 were set to 22267198; 22387016
Brain Calcification v1.40 COL4A2 Zornitza Stark Classified gene: COL4A2 as Red List (low evidence)
Brain Calcification v1.40 COL4A2 Zornitza Stark Gene: col4a2 has been classified as Red List (Low Evidence).
Brain Calcification v1.39 COL4A1 Zornitza Stark Publications for gene: COL4A1 were set to
Brain Calcification v1.38 DENND5A Yetong Chen gene: DENND5A was added
gene: DENND5A was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: DENND5A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DENND5A were set to 32734340; 27866705
Phenotypes for gene: DENND5A were set to Developmental and epileptic encephalopathy 49, MIM# 617281
Review for gene: DENND5A was set to RED
Added comment: Limited evidence supports a causal role of the DENND5A gene in brain calcification.
PMID 27866705 reports that 3 individuals with DENND5A variants, who were from 2 families, developed brain calcification. Co-segregation of the DENND5A variant and pathogenic phenotype is confirmed by sequencing their parents and unaffected sibs.
Sources: Expert list
Brain Calcification v1.38 COL4A2 Yetong Chen changed review comment from: There is no sufficient evidence supporting a causal role of the COL4A2 gene in brain calcification.
PMID 33247988 reports a patient with focal lesions with increased echogenicity in the right basal ganglia, which was suspected to result from either haemorrhage or calcification. However, the patient carries full duplications and deletions of COL4A1 and COL4A2, so it is likely that the brain calcification is not caused by COL4A2.
PMID 33577044 summarises that 4 patients with COL4A2 developed brain calcification, including 1 case from PMID 21357838, 2 cases from PMID 30315939 and 1 from the present paper. This paper does not mention brain calcification found in the 2 reported cases. (Interestingly, there is a calculation mistake for the total number of patients with COL4A2 who had brain calcification. The sum should be 4 instead of 5.)
None of the patients reported by PMID 21357838 carried COL4A2 variants nor developed brain calcification.
Although PMID 30315939 reports 2 patients with COL4A2 variants, they did not show any sign of calcification.
Sources: Expert list; to: There is no sufficient evidence supporting a causal role of the COL4A2 gene in brain calcification.
PMID 33247988 reports a patient with focal lesions with increased echogenicity in the right basal ganglia, which was suspected to result from either haemorrhage or calcification. However, the patient carries full duplications and deletions of COL4A1 and COL4A2, so it is likely that the brain calcification is not caused by COL4A2.
PMID 33577044 summarises that 4 patients with COL4A2 developed brain calcification, including 1 case from PMID 21357838, 2 cases from PMID 30315939 and 1 from the present paper. This paper does not mention brain calcification found in the 2 reported cases. (There is a calculation mistake for the total number of patients with COL4A2 who had brain calcification. The sum should be 4 instead of 5.)
None of the patients reported by PMID 21357838 carried COL4A2 variants nor developed brain calcification.
Although PMID 30315939 reports 2 patients with COL4A2 variants, they did not show any sign of calcification.
Sources: Expert list
Brain Calcification v1.38 CYP2U1 Yetong Chen reviewed gene: CYP2U1: Rating: ; Mode of pathogenicity: None; Publications: 30111349, 33107650, 23176821; Phenotypes: Spastic paraplegia 56, autosomal recessive, MIM# 615030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Deafness_IsolatedAndComplex v1.156 ABHD12 Lilian Downie Deleted their review
Genomic newborn screening: BabyScreen+ v0.2148 TUBB4B Lilian Downie gene: TUBB4B was added
gene: TUBB4B was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TUBB4B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TUBB4B were set to PMID: 29198720, 35240325
Phenotypes for gene: TUBB4B were set to Leber congenital amaurosis with early-onset deafness MIM#617879
Review for gene: TUBB4B was set to RED
Added comment: The TUBB4B gene has been associated with autosomal dominant Leber congenital amaurosis with early-onset deafness
Not consistently hearing phenotype <5years therefore excluded
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2148 SLITRK6 Lilian Downie gene: SLITRK6 was added
gene: SLITRK6 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SLITRK6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLITRK6 were set to PMID: 23543054, PMID: 25590127
Phenotypes for gene: SLITRK6 were set to Deafness and myopia MIM#221200
Review for gene: SLITRK6 was set to GREEN
Added comment: Congenital or prelingual deafness (SNHL or ANSD)
high myopia
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2148 MPZL2 Lilian Downie gene: MPZL2 was added
gene: MPZL2 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: MPZL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MPZL2 were set to PMID: 29982980, 29961571, 35734045,33234333
Phenotypes for gene: MPZL2 were set to Deafness, autosomal recessive 111 MIM#618145
Review for gene: MPZL2 was set to RED
Added comment: Most cases are pre-lingual but 29961571, 35734045 report adult onset so I think should be excluded based on variability of age of onset
Sources: Expert list
Incidentalome v0.226 LRRK2 Sangavi Sivagnanasundram reviewed gene: LRRK2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 20301387, 17200152, 15541308, 16172858; Phenotypes: Parkinson Disease type 8 (MONDO:0005180, MIM#607060); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Brain Calcification v1.38 CTC1 Yetong Chen changed review comment from: An additional case is found.
PMID 22532422 reports a patient with a CTC1 variant who developed right-sided thalamic calcification.

PMID 22899577 reports 4 patients with CTC1 variants who developed intracranial cysts or calcification; however, the exact number of patients who developed intracranial calcification is not specified.; to: An additional case is found.
PMID 22532422 reports a patient with a CTC1 variant who developed right-sided thalamic calcification.

PMID 22899577 reports 4 patients with CTC1 variants from 3 families who developed intracranial cysts or calcification; however, the exact number of patients who developed intracranial calcification is not specified.
Genomic newborn screening: BabyScreen+ v0.2148 CRYM Zornitza Stark Marked gene: CRYM as ready
Genomic newborn screening: BabyScreen+ v0.2148 CRYM Zornitza Stark Gene: crym has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2148 CRYM Zornitza Stark Classified gene: CRYM as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.2148 CRYM Zornitza Stark Gene: crym has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2147 COL4A6 Zornitza Stark Marked gene: COL4A6 as ready
Genomic newborn screening: BabyScreen+ v0.2147 COL4A6 Zornitza Stark Added comment: Comment when marking as ready: Agree, report in males only.
Genomic newborn screening: BabyScreen+ v0.2147 COL4A6 Zornitza Stark Gene: col4a6 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2147 COL4A6 Zornitza Stark Classified gene: COL4A6 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2147 COL4A6 Zornitza Stark Gene: col4a6 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2146 CLDN9 Zornitza Stark Marked gene: CLDN9 as ready
Genomic newborn screening: BabyScreen+ v0.2146 CLDN9 Zornitza Stark Gene: cldn9 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2146 CLDN9 Zornitza Stark Classified gene: CLDN9 as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.2146 CLDN9 Zornitza Stark Gene: cldn9 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2145 CEP250 Zornitza Stark Marked gene: CEP250 as ready
Genomic newborn screening: BabyScreen+ v0.2145 CEP250 Zornitza Stark Gene: cep250 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2145 CEP250 Zornitza Stark Classified gene: CEP250 as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.2145 CEP250 Zornitza Stark Gene: cep250 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2144 ABHD12 Zornitza Stark Marked gene: ABHD12 as ready
Genomic newborn screening: BabyScreen+ v0.2144 ABHD12 Zornitza Stark Gene: abhd12 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2144 ABHD12 Zornitza Stark Classified gene: ABHD12 as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.2144 ABHD12 Zornitza Stark Gene: abhd12 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2143 CD164 Zornitza Stark Marked gene: CD164 as ready
Genomic newborn screening: BabyScreen+ v0.2143 CD164 Zornitza Stark Gene: cd164 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2143 CD164 Zornitza Stark Classified gene: CD164 as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.2143 CD164 Zornitza Stark Gene: cd164 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2142 AP1B1 Zornitza Stark Marked gene: AP1B1 as ready
Genomic newborn screening: BabyScreen+ v0.2142 AP1B1 Zornitza Stark Gene: ap1b1 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2142 AP1B1 Zornitza Stark Classified gene: AP1B1 as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.2142 AP1B1 Zornitza Stark Gene: ap1b1 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2141 AP1B1 Zornitza Stark reviewed gene: AP1B1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Keratitis-ichthyosis-deafness syndrome, autosomal recessive MIM#242150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.226 FA2H Zornitza Stark Marked gene: FA2H as ready
Incidentalome v0.226 FA2H Zornitza Stark Gene: fa2h has been classified as Green List (High Evidence).
Incidentalome v0.226 FA2H Zornitza Stark Phenotypes for gene: FA2H were changed from to Spastic Paraplegia (MIM#612319)
Incidentalome v0.225 FA2H Zornitza Stark Publications for gene: FA2H were set to
Incidentalome v0.224 FA2H Zornitza Stark Mode of inheritance for gene: FA2H was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.223 FA2H Zornitza Stark Tag neurological tag was added to gene: FA2H.
Genomic newborn screening: BabyScreen+ v0.2141 LMX1A Lilian Downie gene: LMX1A was added
gene: LMX1A was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: LMX1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMX1A were set to PMID: 29754270
Phenotypes for gene: LMX1A were set to Deafness, autosomal dominant 7 MIM#601412
Review for gene: LMX1A was set to RED
Added comment: Age of onset too variable
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2141 GREB1L Lilian Downie gene: GREB1L was added
gene: GREB1L was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GREB1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GREB1L were set to PMID: 29955957, 32585897
Phenotypes for gene: GREB1L were set to Deafness, autosomal dominant 80 MIM#619274
Review for gene: GREB1L was set to GREEN
Added comment: Congenital hearing impairment with cochlear abnormalities
This gene also causes Renal hypodysplasia/aplasia 3 MIM#617805 with no clear difference in mutation spectrum
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2141 CRYM Lilian Downie gene: CRYM was added
gene: CRYM was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: CRYM was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CRYM were set to PMID: 12471561, 32742378
Phenotypes for gene: CRYM were set to Deafness, autosomal dominant 40 MIM#616357
Review for gene: CRYM was set to RED
Added comment: Dominant hearing loss
One paper infant onset, the other all adult onset
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2141 COL4A6 Lilian Downie gene: COL4A6 was added
gene: COL4A6 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: COL4A6 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: COL4A6 were set to PMID: 33840813, PMID: 23714752
Phenotypes for gene: COL4A6 were set to Deafness, X-linked 6 MIM#300914
Review for gene: COL4A6 was set to GREEN
Added comment: Pre-lingual or congenital deafness in males
consider not reporting in females (may have adult onset hearing impairment)
Sources: Expert list
Brain Calcification v1.38 CTC1 Yetong Chen reviewed gene: CTC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22267198, 22532422, 22899577, 22387016, 24372060; Phenotypes: Cerebroretinal microangiopathy with calcifications and cysts, MIM# 612199; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2141 CLDN9 Lilian Downie gene: CLDN9 was added
gene: CLDN9 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: CLDN9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLDN9 were set to PMID: 34265170
Phenotypes for gene: CLDN9 were set to Deafness, autosomal recessive 116 MIM#619093
Review for gene: CLDN9 was set to RED
Added comment: Age of onset not consistently <5
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2141 CEP250 Lilian Downie gene: CEP250 was added
gene: CEP250 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: CEP250 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP250 were set to PMID: 34223797, PMID: 29718797, PMID: 30459346, PMID: 28005958
Phenotypes for gene: CEP250 were set to Cone-rod dystrophy and hearing loss 2 MIM#618358
Review for gene: CEP250 was set to RED
Added comment: Hearing loss and RP
Atypical Usher phenotype
Age of onset and penetrance of hearing loss component is variable and seeing as this is the treatable component have excluded from list
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2141 ABHD12 Lilian Downie gene: ABHD12 was added
gene: ABHD12 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: ABHD12 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ABHD12 were set to Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract MIM#612674
Review for gene: ABHD12 was set to RED
Added comment: Age of onset not consistently under 5 for treatable elements such as hearing loss.
Sources: Expert list
Deafness_IsolatedAndComplex v1.156 ABHD12 Lilian Downie Deleted their comment
Deafness_IsolatedAndComplex v1.156 ABHD12 Lilian Downie reviewed gene: ABHD12: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract MIM#612674; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2141 CD164 Lilian Downie gene: CD164 was added
gene: CD164 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: CD164 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CD164 were set to Deafness, autosomal dominant 66 MIM#616969
Review for gene: CD164 was set to RED
Added comment: Green in our mendeliome/deafness but limited evidence by clingen
variable age of onset from newborn to 20's reason for exclusion
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2141 AP1B1 Lilian Downie gene: AP1B1 was added
gene: AP1B1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: AP1B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP1B1 were set to PMID:31630791, 31630788, 33452671
Phenotypes for gene: AP1B1 were set to Keratitis-ichthyosis-deafness syndrome, autosomal recessive MIM#242150
Review for gene: AP1B1 was set to GREEN
Added comment: Icthyosis
progressive hearing loss (childhood) often detected newborn screening
photophobia
corneal scarring/keratitis
variable dev delay
part of copper metabolism pathway but no proven treatment
Sources: Expert list
Brain Calcification v1.38 COL4A2 Yetong Chen gene: COL4A2 was added
gene: COL4A2 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: COL4A2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COL4A2 were set to 33577044; 33247988
Phenotypes for gene: COL4A2 were set to Brain small vessel disease 2, MIM# 614483
Review for gene: COL4A2 was set to RED
Added comment: There is no sufficient evidence supporting a causal role of the COL4A2 gene in brain calcification.
PMID 33247988 reports a patient with focal lesions with increased echogenicity in the right basal ganglia, which was suspected to result from either haemorrhage or calcification. However, the patient carries full duplications and deletions of COL4A1 and COL4A2, so it is likely that the brain calcification is not caused by COL4A2.
PMID 33577044 summarises that 4 patients with COL4A2 developed brain calcification, including 1 case from PMID 21357838, 2 cases from PMID 30315939 and 1 from the present paper. This paper does not mention brain calcification found in the 2 reported cases. (Interestingly, there is a calculation mistake for the total number of patients with COL4A2 who had brain calcification. The sum should be 4 instead of 5.)
None of the patients reported by PMID 21357838 carried COL4A2 variants nor developed brain calcification.
Although PMID 30315939 reports 2 patients with COL4A2 variants, they did not show any sign of calcification.
Sources: Expert list
Incidentalome v0.223 FIG4 Sangavi Sivagnanasundram reviewed gene: FIG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 19118816, 20301623; Phenotypes: Amyotrophic Lateral Sclerosis Type 11 (MONDO: 0012945, MIM#612577); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Susceptibility to Viral Infections v0.109 STAT2 Peter McNaughton changed review comment from: Susceptibility to virus including disseminated vaccine strain measles.; to: Susceptibility to virus including disseminated vaccine strain measles.

Additional publication
PMID: 36976641
Brain Calcification v1.38 COL4A1 Yetong Chen Deleted their comment
Susceptibility to Viral Infections v0.109 STAT2 Peter McNaughton changed review comment from: Susceptibility to virus including disseminated vaccine strain measles.; to: Susceptibility to virus including disseminated vaccine strain measles.
Brain Calcification v1.38 COL4A1 Yetong Chen edited their review of gene: COL4A1: Added comment: In total, 20 patients with COL4A1 variants who developed brain calcification were reported.
PMID 22134833 reports 5 patients with different COL4A1 variants who developed brain calcification.
PMID 24372060 mentions a patient who has been reported by PMID 22134833 (case 3).
PMID 25719457 reports 2 unrelated patients with different COL4A1 variants who developed brain calcification.
PMID 23225343 reports 7 patients with different COL4A1 variants who developed brain calcification.
PMID 22932948 reports 3 patients with COL4A1 variants who developed brain calcification, and mentions 5 patients who have been reported by PMID 22134833.; Changed publications: 24372060, 22134833, 25719457, 23225343, 22932948
Brain Calcification v1.38 COL4A1 Yetong Chen reviewed gene: COL4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24372060, 22134833; Phenotypes: Brain small vessel disease with or without ocular anomalies, MIM#175780; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.223 VPS13A Sangavi Sivagnanasundram reviewed gene: VPS13A: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301561, 12404112, 15824261, 12404112; Phenotypes: Chorea-acanthocytosis (MONDO: 0008695, MIM#200150); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.223 VPS13A Sangavi Sivagnanasundram Deleted their review
Incidentalome v0.223 VPS13A Sangavi Sivagnanasundram reviewed gene: VPS13A: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301561, 12404112, 15824261, 12404112; Phenotypes: Chorea-acanthocytosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.223 XK Sangavi Sivagnanasundram reviewed gene: XK: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301528, 17133513; Phenotypes: McLeod Syndrome with or without chronic granulomatous disease (MIM#300842); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Incidentalome v0.223 CLU Sangavi Sivagnanasundram reviewed gene: CLU: Rating: RED; Mode of pathogenicity: Other; Publications: 19734903, 20301340; Phenotypes: Alzheimer's Disease (MIM#104300); Mode of inheritance: Unknown
Incidentalome v0.223 FA2H Sangavi Sivagnanasundram reviewed gene: FA2H: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31135052, 29395073, 18463364, 19068277, 20104589; Phenotypes: Spastic Paraplegia (MIM#612319); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2141 LAMP2 Zornitza Stark Classified gene: LAMP2 as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.2141 LAMP2 Zornitza Stark Gene: lamp2 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2140 LAMP2 Zornitza Stark edited their review of gene: LAMP2: Added comment: Treatment is currently symptomatic.

On watch list with regards to specific treatment/clinical trials.; Changed rating: AMBER
Genomic newborn screening: BabyScreen+ v0.2140 NKX2-5 Zornitza Stark Tag treatable tag was added to gene: NKX2-5.
Genomic newborn screening: BabyScreen+ v0.2140 MYH7 Zornitza Stark Phenotypes for gene: MYH7 were changed from Laing early-onset distal myopathy, MONDO:0008050; Cardiomyopathy, hypertrophic, 1, OMIM:192600; Dilated cardiomyopathy 1S, MONDO:0013262; Hypertrophic cardiomyopathy 1, MONDO:0008647; Laing distal myopathy, OMIM:160500; Left ventricular noncompaction 5, OMIM:613426; Cardiomyopathy, dilated, 1S, OMIM:613426 to Cardiomyopathy, hypertrophic, 1, MIM# 192600
Genomic newborn screening: BabyScreen+ v0.2139 MYH7 Zornitza Stark Mode of inheritance for gene: MYH7 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2138 MYH7 Zornitza Stark Classified gene: MYH7 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2138 MYH7 Zornitza Stark Gene: myh7 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2137 MYH7 Zornitza Stark Tag cardiac tag was added to gene: MYH7.
Tag treatable tag was added to gene: MYH7.
Genomic newborn screening: BabyScreen+ v0.2137 MYH7 Zornitza Stark edited their review of gene: MYH7: Added comment: Discussed with paedric cardiologist: include bi-allelic cardiac variants as can present in the neonatal period with an aggressive cardiomyopathy and associated arrhythmias.; Changed rating: GREEN; Changed phenotypes: Cardiomyopathy, hypertrophic, 1, MIM# 192600; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2137 KCNJ2 Zornitza Stark Phenotypes for gene: KCNJ2 were changed from Andersen syndrome MIM#170390; Atrial fibrillation, familial, 9 MIM#613980; Short QT syndrome 3 MIM#609622 to Andersen syndrome MIM#170390
Incidentalome v0.223 CALHM1 Sangavi Sivagnanasundram changed review comment from: PMID:19472444 – Study to identify whether mutation sin CALHM1 had any correlation to Alzheimers Disease. Study showed no association between CALHM1 and Alzheimers Disease; to: PMID:19472444 – Study to identify whether mutations in CALHM1 had any correlation to Alzheimers Disease. Study showed no association between CALHM1 and Alzheimers Disease (AD)

No evidence showing correlation between CALHM1 mutations and AD
Incidentalome v0.223 CALHM1 Sangavi Sivagnanasundram reviewed gene: CALHM1: Rating: RED; Mode of pathogenicity: Other; Publications: 19472444; Phenotypes: ; Mode of inheritance: Unknown
Genomic newborn screening: BabyScreen+ v0.2136 KCNJ2 Zornitza Stark Classified gene: KCNJ2 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2136 KCNJ2 Zornitza Stark Gene: kcnj2 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2135 KCNJ2 Zornitza Stark edited their review of gene: KCNJ2: Added comment: Include for Andersen syndrome and Long QT-associated variants only. Onset in infancy.; Changed rating: GREEN; Changed phenotypes: Andersen syndrome MIM#170390
Genomic newborn screening: BabyScreen+ v0.2135 TRDN Zornitza Stark Classified gene: TRDN as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.2135 TRDN Zornitza Stark Gene: trdn has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2134 TRDN Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

For review: age of onset and penetrance.; to: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

Reviewed with paediatric cardiologist: variable penetrance and age of onset, does not fulfil criteria for gNBS.
Genomic newborn screening: BabyScreen+ v0.2134 TRDN Zornitza Stark edited their review of gene: TRDN: Changed rating: AMBER
Genomic newborn screening: BabyScreen+ v0.2134 TECRL Zornitza Stark Classified gene: TECRL as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.2134 TECRL Zornitza Stark Gene: tecrl has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2133 TECRL Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

For review: age of onset and penetrance.
Sources: ClinGen; to: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

Reviewed with a paediatric cardiologist: variable penetrance and age of onset, does not fulfil criteria for gNBS.
Genomic newborn screening: BabyScreen+ v0.2133 TECRL Zornitza Stark edited their review of gene: TECRL: Changed rating: AMBER; Changed phenotypes: Ventricular tachycardia, catecholaminergic polymorphic, 3, MIM# 614021
Genomic newborn screening: BabyScreen+ v0.2133 SCN5A Zornitza Stark Classified gene: SCN5A as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.2133 SCN5A Zornitza Stark Gene: scn5a has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2132 SCN5A Zornitza Stark changed review comment from: These two associations have been rated as 'strong actionability' in paediatric patients by ClinGen.

Note LongQT generally has symptom onset in adolescence and Brugada typically presents in adulthood.

For review: age of onset and penetrance.; to: These two associations have been rated as 'strong actionability' in paediatric patients by ClinGen.

Note LongQT generally has symptom onset in adolescence and Brugada typically presents in adulthood.

Reviewed with paediatric cardiologist: generally later age of onset, does not fulfil criteria for gNBS.
Genomic newborn screening: BabyScreen+ v0.2132 SCN5A Zornitza Stark edited their review of gene: SCN5A: Changed rating: AMBER
Genomic newborn screening: BabyScreen+ v0.2132 PRKG1 Zornitza Stark Classified gene: PRKG1 as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.2132 PRKG1 Zornitza Stark Gene: prkg1 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2131 PRKG1 Zornitza Stark changed review comment from: Assessed as 'strong actionability' in paediatric patients by ClinGen.

FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta).

Variable age of clinical presentation.

Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2.

Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol.

Penetrance: A study of 31 individuals with PRKG1 pathogenic variants indicated that 63% presented with an aortic dissection and 37% had aortic root enlargement. The cumulative risk of an aortic dissection or repair of an aortic aneurysm by age 55 has been estimated as 86% (95% CI: 70-95%).
Sources: ClinGen; to: Assessed as 'strong actionability' in paediatric patients by ClinGen.

FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta).

Variable age of clinical presentation.

Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2.

Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol.

Penetrance: A study of 31 individuals with PRKG1 pathogenic variants indicated that 63% presented with an aortic dissection and 37% had aortic root enlargement. The cumulative risk of an aortic dissection or repair of an aortic aneurysm by age 55 has been estimated as 86% (95% CI: 70-95%).

Discussed with a paediatric cardiologist: variable penetrance and age of onset, does not fulfil criteria for gNBS.
Sources: ClinGen
Genomic newborn screening: BabyScreen+ v0.2131 PRKG1 Zornitza Stark edited their review of gene: PRKG1: Changed rating: AMBER
Genomic newborn screening: BabyScreen+ v0.2131 MYH11 Zornitza Stark Classified gene: MYH11 as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.2131 MYH11 Zornitza Stark Gene: myh11 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2130 MYH11 Zornitza Stark changed review comment from: Assessed as 'strong actionability' in paediatric patients by ClinGen.

FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta).

Variable age of clinical presentation.

Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2.

Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol.

Penetrance: A study of 12 individuals with MYH11 pathogenic variants indicated that 34% had an aortic dissection and one individual (8%) underwent prophylactic aortic aneurysm repair.; to: Assessed as 'strong actionability' in paediatric patients by ClinGen.

FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta).

Variable age of clinical presentation.

Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2.

Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol.

Penetrance: A study of 12 individuals with MYH11 pathogenic variants indicated that 34% had an aortic dissection and one individual (8%) underwent prophylactic aortic aneurysm repair.

Reviewed with a paediatric cardiologist: variable penetrance and age of onset, does not meet criteria for gNBS.
Genomic newborn screening: BabyScreen+ v0.2130 MYH11 Zornitza Stark edited their review of gene: MYH11: Changed rating: AMBER
Genomic newborn screening: BabyScreen+ v0.2130 LOX Zornitza Stark Classified gene: LOX as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.2130 LOX Zornitza Stark Gene: lox has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2129 LOX Zornitza Stark changed review comment from: Assessed as 'strong actionability' in paediatric patients by ClinGen.

FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta).

Variable age of clinical presentation.

Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2.

Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol.

Penetrance: A study of 15 individuals with LOX pathogenic variants indicated that 73% had aortic aneurysms and 1 individual (7%) had an aortic dissection.
Sources: ClinGen; to: Assessed as 'strong actionability' in paediatric patients by ClinGen.

FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta).

Variable age of clinical presentation.

Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2.

Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol.

Penetrance: A study of 15 individuals with LOX pathogenic variants indicated that 73% had aortic aneurysms and 1 individual (7%) had an aortic dissection.

Discussed with paediatric cardiologist: variable penetrance and age of onset, does not fit with criteria for gNBS.
Sources: ClinGen
Genomic newborn screening: BabyScreen+ v0.2129 LOX Zornitza Stark edited their review of gene: LOX: Changed rating: AMBER
Genomic newborn screening: BabyScreen+ v0.2129 JUP Zornitza Stark Classified gene: JUP as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.2129 JUP Zornitza Stark Gene: jup has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2128 JUP Zornitza Stark changed review comment from: Screen for bi-allelic disease as can be earlier onset, more severe.; to: Discussed potentially just screening for bi-allelic disease as can be earlier onset, more severe.

Discussed further with a paediatric cardiologist: variable age of onset and penetrance, therefore does not meet criteria.
Genomic newborn screening: BabyScreen+ v0.2128 JUP Zornitza Stark edited their review of gene: JUP: Changed rating: AMBER
Genomic newborn screening: BabyScreen+ v0.2128 DSP Zornitza Stark Classified gene: DSP as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.2128 DSP Zornitza Stark Gene: dsp has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2127 DSP Zornitza Stark changed review comment from: Screen for bi-allelic disease as can be more severe, earlier onset.; to: Discussed screening for bi-allelic disease as can be more severe, earlier onset.

Also discussed with paediatric cardiologist: variable age of onset and penetrance, exclude.
Genomic newborn screening: BabyScreen+ v0.2127 DSP Zornitza Stark edited their review of gene: DSP: Changed rating: AMBER
Bone Marrow Failure v1.32 SRP54 Raja Vasireddy reviewed gene: SRP54: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29914977; Phenotypes: Neutropenia, promyelocytic maturation arrest, neurodevelopmental delay, exocrine pancreatic insuffciency.; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: BabyScreen+ v0.2127 CASQ2 Zornitza Stark Classified gene: CASQ2 as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.2127 CASQ2 Zornitza Stark Gene: casq2 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2126 CASQ2 Zornitza Stark changed review comment from: Well established gene-disease association.

ClinGen: 'strong actionability' both for adult and paediatric patients. Treatment: beta blockers first line; ICD. There are also numerous known arrhythmia triggers which can be avoided.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease.

; to: Well established gene-disease association.

ClinGen: 'strong actionability' both for adult and paediatric patients. Treatment: beta blockers first line; ICD. There are also numerous known arrhythmia triggers which can be avoided.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease.

Reviewed with paediatric cardiologist: variable penetrance and age of onset.
Genomic newborn screening: BabyScreen+ v0.2126 CASQ2 Zornitza Stark edited their review of gene: CASQ2: Changed rating: AMBER
Incidentalome v0.223 APP Sangavi Sivagnanasundram changed review comment from: PubMed: 17121991: transgenic mouse study identified that hypoxia increase BACE1 activity which resulted in a significant increase in the production of beta-amyloid in AD-related APP mutations. The study showed that hypoxia up-regulated Bace1 mRNA and increased deposition of beta proteins.

PMID: 1520398 – V717I variant identified in multiple members in a Canadian family of European decent with a dominant inheritance of Alzheimers disease
PMID: 15365148 – 1 family with 6 affected individuals over 3 generations with heterozygous mutations in APP gene – phenotypic features of Alzheimers. Individuals had MRI conducted showing multiple white matter infarcts along the long penetrating arteries
PubMed: 15668448 – two siblings in an African American family with distinctive features of early-onset AD with APP mutations
PMID: 1671712 - V717I mutation identified in 2 unrelated UK families with Alzheimers disease via a genetic linkage study
PMID: 1678058 – 2 individuals from 2 unrelated Japanese families with early onset Alzheimers disease via a genetic linkage study; to: PubMed: 17121991: transgenic mouse study identified that hypoxia increase BACE1 activity which resulted in a significant increase in the production of beta-amyloid in AD-related APP mutations. The study showed that hypoxia up-regulated Bace1 mRNA leading to an increased deposition of beta proteins.

PMID: 1520398 – V717I variant identified in multiple members in a Canadian family of European decent with a dominant inheritance of Alzheimers disease
PMID: 15365148 – 1 family with 6 affected individuals over 3 generations with heterozygous mutations in APP gene – phenotypic features of Alzheimers. Individuals had MRI conducted showing multiple white matter infarcts along the long penetrating arteries
PubMed: 15668448 – two siblings in an African American family with distinctive features of early-onset AD with APP mutations
PMID: 1671712 - V717I mutation identified in 2 unrelated UK families with Alzheimers disease via a genetic linkage study
PMID: 1678058 – 2 individuals from 2 unrelated Japanese families with early onset Alzheimers disease via a genetic linkage study
Incidentalome v0.223 APP Sangavi Sivagnanasundram reviewed gene: APP: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 17121991, 1520398, 15365148, 15668448, 1671712, 1678058; Phenotypes: Alzheimer's Disease (MIM#104300); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genomic newborn screening: BabyScreen+ v0.2126 CALM1 Zornitza Stark Classified gene: CALM1 as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.2126 CALM1 Zornitza Stark Gene: calm1 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2125 CALM3 Zornitza Stark Phenotypes for gene: CALM3 were changed from Ventricular tachycardia, catecholaminergic polymorphic 6 , MIM# 618782; Long QT syndrome 16, MIM#618782 to Long QT syndrome 16, MIM#618782
Genomic newborn screening: BabyScreen+ v0.2124 CALM3 Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2.

Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

For review: age of onset and penetrance.
Sources: ClinGen; to: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2.

Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

Exclude for CPVT: association has moderate evidence, there are issues with penetrance, and treatment is generally only recommended in symptomatic individuals.
Sources: ClinGen
Genomic newborn screening: BabyScreen+ v0.2124 CALM3 Zornitza Stark edited their review of gene: CALM3: Changed phenotypes: Long QT syndrome 16, MIM#618782
Genomic newborn screening: BabyScreen+ v0.2124 CALM3 Zornitza Stark edited their review of gene: CALM3: Changed rating: GREEN
Genomic newborn screening: BabyScreen+ v0.2124 CALM3 Zornitza Stark edited their review of gene: CALM3: Changed rating: AMBER
Genomic newborn screening: BabyScreen+ v0.2124 CALM2 Zornitza Stark Classified gene: CALM2 as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.2124 CALM2 Zornitza Stark Gene: calm2 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2123 CALM2 Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2.

Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

For review: age of onset and penetrance.
Sources: ClinGen; to: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2.

Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

Reviewed with paediatric cardiologist: not for inclusion due to issues with penetrance, plus guidelines only generally recommend treatment is symptomatic individuals.
Genomic newborn screening: BabyScreen+ v0.2123 CALM2 Zornitza Stark edited their review of gene: CALM2: Changed rating: AMBER
Genomic newborn screening: BabyScreen+ v0.2123 CALM1 Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2.

Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

For review: age of onset and penetrance.
Sources: ClinGen; to: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2.

Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

Reviewed with paediatric cardiologist: not for inclusion due to issues with penetrance, plus guidelines only generally recommend treatment is symptomatic individuals.
Genomic newborn screening: BabyScreen+ v0.2123 CALM1 Zornitza Stark edited their review of gene: CALM1: Changed rating: AMBER
Incidentalome v0.223 ANG Sangavi Sivagnanasundram reviewed gene: ANG: Rating: GREEN; Mode of pathogenicity: None; Publications: 17886298, 16501576, 18087731, 20301623; Phenotypes: Amyotrophic Lateral Sclerosis (MONDO: 0012753, MIM#611895); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.223 ATP7B Sangavi Sivagnanasundram reviewed gene: ATP7B: Rating: GREEN; Mode of pathogenicity: None; Publications: 8298639, 9554743, 10790207, 7626145, 16133174; Phenotypes: Wilson Disease (MONDO:0010200, MIM #277900); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.223 ATP7B Sangavi Sivagnanasundram Deleted their review
Incidentalome v0.223 ATP7B Sangavi Sivagnanasundram changed review comment from: Well established gene known to be causative of Wilson Disease (Gene Reviews: NBK1512); Loss of function is a well established mechanism - functional study showed impaired production of copper transport and abberant cellular localization of mutant ATP7B proteins – PMID: 16133174; to: Well established gene known to be causative of Wilson Disease (Gene Reviews: NBK1512); Loss of function is a well established mechanism - functional study showed impaired production of copper transport and abberant cellular localization of mutant ATP7B proteins – PMID: 16133174
Incidentalome v0.223 ATP7B Sangavi Sivagnanasundram reviewed gene: ATP7B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 8298639, 9554743, 10790207, 7626145, 16133174; Phenotypes: Wilson Disease (MIM#277900); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.106 Bryony Thompson Panel name changed from Osteogenesis Imperfecta to Osteogenesis Imperfecta and Osteoporosis
Brain Calcification v1.38 COASY Zornitza Stark Marked gene: COASY as ready
Brain Calcification v1.38 COASY Zornitza Stark Gene: coasy has been classified as Red List (Low Evidence).
Brain Calcification v1.38 COASY Zornitza Stark Phenotypes for gene: COASY were changed from Neurodegeneration with brain iron accumulation 6 (COPAN); NBIA6 to Neurodegeneration with brain iron accumulation 6, MIM# 615643
Brain Calcification v1.37 COASY Zornitza Stark Classified gene: COASY as Red List (low evidence)
Brain Calcification v1.37 COASY Zornitza Stark Gene: coasy has been classified as Red List (Low Evidence).
Brain Calcification v1.36 CA2 Zornitza Stark Phenotypes for gene: CA2 were changed from Osteopetrosis, autosomal recessive 3, with renal tubular acidosis, MIM# 259730 to Osteopetrosis, autosomal recessive 3, with renal tubular acidosis, MIM# 259730
Brain Calcification v1.35 CASR Zornitza Stark Marked gene: CASR as ready
Brain Calcification v1.35 CASR Zornitza Stark Gene: casr has been classified as Green List (High Evidence).
Brain Calcification v1.35 CASR Zornitza Stark Phenotypes for gene: CASR were changed from Hypocalcemia, autosomal dominant; HYPOC1; Hypercalciuric Hypocalcemia; Hypocalcemia, familial to Hypocalcemia, autosomal dominant, MIM# 601198
Brain Calcification v1.34 CASR Zornitza Stark Publications for gene: CASR were set to 32775520; 35402765
Brain Calcification v1.33 CA2 Zornitza Stark Phenotypes for gene: CA2 were changed from Osteopetrosis, autosomal recessive 3, with renal tubular acidosis; OPTB3 to Osteopetrosis, autosomal recessive 3, with renal tubular acidosis, MIM# 259730
Brain Calcification v1.33 CASR Zornitza Stark Classified gene: CASR as Green List (high evidence)
Brain Calcification v1.33 CASR Zornitza Stark Gene: casr has been classified as Green List (High Evidence).
Brain Calcification v1.32 CA2 Zornitza Stark Marked gene: CA2 as ready
Brain Calcification v1.32 CA2 Zornitza Stark Gene: ca2 has been classified as Green List (High Evidence).
Brain Calcification v1.32 CASR Zornitza Stark reviewed gene: CASR: Rating: GREEN; Mode of pathogenicity: None; Publications: 8733126, 8813042; Phenotypes: Hypocalcemia, autosomal dominant, MIM# 601198; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Brain Calcification v1.32 C1QB Zornitza Stark Phenotypes for gene: C1QB were changed from C1q deficiency; C1QD to C1q deficiency, MIM# 613652
Brain Calcification v1.32 ATN1 Zornitza Stark Marked gene: ATN1 as ready
Brain Calcification v1.32 ATN1 Zornitza Stark Gene: atn1 has been classified as Red List (Low Evidence).
Brain Calcification v1.32 CA2 Zornitza Stark Classified gene: CA2 as Green List (high evidence)
Brain Calcification v1.32 CA2 Zornitza Stark Gene: ca2 has been classified as Green List (High Evidence).
Brain Calcification v1.31 CA2 Zornitza Stark reviewed gene: CA2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis, MIM# 259730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.31 C1QB Zornitza Stark Classified gene: C1QB as Red List (low evidence)
Brain Calcification v1.31 C1QB Zornitza Stark Gene: c1qb has been classified as Red List (Low Evidence).
Brain Calcification v1.30 BTD Zornitza Stark Marked gene: BTD as ready
Brain Calcification v1.30 BTD Zornitza Stark Gene: btd has been classified as Red List (Low Evidence).
Brain Calcification v1.30 C1QB Zornitza Stark reviewed gene: C1QB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: C1q deficiency, MIM# 613652; Mode of inheritance: None
Brain Calcification v1.30 BTD Zornitza Stark Phenotypes for gene: BTD were changed from Biotinidase Deficiency to Biotinidase deficiency, MIM# 253260
Brain Calcification v1.29 ATN1 Zornitza Stark Phenotypes for gene: ATN1 were changed from Dentatorubral-pallidoluysian atrophy; DRPLA to Dentatorubral-pallidoluysian atrophy, MIM# 125370
Brain Calcification v1.28 BTD Zornitza Stark Classified gene: BTD as Red List (low evidence)
Brain Calcification v1.28 BTD Zornitza Stark Gene: btd has been classified as Red List (Low Evidence).
Brain Calcification v1.27 BTD Zornitza Stark reviewed gene: BTD: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Biotinidase deficiency, MIM# 253260; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.27 ATN1 Zornitza Stark Classified gene: ATN1 as Red List (low evidence)
Brain Calcification v1.27 ATN1 Zornitza Stark Gene: atn1 has been classified as Red List (Low Evidence).
Brain Calcification v1.26 ATN1 Zornitza Stark Tag STR tag was added to gene: ATN1.
Brain Calcification v1.26 AP1S2 Zornitza Stark Publications for gene: AP1S2 were set to
Brain Calcification v1.25 ACVR1 Zornitza Stark Marked gene: ACVR1 as ready
Brain Calcification v1.25 ACVR1 Zornitza Stark Gene: acvr1 has been classified as Green List (High Evidence).
Brain Calcification v1.25 ACVR1 Zornitza Stark Phenotypes for gene: ACVR1 were changed from Fibrodysplasia ossificans progressiva; FOP to Fibrodysplasia ossificans progressiva, MIM# 135100
Brain Calcification v1.25 ADAR Zornitza Stark Publications for gene: ADAR were set to 23001123; 24262145
Brain Calcification v1.24 ACVR1 Zornitza Stark Classified gene: ACVR1 as Green List (high evidence)
Brain Calcification v1.24 ACVR1 Zornitza Stark Gene: acvr1 has been classified as Green List (High Evidence).
Brain Calcification v1.23 ACVR1 Zornitza Stark reviewed gene: ACVR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fibrodysplasia ossificans progressiva, MIM# 135100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Brain Calcification v1.23 ACP5 Zornitza Stark Phenotypes for gene: ACP5 were changed from Spondyloenchondrodysplasia with immune dysregulation, MIM# 607944 to Spondyloenchondrodysplasia with immune dysregulation, MIM# 607944
Brain Calcification v1.23 ACP5 Zornitza Stark Phenotypes for gene: ACP5 were changed from Spondyloenchondrodysplasia, short stature, SLE, intracranial calcification, spasticity, chilblains, autoimmune haemolytic anaemia to Spondyloenchondrodysplasia with immune dysregulation, MIM# 607944
Brain Calcification v1.22 ACP5 Zornitza Stark edited their review of gene: ACP5: Changed phenotypes: Spondyloenchondrodysplasia with immune dysregulation, MIM# 607944
Brain Calcification v1.22 AP1S2 Yetong Chen changed review comment from: PMID 17617514 reports a linkage study of AP1S2 in 2 unrelated families with multiple generations affected by Fried syndrome. Cosegregation of the phenotype and AP1S2 variants is demonstrated. Two patients from the French family and 3 patients from the Scottish family developed brain calcification.; to: PMID 17617514 reports a linkage study of AP1S2 in 2 unrelated families with multiple generations affected by Fried syndrome. Cosegregation of the phenotype and AP1S2 variants is demonstrated. Two patients from the French family and 3 patients from the Scottish family developed brain calcification.
PMID 19161147 reports 8 individuals from 2 interrelated Omani families who developed brain calcification.
Brain Calcification v1.22 COASY Yetong Chen gene: COASY was added
gene: COASY was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: COASY was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COASY were set to 27487380; 24360804
Phenotypes for gene: COASY were set to Neurodegeneration with brain iron accumulation 6 (COPAN); NBIA6
Review for gene: COASY was set to RED
Added comment: There is limited evidence to support a causal role for the COASY gene in brain calcification.
PMID 24360804 demonstrates variants in COASY as a cause of brain iron accumulation, which includes brain calcification, by using segregation analysis. Brain calcification was found in one patient with a homozygous variant of COASY.
Sources: Expert list
Brain Calcification v1.22 CASR Yetong Chen gene: CASR was added
gene: CASR was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: CASR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CASR were set to 32775520; 35402765
Phenotypes for gene: CASR were set to Hypocalcemia, autosomal dominant; HYPOC1; Hypercalciuric Hypocalcemia; Hypocalcemia, familial
Review for gene: CASR was set to RED
Added comment: PMID 32775520 reports co-segregation of a CASR variant and intracranial calcification found in 2 patients from the same family.
PMID 35402765 reports a patient with a CASR variant who developed multiple intracerebral calcifications. A pedigree including the patient and her parents can be found in the paper, but CASR genetic testing was not done on the proband's parents so it could not confirm whether the variant is de novo.
Sources: Expert list
Brain Calcification v1.22 CA2 Yetong Chen gene: CA2 was added
gene: CA2 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: CA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CA2 were set to 25674028
Phenotypes for gene: CA2 were set to Osteopetrosis, autosomal recessive 3, with renal tubular acidosis; OPTB3
Review for gene: CA2 was set to GREEN
Added comment: PMID 25674028 reports a female patient with a homozygous variant in the CA2 gene who developed extensive symmetric intracranial calcification.
PMID 22120147 reports brain calcification in 18 individuals, who carry a CA2 variant, from 10 unrelated families. Pedigrees show co-segregation of genotype (homozygous mutant allele) and phenotype.
Sources: Expert list
Fetal anomalies v1.92 PLXND1 Zornitza Stark Phenotypes for gene: PLXND1 were changed from Congenital heart disease, MONDO:0005453, PLXND1-related to Congenital heart defects, multiple types, 9, MIM# 620294
Fetal anomalies v1.91 PLXND1 Zornitza Stark edited their review of gene: PLXND1: Changed phenotypes: Congenital heart defects, multiple types, 9, MIM# 620294
Mendeliome v1.755 PLXND1 Zornitza Stark Phenotypes for gene: PLXND1 were changed from Möbius syndrome, MONDO:0008006; Congenital heart disease, MONDO:0005453, PLXND1-related to Möbius syndrome, MONDO:0008006; Congenital heart defects, multiple types, 9, MIM# 620294
Mendeliome v1.754 PLXND1 Zornitza Stark edited their review of gene: PLXND1: Changed phenotypes: Möbius syndrome, Congenital heart defects, multiple types, 9, MIM# 620294
Congenital Heart Defect v0.277 PLXND1 Zornitza Stark Phenotypes for gene: PLXND1 were changed from Congenital heart disease, MONDO:0005453, PLXND1-related to Congenital heart defects, multiple types, 9, MIM# 620294
Congenital Heart Defect v0.276 PLXND1 Zornitza Stark edited their review of gene: PLXND1: Changed phenotypes: Congenital heart defects, multiple types, 9, MIM# 620294
Intellectual disability syndromic and non-syndromic v0.5193 AGO1 Zornitza Stark Phenotypes for gene: AGO1 were changed from Intellectual disability; autism to Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures, MIM# 620292
Intellectual disability syndromic and non-syndromic v0.5192 AGO1 Zornitza Stark edited their review of gene: AGO1: Changed phenotypes: Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures, MIM# 620292
Genetic Epilepsy v0.1834 AGO1 Zornitza Stark Phenotypes for gene: AGO1 were changed from Neurodevelopmental disorder MONDO:0700092, AGO1-related; non-syndromic ID and seizures to Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures, MIM# 620292
Genetic Epilepsy v0.1833 AGO1 Zornitza Stark edited their review of gene: AGO1: Changed phenotypes: Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures, MIM# 620292
Mendeliome v1.754 AGO1 Zornitza Stark Phenotypes for gene: AGO1 were changed from Neurodevelopmental disorder MONDO:0700092, AGO1-related; non-syndromic ID and seizures to Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures, MIM# 620292
Mendeliome v1.753 AGO1 Zornitza Stark edited their review of gene: AGO1: Changed phenotypes: Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures, MIM# 620292
Mendeliome v1.753 PRDM10 Zornitza Stark Marked gene: PRDM10 as ready
Mendeliome v1.753 PRDM10 Zornitza Stark Gene: prdm10 has been classified as Red List (Low Evidence).
Mendeliome v1.753 PRDM10 Zornitza Stark Classified gene: PRDM10 as Red List (low evidence)
Mendeliome v1.753 PRDM10 Zornitza Stark Gene: prdm10 has been classified as Red List (Low Evidence).
Brain Calcification v1.22 C1QB Yetong Chen gene: C1QB was added
gene: C1QB was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: C1QB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1QB were set to 23651859
Phenotypes for gene: C1QB were set to C1q deficiency; C1QD
Review for gene: C1QB was set to RED
Added comment: Limited evidence supports a casual role of the C1QB gene in brain calcification.
PMID 23651859 reports a patient with a novel homozygous variant in C1QB who developed bilateral frontal infarcts and basal ganglia calcification.
Sources: Expert list
Brain Calcification v1.22 BTD Yetong Chen gene: BTD was added
gene: BTD was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: BTD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BTD were set to 32734340; 3399084
Phenotypes for gene: BTD were set to Biotinidase Deficiency
Review for gene: BTD was set to RED
Added comment: PMID 3399084 reports one case of Biotinidase Deficiency with basal ganglia calcification. However, no strong or moderate evidence suggests that variants in the BTN gene can cause brain calcification.
Sources: Expert list
Brain Calcification v1.22 ATN1 Yetong Chen gene: ATN1 was added
gene: ATN1 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: ATN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATN1 were set to 2742549
Phenotypes for gene: ATN1 were set to Dentatorubral-pallidoluysian atrophy; DRPLA
Review for gene: ATN1 was set to RED
Added comment: PMID 2742549 reports the calcification of the globus pallidus in 4 out of the 10 assessed patients with Haw River Syndrome. Although both Haw River Syndrome and DRPLA are caused by the same expanded CAG repeat in the ATN1 gene, no genetic testing was done on the patients to confirm whether they carried ATN1 variants.
Sources: Expert list
Brain Calcification v1.22 AP1S2 Yetong Chen reviewed gene: AP1S2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19161147, 17617514; Phenotypes: Pettigrew syndrome, Fried syndrome, PG5; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Brain Calcification v1.22 ADAR Yetong Chen reviewed gene: ADAR: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301648, 23001123, 24262145, 30692772; Phenotypes: Aicardi-Goutieres syndrome 6, AGS6; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.752 PRDM10 Achchuthan Shanmugasundram gene: PRDM10 was added
gene: PRDM10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRDM10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRDM10 were set to 36440963
Phenotypes for gene: PRDM10 were set to Fibrofolliculoma, HP:0030436; lipomatosis, MONDO:0006574; renal cell carcinoma, MONDO:0005086
Review for gene: PRDM10 was set to RED
Added comment: PMID:36440963 reported a family presenting with skin and mucosal lesions, extensive lipomatosis and renal cell carcinomas. The proband was initially diagnosed with Birt-Hogg-Dubé syndrome (BHD, MIM #135150) based on the presence of fibrofolliculomas, but no pathogenic germline variant was detected in FLCN, the gene associated with BHD. A heterozygous missense variant (p.Cys677Tyr) was identified, which co-segregated with the phenotype in the family.

Functional studies show that Cys677Tyr loses affinity for a regulatory binding motif in the FLCN promoter, abrogating cellular FLCN mRNA and protein levels. Overexpressing inducible PRDM10Cys677Tyr in renal epithelial cells altered the transcription of multiple genes, showing overlap but also differences with the effects of knocking out FLCN.

This gene has not yet been associated with phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Brain Calcification v1.22 ACVR1 Yetong Chen gene: ACVR1 was added
gene: ACVR1 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: ACVR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACVR1 were set to 27565519
Phenotypes for gene: ACVR1 were set to Fibrodysplasia ossificans progressiva; FOP
Review for gene: ACVR1 was set to GREEN
Added comment: PMID 27565519 reports that 4 individuals with an ACVR1 variant developed T2-hyperintensity with calcifications, while 2 individuals developed isolated calcification in the dentate nuclei. In addition, 7 individuals with an ACVR1 variant developed striatal calcifications in the basal ganglia. (However, the relationship between the reported individuals and their clinical presentations is not clear, and the online supplementary Table S3, which contains the clinico-genetic characteristics of patients, cannot be found.)
Sources: Expert list
Brain Calcification v1.22 ACP5 Yetong Chen changed review comment from: PMID 21217755 reports 4 unrelated individuals with ACP5 variants who developed intracranial calcification.
PMID 21217752 reports 4 individuals with ACP5 variants who developed brain calcification.; to: PMID 21217755 reports 4 unrelated individuals with ACP5 variants who developed intracranial calcification.
PMID 21217752 reports 4 individuals with ACP5 variants who developed brain calcification.
Brain Calcification v1.22 ACP5 Yetong Chen reviewed gene: ACP5: Rating: GREEN; Mode of pathogenicity: None; Publications: 24372060, 21217755; Phenotypes: Spondyloenchondrodysplasia with immune dysregulation, SPENCDI; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.752 COL12A1 Elena Savva commented on gene: COL12A1
Muscular dystrophy and myopathy_Paediatric v0.128 COL12A1 Elena Savva changed review comment from: Additional infant proband but with limited clinical information, had chet canonical splice with a PTC.

VCGS patient: homozygous for a canonical splice variant with a severe neonatal presentation of arthrogryposis and muscular hypotonia.

Total: three reports, upgraded to green; to: Additional infant proband but with limited clinical information, had chet canonical splice with a PTC.

VCGS patient: homozygous for a canonical splice variant with a severe neonatal presentation of arthrogryposis and muscular hypotonia.

Total: three reports, upgraded to green
Muscular dystrophy and myopathy_Paediatric v0.128 COL12A1 Elena Savva changed review comment from: Additional infant proband but with limited clinical information, had chet canonical splice with a PTC; to: Additional infant proband but with limited clinical information, had chet canonical splice with a PTC.

VCGS patient: homozygous for a canonical splice variant with a severe neonatal presentation of arthrogryposis and muscular hypotonia.

Total: three reports, upgraded to green
Muscular dystrophy and myopathy_Paediatric v0.128 COL12A1 Elena Savva Classified gene: COL12A1 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v0.128 COL12A1 Elena Savva Gene: col12a1 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.127 COL12A1 Elena Savva Publications for gene: COL12A1 were set to 24334604
Muscular dystrophy and myopathy_Paediatric v0.127 COL12A1 Elena Savva Classified gene: COL12A1 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v0.127 COL12A1 Elena Savva Gene: col12a1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2123 VAMP1 Zornitza Stark Marked gene: VAMP1 as ready
Genomic newborn screening: BabyScreen+ v0.2123 VAMP1 Zornitza Stark Gene: vamp1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2123 VAMP1 Zornitza Stark Phenotypes for gene: VAMP1 were changed from Spastic ataxia; Myasthenic syndrome, congenital, 25, MIM# 618323 to Myasthenic syndrome, congenital, 25, MIM# 618323
Genomic newborn screening: BabyScreen+ v0.2122 VAMP1 Zornitza Stark Publications for gene: VAMP1 were set to
Genomic newborn screening: BabyScreen+ v0.2121 VAMP1 Zornitza Stark Mode of inheritance for gene: VAMP1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2120 VAMP1 Zornitza Stark Classified gene: VAMP1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2120 VAMP1 Zornitza Stark Gene: vamp1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2119 VAMP1 Zornitza Stark Tag treatable tag was added to gene: VAMP1.
Tag neurological tag was added to gene: VAMP1.
Genomic newborn screening: BabyScreen+ v0.2119 VAMP1 Zornitza Stark reviewed gene: VAMP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28168212, 28253535, 28600779, 17102983; Phenotypes: Myasthenic syndrome, congenital, 25, MIM# 618323; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2119 TUBB1 Zornitza Stark Marked gene: TUBB1 as ready
Genomic newborn screening: BabyScreen+ v0.2119 TUBB1 Zornitza Stark Gene: tubb1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2119 TUBB1 Zornitza Stark Classified gene: TUBB1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2119 TUBB1 Zornitza Stark Gene: tubb1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2118 TUBB1 Zornitza Stark Tag treatable tag was added to gene: TUBB1.
Tag endocrine tag was added to gene: TUBB1.
Genomic newborn screening: BabyScreen+ v0.2118 TUBB1 Zornitza Stark gene: TUBB1 was added
gene: TUBB1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TUBB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TUBB1 were set to 30446499
Phenotypes for gene: TUBB1 were set to Congenital hypothyroidism, MONDO:0018612, TUBB1-related; Macrothrombocytopenia, autosomal dominant, TUBB1-related, OMIM # 613112
Review for gene: TUBB1 was set to GREEN
Added comment: At least 3 families reported with congenital hypothyroidism associated with TUBB1 variants. Platelet abnormalities reported.

Treatment: thyroxine.

Non-genetic confirmatory testing: TFTs, blood film.
Sources: Expert list
Congenital hypothyroidism v0.43 TUBB1 Zornitza Stark changed review comment from: Comment when marking as ready: Green for mono allelic variants, limited evidence for bi-allelic variants.; to: Comment when marking as ready: Green for mono allelic variants, limited evidence for bi-allelic variants.

Congenital hypothyroidism in some.
Mendeliome v1.752 SLC26A7 Zornitza Stark Marked gene: SLC26A7 as ready
Mendeliome v1.752 SLC26A7 Zornitza Stark Gene: slc26a7 has been classified as Green List (High Evidence).
Mendeliome v1.752 SLC26A7 Zornitza Stark Classified gene: SLC26A7 as Green List (high evidence)
Mendeliome v1.752 SLC26A7 Zornitza Stark Gene: slc26a7 has been classified as Green List (High Evidence).
Mendeliome v1.751 SLC26A7 Zornitza Stark gene: SLC26A7 was added
gene: SLC26A7 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SLC26A7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC26A7 were set to 34780050; 32486989; 31372509; 30333321
Phenotypes for gene: SLC26A7 were set to Congenital hypothyroidism, MONDO:0018612, SLC26A7-related
Review for gene: SLC26A7 was set to GREEN
Added comment: More than 10 unrelated families reported.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2117 SLC26A7 Zornitza Stark Marked gene: SLC26A7 as ready
Genomic newborn screening: BabyScreen+ v0.2117 SLC26A7 Zornitza Stark Gene: slc26a7 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2117 SLC26A7 Zornitza Stark Classified gene: SLC26A7 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2117 SLC26A7 Zornitza Stark Gene: slc26a7 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2116 SLC26A7 Zornitza Stark gene: SLC26A7 was added
gene: SLC26A7 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: SLC26A7.
Mode of inheritance for gene: SLC26A7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC26A7 were set to 34780050; 32486989; 31372509; 30333321
Phenotypes for gene: SLC26A7 were set to Congenital hypothyroidism, MONDO:0018612, SLC26A7-related
Review for gene: SLC26A7 was set to GREEN
Added comment: More than 10 unrelated families reported.

Congenital hypothyroidism.

Treatment: thyroxine.

Should be detected through standard NBS.
Sources: Expert list
Congenital hypothyroidism v0.43 SLC26A7 Zornitza Stark Marked gene: SLC26A7 as ready
Congenital hypothyroidism v0.43 SLC26A7 Zornitza Stark Gene: slc26a7 has been classified as Green List (High Evidence).
Congenital hypothyroidism v0.43 SLC26A7 Zornitza Stark Phenotypes for gene: SLC26A7 were changed from Primary congenital hypothyroidism (dyshormonogenesis) to Congenital hypothyroidism, MONDO:0018612, SLC26A7-related
Congenital hypothyroidism v0.42 SLC26A7 Zornitza Stark Publications for gene: SLC26A7 were set to 30333321; 29546359
Congenital hypothyroidism v0.41 SLC26A7 Zornitza Stark reviewed gene: SLC26A7: Rating: GREEN; Mode of pathogenicity: None; Publications: 34780050, 32486989, 31372509, 30333321; Phenotypes: Congenital hypothyroidism, MONDO:0018612, SLC26A7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2115 OTX2 Zornitza Stark Marked gene: OTX2 as ready
Genomic newborn screening: BabyScreen+ v0.2115 OTX2 Zornitza Stark Gene: otx2 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2115 OTX2 Zornitza Stark Classified gene: OTX2 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2115 OTX2 Zornitza Stark Gene: otx2 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2114 OTX2 Zornitza Stark gene: OTX2 was added
gene: OTX2 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: OTX2.
Mode of inheritance for gene: OTX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: OTX2 were set to 18728160; 35320640; 33950863
Phenotypes for gene: OTX2 were set to Pituitary hormone deficiency, combined, 6, MIM# 613986
Review for gene: OTX2 was set to GREEN
Added comment: Variants in this gene have been associated with pituitary hormone deficiency with or without microphthalmia, including of TSH.

Congenital onset.

Microphthalmia would present clinically in the newborn period. Infants with TSH deficiency should be detected by standard NBS.

Treatment: thyroxine and other hormone replacements.
Sources: Expert list
Congenital hypothyroidism v0.41 OTX2 Zornitza Stark Marked gene: OTX2 as ready
Congenital hypothyroidism v0.41 OTX2 Zornitza Stark Gene: otx2 has been classified as Green List (High Evidence).
Congenital hypothyroidism v0.41 OTX2 Zornitza Stark Phenotypes for gene: OTX2 were changed from GH, TSH, ACTH, LH, FSH deficiency; ectopic posterior pituitary; Anophthalmia Retinal dystrophy; normal or hypoplastic anterior pituitary; Pituitary hormone deficiency, combined, 6, 613986 to Pituitary hormone deficiency, combined, 6, MIM# 613986
Congenital hypothyroidism v0.40 OTX2 Zornitza Stark Publications for gene: OTX2 were set to 18628516; 26416826 (2015 review)
Congenital hypothyroidism v0.39 OTX2 Zornitza Stark reviewed gene: OTX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18728160, 35320640, 33950863; Phenotypes: Pituitary hormone deficiency, combined, 6, MIM# 613986; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: BabyScreen+ v0.2113 HESX1 Zornitza Stark Marked gene: HESX1 as ready
Genomic newborn screening: BabyScreen+ v0.2113 HESX1 Zornitza Stark Gene: hesx1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2113 HESX1 Zornitza Stark Phenotypes for gene: HESX1 were changed from Septooptic dysplasia, MIM# 182230; Pituitary hypoplasia to Pituitary hormone deficiency, combined, 5, MIM# 182230
Genomic newborn screening: BabyScreen+ v0.2112 HESX1 Zornitza Stark Mode of inheritance for gene: HESX1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2111 HESX1 Zornitza Stark Classified gene: HESX1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2111 HESX1 Zornitza Stark Gene: hesx1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2110 HESX1 Zornitza Stark Tag treatable tag was added to gene: HESX1.
Tag endocrine tag was added to gene: HESX1.
Genomic newborn screening: BabyScreen+ v0.2110 HESX1 Zornitza Stark reviewed gene: HESX1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pituitary hormone deficiency, combined, 5, MIM# 182230; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital hypothyroidism v0.39 CDCA8 Zornitza Stark Phenotypes for gene: CDCA8 were changed from Congenital hypothyroidism; No OMIM number; thyroid dysgenesis to Congenital hypothyroidism, MONDO:0018612, CDCA8-related
Genomic newborn screening: BabyScreen+ v0.2110 CDCA8 Zornitza Stark Marked gene: CDCA8 as ready
Genomic newborn screening: BabyScreen+ v0.2110 CDCA8 Zornitza Stark Gene: cdca8 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2110 CDCA8 Zornitza Stark Classified gene: CDCA8 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2110 CDCA8 Zornitza Stark Gene: cdca8 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2109 CDCA8 Zornitza Stark gene: CDCA8 was added
gene: CDCA8 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: CDCA8.
Mode of inheritance for gene: CDCA8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CDCA8 were set to 28025328; 29546359
Phenotypes for gene: CDCA8 were set to Congenital hypothyroidism, MONDO:0018612, CDCA8-related
Review for gene: CDCA8 was set to GREEN
Added comment: 4 families (1 with bilallelic variants [parent affected as HTZ], 3 with monoallelic variants) with functional evidence of variants.

Treatment: thyroxine

Likely to be detected on standard NBS.
Sources: Expert list
Mendeliome v1.750 LCP2 Zornitza Stark Publications for gene: LCP2 were set to 33231617
Mendeliome v1.749 LCP2 Zornitza Stark Classified gene: LCP2 as Green List (high evidence)
Mendeliome v1.749 LCP2 Zornitza Stark Gene: lcp2 has been classified as Green List (High Evidence).
Mendeliome v1.748 LCP2 Zornitza Stark edited their review of gene: LCP2: Added comment: PMID 36474126: second individual reported. Functional data.; Changed rating: GREEN; Changed publications: 33231617, 36474126
Combined Immunodeficiency v1.34 LCP2 Zornitza Stark Marked gene: LCP2 as ready
Combined Immunodeficiency v1.34 LCP2 Zornitza Stark Gene: lcp2 has been classified as Green List (High Evidence).
Combined Immunodeficiency v1.34 LCP2 Zornitza Stark Phenotypes for gene: LCP2 were changed from to Immunodeficiency 81, MIM# 619374
Combined Immunodeficiency v1.33 LCP2 Zornitza Stark reviewed gene: LCP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 81, MIM# 619374; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v1.33 LCP2 Zornitza Stark Classified gene: LCP2 as Green List (high evidence)
Combined Immunodeficiency v1.33 LCP2 Zornitza Stark Gene: lcp2 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2108 FOXN1 Zornitza Stark Marked gene: FOXN1 as ready
Genomic newborn screening: BabyScreen+ v0.2108 FOXN1 Zornitza Stark Gene: foxn1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2108 FOXN1 Zornitza Stark Phenotypes for gene: FOXN1 were changed from Congenital alopecia with T-cell immunodeficiency; T-cell immunodeficiency, congenital alopecia, and nail dystrophy , MIM#601705; T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant, MIM# 618806 to T-cell immunodeficiency, congenital alopecia, and nail dystrophy, autosomal recessive MIM# 601705; T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant, MIM#t 618806
Genomic newborn screening: BabyScreen+ v0.2107 FOXN1 Zornitza Stark Publications for gene: FOXN1 were set to
Genomic newborn screening: BabyScreen+ v0.2106 FOXN1 Zornitza Stark Mode of inheritance for gene: FOXN1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2105 FOXN1 Zornitza Stark Classified gene: FOXN1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2105 FOXN1 Zornitza Stark Gene: foxn1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2104 FOXN1 Zornitza Stark Tag treatable tag was added to gene: FOXN1.
Tag immunological tag was added to gene: FOXN1.
Genomic newborn screening: BabyScreen+ v0.2104 FOXN1 Zornitza Stark reviewed gene: FOXN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31447097, 18339010, 10206641; Phenotypes: T-cell immunodeficiency, congenital alopecia, and nail dystrophy, autosomal recessive MIM# 601705, T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant, MIM#t 618806; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Muscular dystrophy and myopathy_Paediatric v0.126 COL12A1 Elena Savva reviewed gene: COL12A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28973083, 24334604; Phenotypes: ?Ullrich congenital muscular dystrophy 2 MIM#616470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.105 TRPV6 Zornitza Stark Marked gene: TRPV6 as ready
Osteogenesis Imperfecta and Osteoporosis v0.105 TRPV6 Zornitza Stark Gene: trpv6 has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v0.105 TRPV6 Zornitza Stark Phenotypes for gene: TRPV6 were changed from to Hyperparathyroidism, transient neonatal, MIM# 618188
Osteogenesis Imperfecta and Osteoporosis v0.104 TRPV6 Zornitza Stark Publications for gene: TRPV6 were set to
Osteogenesis Imperfecta and Osteoporosis v0.103 TRPV6 Zornitza Stark Mode of inheritance for gene: TRPV6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.102 TRPV6 Zornitza Stark reviewed gene: TRPV6: Rating: GREEN; Mode of pathogenicity: None; Publications: 29861107; Phenotypes: Hyperparathyroidism, transient neonatal, MIM# 618188; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2104 TMEM38B Zornitza Stark Marked gene: TMEM38B as ready
Genomic newborn screening: BabyScreen+ v0.2104 TMEM38B Zornitza Stark Gene: tmem38b has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2104 TMEM38B Zornitza Stark Classified gene: TMEM38B as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2104 TMEM38B Zornitza Stark Gene: tmem38b has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2103 TMEM38B Zornitza Stark Tag treatable tag was added to gene: TMEM38B.
Tag skeletal tag was added to gene: TMEM38B.
Genomic newborn screening: BabyScreen+ v0.2103 TMEM38B Zornitza Stark gene: TMEM38B was added
gene: TMEM38B was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TMEM38B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM38B were set to 23054245; 28323974
Phenotypes for gene: TMEM38B were set to Osteogenesis imperfecta, type XIV , MIM#615066
Review for gene: TMEM38B was set to GREEN
Added comment: More than 10 families reported.

Variable severity, onset of fractures generally in infancy.

Treatment: bisphosphanates; improvement in BMD reported.

Non-genetic confirmatory testing: skeletal survey.
Sources: Expert list
Osteogenesis Imperfecta and Osteoporosis v0.102 TMEM38B Zornitza Stark Marked gene: TMEM38B as ready
Osteogenesis Imperfecta and Osteoporosis v0.102 TMEM38B Zornitza Stark Gene: tmem38b has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v0.102 TMEM38B Zornitza Stark Phenotypes for gene: TMEM38B were changed from to Osteogenesis imperfecta, type XIV , MIM#615066
Osteogenesis Imperfecta and Osteoporosis v0.101 TMEM38B Zornitza Stark Publications for gene: TMEM38B were set to
Osteogenesis Imperfecta and Osteoporosis v0.100 TMEM38B Zornitza Stark Mode of inheritance for gene: TMEM38B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.99 TMEM38B Zornitza Stark reviewed gene: TMEM38B: Rating: GREEN; Mode of pathogenicity: None; Publications: 23054245, 28323974; Phenotypes: Osteogenesis imperfecta, type XIV , MIM#615066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.99 SPARC Zornitza Stark Marked gene: SPARC as ready
Osteogenesis Imperfecta and Osteoporosis v0.99 SPARC Zornitza Stark Gene: sparc has been classified as Green List (High Evidence).
Inflammatory bowel disease v0.99 C17orf62 Aimee Huynh gene: C17orf62 was added
gene: C17orf62 was added to Inflammatory bowel disease. Sources: Expert Review
Mode of inheritance for gene: C17orf62 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C17orf62 were set to 28600779, 30361506
Phenotypes for gene: C17orf62 were set to Chronic granulomatous disease
Penetrance for gene: C17orf62 were set to unknown
Review for gene: C17orf62 was set to AMBER
gene: C17orf62 was marked as current diagnostic
Added comment: Homozygous LOF mutation leading to CYBC1 deficiency causes CGD in pair of Icelandic brothers and 6 other individuals - colitis an early feature. Brothers diagnosed with Crohn's at ages 7 and 9 years. 3 out of 6 other individuals also had colitis.
Sources: Expert Review
Osteogenesis Imperfecta and Osteoporosis v0.99 SPARC Zornitza Stark Phenotypes for gene: SPARC were changed from to Osteogenesis imperfecta, type XVII, MIM# 616507
Genomic newborn screening: BabyScreen+ v0.2102 SPARC Zornitza Stark Marked gene: SPARC as ready
Genomic newborn screening: BabyScreen+ v0.2102 SPARC Zornitza Stark Gene: sparc has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2102 SPARC Zornitza Stark gene: SPARC was added
gene: SPARC was added to Baby Screen+ newborn screening. Sources: Expert list
skeletal tags were added to gene: SPARC.
Mode of inheritance for gene: SPARC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPARC were set to 26027498; 34462290
Phenotypes for gene: SPARC were set to Osteogenesis imperfecta, type XVII, MIM# 616507
Review for gene: SPARC was set to RED
Added comment: Established gene-disease association, 5 families reported.

Onset of fractures in infancy.

Prominent neuromuscular features, MRI brain changes; some with ID.

Treatment: bisphosphanates are generally used in OI but the case reports where these have been used do not seem terribly convincing in terms of response/improvement.

Exclude for now.
Sources: Expert list
Osteogenesis Imperfecta and Osteoporosis v0.98 SPARC Zornitza Stark Publications for gene: SPARC were set to
Osteogenesis Imperfecta and Osteoporosis v0.97 SPARC Zornitza Stark Mode of inheritance for gene: SPARC was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.96 SPARC Zornitza Stark edited their review of gene: SPARC: Changed rating: GREEN
Osteogenesis Imperfecta and Osteoporosis v0.96 SPARC Zornitza Stark reviewed gene: SPARC: Rating: ; Mode of pathogenicity: None; Publications: 26027498, 34462290; Phenotypes: Osteogenesis imperfecta, type XVII, MIM# 616507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2101 SP7 Zornitza Stark Marked gene: SP7 as ready
Genomic newborn screening: BabyScreen+ v0.2101 SP7 Zornitza Stark Gene: sp7 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2101 SP7 Zornitza Stark Phenotypes for gene: SP7 were changed from Osteogenesis imperfecta, type XII to Osteogenesis imperfecta, type XII, MIM# 613849
Genomic newborn screening: BabyScreen+ v0.2100 SP7 Zornitza Stark Publications for gene: SP7 were set to
Genomic newborn screening: BabyScreen+ v0.2099 SP7 Zornitza Stark Mode of inheritance for gene: SP7 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2098 SP7 Zornitza Stark Classified gene: SP7 as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.2098 SP7 Zornitza Stark Gene: sp7 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2097 SP7 Zornitza Stark Tag skeletal tag was added to gene: SP7.
Genomic newborn screening: BabyScreen+ v0.2097 SP7 Zornitza Stark reviewed gene: SP7: Rating: AMBER; Mode of pathogenicity: None; Publications: 36881265; Phenotypes: Osteogenesis imperfecta, type XII, MIM# 613849; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2097 SERPINH1 Zornitza Stark Marked gene: SERPINH1 as ready
Genomic newborn screening: BabyScreen+ v0.2097 SERPINH1 Zornitza Stark Gene: serpinh1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2097 SERPINH1 Zornitza Stark Classified gene: SERPINH1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2097 SERPINH1 Zornitza Stark Gene: serpinh1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2096 SERPINH1 Zornitza Stark gene: SERPINH1 was added
gene: SERPINH1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, skeletal tags were added to gene: SERPINH1.
Mode of inheritance for gene: SERPINH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SERPINH1 were set to 29520608; 25510505; 33524049
Phenotypes for gene: SERPINH1 were set to Osteogenesis imperfecta, type X, MIM# 613848
Review for gene: SERPINH1 was set to GREEN
Added comment: Established gene-disease association.

Onset of fractures is in infancy.

Treatment: bisphosphanates.

Non-genetic confirmatory testing: skeletal survey.
Sources: Expert list
Osteogenesis Imperfecta and Osteoporosis v0.96 SERPINF1 Zornitza Stark Marked gene: SERPINF1 as ready
Osteogenesis Imperfecta and Osteoporosis v0.96 SERPINF1 Zornitza Stark Gene: serpinf1 has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v0.96 SERPINF1 Zornitza Stark Phenotypes for gene: SERPINF1 were changed from to Osteogenesis imperfecta, type VI, MIM# 613982
Osteogenesis Imperfecta and Osteoporosis v0.95 SERPINF1 Zornitza Stark Publications for gene: SERPINF1 were set to
Osteogenesis Imperfecta and Osteoporosis v0.94 SERPINF1 Zornitza Stark Mode of inheritance for gene: SERPINF1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2095 SERPINF1 Zornitza Stark Marked gene: SERPINF1 as ready
Genomic newborn screening: BabyScreen+ v0.2095 SERPINF1 Zornitza Stark Gene: serpinf1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2095 SERPINF1 Zornitza Stark Classified gene: SERPINF1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2095 SERPINF1 Zornitza Stark Gene: serpinf1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2094 SERPINF1 Zornitza Stark gene: SERPINF1 was added
gene: SERPINF1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, skeletal tags were added to gene: SERPINF1.
Mode of inheritance for gene: SERPINF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SERPINF1 were set to 28689307
Phenotypes for gene: SERPINF1 were set to Osteogenesis imperfecta, type VI, MIM# 613982
Review for gene: SERPINF1 was set to GREEN
Added comment: Established gene-disease association.

Onset of fractures is in infancy.

Treatment: bisphosphanates.

Non-genetic confirmatory testing: skeletal survey.
Sources: Expert list
Osteogenesis Imperfecta and Osteoporosis v0.93 SERPINF1 Zornitza Stark reviewed gene: SERPINF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28689307; Phenotypes: Osteogenesis imperfecta, type VI, MIM# 613982; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2093 PPIB Zornitza Stark Marked gene: PPIB as ready
Genomic newborn screening: BabyScreen+ v0.2093 PPIB Zornitza Stark Gene: ppib has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2093 PPIB Zornitza Stark gene: PPIB was added
gene: PPIB was added to Baby Screen+ newborn screening. Sources: Expert list
skeletal tags were added to gene: PPIB.
Mode of inheritance for gene: PPIB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPIB were set to 19781681; 32392875
Phenotypes for gene: PPIB were set to Osteogenesis imperfecta, type IX, MIM# 259440
Review for gene: PPIB was set to RED
Added comment: Established gene-diseases association.

Most reported families have had severe OI, presenting perinatally, therefore exclude.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2092 PLOD2 Zornitza Stark Marked gene: PLOD2 as ready
Genomic newborn screening: BabyScreen+ v0.2092 PLOD2 Zornitza Stark Gene: plod2 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2092 PLOD2 Zornitza Stark Phenotypes for gene: PLOD2 were changed from Bruck syndrome to Bruck syndrome 2, MIM# 609220
Genomic newborn screening: BabyScreen+ v0.2091 PLOD2 Zornitza Stark reviewed gene: PLOD2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Bruck syndrome 2, MIM# 609220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.93 PLOD2 Zornitza Stark Marked gene: PLOD2 as ready
Osteogenesis Imperfecta and Osteoporosis v0.93 PLOD2 Zornitza Stark Gene: plod2 has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v0.93 PLOD2 Zornitza Stark Phenotypes for gene: PLOD2 were changed from to Bruck syndrome 2, MIM# 609220
Osteogenesis Imperfecta and Osteoporosis v0.92 PLOD2 Zornitza Stark Publications for gene: PLOD2 were set to
Osteogenesis Imperfecta and Osteoporosis v0.91 PLOD2 Zornitza Stark Mode of inheritance for gene: PLOD2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.90 PLOD2 Zornitza Stark reviewed gene: PLOD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 12881513, 15523624, 22689593; Phenotypes: Bruck syndrome 2, MIM# 609220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.90 P4HB Zornitza Stark changed review comment from: Four unrelated individuals reported with same recurrent de novo missense variant, p.Tyr393Cys, and an additional individual with de novo intragenic deletion of exons 5-8. Hydrocephalus is part of the phenotype.; to: Four unrelated individuals reported with same recurrent de novo missense variant, p.Tyr393Cys, and an additional individual with de novo intragenic deletion of exons 5-8. Bone fragility is part of the phenotype.
Genomic newborn screening: BabyScreen+ v0.2091 P3H1 Zornitza Stark Marked gene: P3H1 as ready
Genomic newborn screening: BabyScreen+ v0.2091 P3H1 Zornitza Stark Gene: p3h1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2091 P3H1 Zornitza Stark Classified gene: P3H1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2091 P3H1 Zornitza Stark Gene: p3h1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2090 P3H1 Zornitza Stark gene: P3H1 was added
gene: P3H1 was added to Baby Screen+ newborn screening. Sources: Expert Review
treatable, skeletal tags were added to gene: P3H1.
Mode of inheritance for gene: P3H1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: P3H1 were set to 17277775; 18566967
Phenotypes for gene: P3H1 were set to Osteogenesis imperfecta, type VIII, (MIM# 610915)
Review for gene: P3H1 was set to GREEN
Added comment: More than 15 families reported.

Congenital onset.

Treatment: bisphosphanates.

Non-genetic confirmatory testing: skeletal survey.
Sources: Expert Review
Genomic newborn screening: BabyScreen+ v0.2089 MESD Zornitza Stark Marked gene: MESD as ready
Genomic newborn screening: BabyScreen+ v0.2089 MESD Zornitza Stark Gene: mesd has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2089 MESD Zornitza Stark Classified gene: MESD as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2089 MESD Zornitza Stark Gene: mesd has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2088 MESD Zornitza Stark gene: MESD was added
gene: MESD was added to Baby Screen+ newborn screening. Sources: Expert Review
treatable, skeletal tags were added to gene: MESD.
Mode of inheritance for gene: MESD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MESD were set to 31564437; 35092157; 33596325; 31564437
Phenotypes for gene: MESD were set to Osteogenesis imperfecta, type XX, MIM# 618644
Review for gene: MESD was set to GREEN
Added comment: More than 5 families reported.

Severe form of OI, some perinatal lethal.

Treatment: bisphosphanates.

Non-genetic confirmatory testing: skeletal survey.
Sources: Expert Review
Genomic newborn screening: BabyScreen+ v0.2087 KDELR2 Zornitza Stark Marked gene: KDELR2 as ready
Genomic newborn screening: BabyScreen+ v0.2087 KDELR2 Zornitza Stark Gene: kdelr2 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2087 KDELR2 Zornitza Stark Classified gene: KDELR2 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2087 KDELR2 Zornitza Stark Gene: kdelr2 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2086 KDELR2 Zornitza Stark gene: KDELR2 was added
gene: KDELR2 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, skeletal tags were added to gene: KDELR2.
Mode of inheritance for gene: KDELR2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: KDELR2 were set to Osteogenesis imperfecta 21, MIM# 619131
Review for gene: KDELR2 was set to GREEN
Added comment: 4 families with osteogenesis imperfecta reported with functional studies.

Onset in infancy.

Improvement reported with bisphosphanates, similar to other OI.

Non-genetic confirmatory testing: skeletal survey.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2085 FKBP10 Zornitza Stark Marked gene: FKBP10 as ready
Genomic newborn screening: BabyScreen+ v0.2085 FKBP10 Zornitza Stark Gene: fkbp10 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2085 FKBP10 Zornitza Stark Classified gene: FKBP10 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2085 FKBP10 Zornitza Stark Gene: fkbp10 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2084 FKBP10 Zornitza Stark Tag treatable tag was added to gene: FKBP10.
Tag skeletal tag was added to gene: FKBP10.
Genomic newborn screening: BabyScreen+ v0.2084 FKBP10 Zornitza Stark gene: FKBP10 was added
gene: FKBP10 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: FKBP10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FKBP10 were set to 34173012
Phenotypes for gene: FKBP10 were set to Osteogenesis imperfecta, type XI, OMIM:610968
Review for gene: FKBP10 was set to GREEN
Added comment: Well established gene-disease association.

Early-onset bone fractures and progressive skeletal deformities.

Treatment: bisphosphanates.

Non-genetic confirmatory testing: skeletal survey.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2083 BMP1 Zornitza Stark Marked gene: BMP1 as ready
Genomic newborn screening: BabyScreen+ v0.2083 BMP1 Zornitza Stark Gene: bmp1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2083 BMP1 Zornitza Stark Classified gene: BMP1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2083 BMP1 Zornitza Stark Gene: bmp1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2082 BMP1 Zornitza Stark gene: BMP1 was added
gene: BMP1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: BMP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BMP1 were set to 33818922
Phenotypes for gene: BMP1 were set to Osteogenesis imperfecta, type XIII , MIM#614856
Review for gene: BMP1 was set to GREEN
Added comment: Rare cause of OI. 20 families reported.

Treatment: bisphosphanates.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2081 PTH1R Zornitza Stark changed review comment from: Variants in this gene are associated with a range of skeletal disorder.

Wide variability in severity, with BOCD manifesting antenatally.

No specific treatment.; to: Variants in this gene are associated with a range of skeletal disorders.

Wide variability in severity, with BOCD manifesting antenatally.

No specific treatment.
Inflammatory bowel disease v0.99 IL2RB Zornitza Stark Marked gene: IL2RB as ready
Inflammatory bowel disease v0.99 IL2RB Zornitza Stark Gene: il2rb has been classified as Green List (High Evidence).
Inflammatory bowel disease v0.99 IL2RB Zornitza Stark Phenotypes for gene: IL2RB were changed from immunodeficiency; autoimmune enteropathy to Immunodeficiency 63 with lymphoproliferation and autoimmunity, MIM# 618495
Inflammatory bowel disease v0.98 IL2RB Zornitza Stark Classified gene: IL2RB as Green List (high evidence)
Inflammatory bowel disease v0.98 IL2RB Zornitza Stark Gene: il2rb has been classified as Green List (High Evidence).
Inflammatory bowel disease v0.97 IL2RB Zornitza Stark reviewed gene: IL2RB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 63 with lymphoproliferation and autoimmunity, MIM# 618495; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inflammatory bowel disease v0.97 IL21 Zornitza Stark Marked gene: IL21 as ready
Inflammatory bowel disease v0.97 IL21 Zornitza Stark Gene: il21 has been classified as Amber List (Moderate Evidence).
Inflammatory bowel disease v0.97 IL21 Zornitza Stark Phenotypes for gene: IL21 were changed from immunodeficiency; inflammatory bowel disease to Immunodeficiency, common variable, 11, MIM# 615767
Inflammatory bowel disease v0.96 IL21 Zornitza Stark Classified gene: IL21 as Amber List (moderate evidence)
Inflammatory bowel disease v0.96 IL21 Zornitza Stark Gene: il21 has been classified as Amber List (Moderate Evidence).
Inflammatory bowel disease v0.95 IL21 Zornitza Stark reviewed gene: IL21: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency, common variable, 11, MIM# 615767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inflammatory bowel disease v0.95 DKC1 Zornitza Stark Marked gene: DKC1 as ready
Inflammatory bowel disease v0.95 DKC1 Zornitza Stark Gene: dkc1 has been classified as Amber List (Moderate Evidence).
Inflammatory bowel disease v0.95 DKC1 Zornitza Stark Phenotypes for gene: DKC1 were changed from Dyskeratosis congenita to Dyskeratosis congenita, X-linked, MIM# 305000
Inflammatory bowel disease v0.94 DKC1 Zornitza Stark Classified gene: DKC1 as Amber List (moderate evidence)
Inflammatory bowel disease v0.94 DKC1 Zornitza Stark Gene: dkc1 has been classified as Amber List (Moderate Evidence).
Inflammatory bowel disease v0.93 DKC1 Zornitza Stark reviewed gene: DKC1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Dyskeratosis congenita, X-linked, MIM# 305000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Stickler Syndrome v1.6 SLC29A3 Zornitza Stark Marked gene: SLC29A3 as ready
Stickler Syndrome v1.6 SLC29A3 Zornitza Stark Gene: slc29a3 has been classified as Amber List (Moderate Evidence).
Stickler Syndrome v1.6 SLC29A3 Zornitza Stark Classified gene: SLC29A3 as Amber List (moderate evidence)
Stickler Syndrome v1.6 SLC29A3 Zornitza Stark Gene: slc29a3 has been classified as Amber List (Moderate Evidence).
Stickler Syndrome v1.5 SLC29A3 Zornitza Stark reviewed gene: SLC29A3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Histiocytosis-lymphadenopathy plus syndrome - MIM#602782; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.748 STX4 Zornitza Stark Phenotypes for gene: STX4 were changed from to Non-syndromic genetic hearing loss, MONDO:0019497, STX4-related.
Mendeliome v1.747 STX4 Zornitza Stark Publications for gene: STX4 were set to
Mendeliome v1.746 STX4 Zornitza Stark Mode of inheritance for gene: STX4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.745 STX4 Zornitza Stark Classified gene: STX4 as Amber List (moderate evidence)
Mendeliome v1.745 STX4 Zornitza Stark Gene: stx4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.744 ARF1 Zornitza Stark Publications for gene: ARF1 were set to 28868155; 34353862
Genomic newborn screening: BabyScreen+ v0.2081 SARS Zornitza Stark Marked gene: SARS as ready
Genomic newborn screening: BabyScreen+ v0.2081 SARS Zornitza Stark Gene: sars has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2081 SARS Zornitza Stark Classified gene: SARS as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.2081 SARS Zornitza Stark Gene: sars has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2080 SCARB2 Zornitza Stark Marked gene: SCARB2 as ready
Genomic newborn screening: BabyScreen+ v0.2080 SCARB2 Zornitza Stark Gene: scarb2 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2080 SCARB2 Zornitza Stark Classified gene: SCARB2 as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.2080 SCARB2 Zornitza Stark Gene: scarb2 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2079 SERPING1 Zornitza Stark Marked gene: SERPING1 as ready
Genomic newborn screening: BabyScreen+ v0.2079 SERPING1 Zornitza Stark Gene: serping1 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2079 SERPING1 Zornitza Stark Classified gene: SERPING1 as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.2079 SERPING1 Zornitza Stark Gene: serping1 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2078 SERPING1 Zornitza Stark Tag treatable tag was added to gene: SERPING1.
Tag immunological tag was added to gene: SERPING1.
Genomic newborn screening: BabyScreen+ v0.2078 SGPL1 Zornitza Stark Marked gene: SGPL1 as ready
Genomic newborn screening: BabyScreen+ v0.2078 SGPL1 Zornitza Stark Gene: sgpl1 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2078 SGPL1 Zornitza Stark Classified gene: SGPL1 as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.2078 SGPL1 Zornitza Stark Gene: sgpl1 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2077 SGPL1 Zornitza Stark Tag renal tag was added to gene: SGPL1.
Genomic newborn screening: BabyScreen+ v0.2077 SLC1A3 Zornitza Stark Marked gene: SLC1A3 as ready
Genomic newborn screening: BabyScreen+ v0.2077 SLC1A3 Zornitza Stark Gene: slc1a3 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2077 SLC1A3 Zornitza Stark Classified gene: SLC1A3 as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.2077 SLC1A3 Zornitza Stark Gene: slc1a3 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2076 SLC1A3 Zornitza Stark Tag neurological tag was added to gene: SLC1A3.
Genomic newborn screening: BabyScreen+ v0.2076 SMARCD2 Zornitza Stark Marked gene: SMARCD2 as ready
Genomic newborn screening: BabyScreen+ v0.2076 SMARCD2 Zornitza Stark Gene: smarcd2 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2076 SMARCD2 Zornitza Stark Classified gene: SMARCD2 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2076 SMARCD2 Zornitza Stark Gene: smarcd2 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2075 SMARCD2 Zornitza Stark Tag treatable tag was added to gene: SMARCD2.
Tag immunological tag was added to gene: SMARCD2.
Genomic newborn screening: BabyScreen+ v0.2075 SMARCD2 Zornitza Stark reviewed gene: SMARCD2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Specific granule deficiency 2 MIM#617475; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2075 SNX10 Zornitza Stark Marked gene: SNX10 as ready
Genomic newborn screening: BabyScreen+ v0.2075 SNX10 Zornitza Stark Gene: snx10 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2075 SNX10 Zornitza Stark Classified gene: SNX10 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2075 SNX10 Zornitza Stark Gene: snx10 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2074 SNX10 Zornitza Stark Tag treatable tag was added to gene: SNX10.
Tag skeletal tag was added to gene: SNX10.
Genomic newborn screening: BabyScreen+ v0.2074 SORD Zornitza Stark Marked gene: SORD as ready
Genomic newborn screening: BabyScreen+ v0.2074 SORD Zornitza Stark Gene: sord has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2074 SORD Zornitza Stark Classified gene: SORD as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.2074 SORD Zornitza Stark Gene: sord has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2073 SORD Zornitza Stark Tag treatable tag was added to gene: SORD.
Tag metabolic tag was added to gene: SORD.
Genomic newborn screening: BabyScreen+ v0.2073 SOX3 Zornitza Stark Marked gene: SOX3 as ready
Genomic newborn screening: BabyScreen+ v0.2073 SOX3 Zornitza Stark Gene: sox3 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2073 SOX3 Zornitza Stark Classified gene: SOX3 as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.2073 SOX3 Zornitza Stark Gene: sox3 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2072 SOX3 Zornitza Stark Tag for review tag was added to gene: SOX3.
Tag treatable tag was added to gene: SOX3.
Tag endocrine tag was added to gene: SOX3.
Genomic newborn screening: BabyScreen+ v0.2072 SOX3 Zornitza Stark reviewed gene: SOX3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Panhypopituitarism, X-linked MIM#312000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pituitary hormone deficiency v0.32 SOX3 Zornitza Stark Marked gene: SOX3 as ready
Pituitary hormone deficiency v0.32 SOX3 Zornitza Stark Gene: sox3 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v0.32 SOX3 Zornitza Stark Classified gene: SOX3 as Amber List (moderate evidence)
Pituitary hormone deficiency v0.32 SOX3 Zornitza Stark Gene: sox3 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v0.31 SOX3 Zornitza Stark Tag SV/CNV tag was added to gene: SOX3.
Pituitary hormone deficiency v0.31 SOX3 Zornitza Stark reviewed gene: SOX3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Panhypopituitarism, X-linked, MIM# 312000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genomic newborn screening: BabyScreen+ v0.2072 STAT1 Zornitza Stark Marked gene: STAT1 as ready
Genomic newborn screening: BabyScreen+ v0.2072 STAT1 Zornitza Stark Gene: stat1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2072 STAT1 Zornitza Stark Mode of inheritance for gene: STAT1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2071 STAT1 Zornitza Stark Classified gene: STAT1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2071 STAT1 Zornitza Stark Gene: stat1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2070 STAT1 Zornitza Stark Tag treatable tag was added to gene: STAT1.
Tag immunological tag was added to gene: STAT1.
Genomic newborn screening: BabyScreen+ v0.2070 STAT1 Zornitza Stark reviewed gene: STAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 31B, mycobacterial and viral infections, autosomal recessive, MIM# 613796; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2070 STIM1 Zornitza Stark Marked gene: STIM1 as ready
Genomic newborn screening: BabyScreen+ v0.2070 STIM1 Zornitza Stark Gene: stim1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2070 STIM1 Zornitza Stark Classified gene: STIM1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2070 STIM1 Zornitza Stark Gene: stim1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2069 STIM1 Zornitza Stark Tag treatable tag was added to gene: STIM1.
Tag immunological tag was added to gene: STIM1.
Genomic newborn screening: BabyScreen+ v0.2069 STIM1 Zornitza Stark reviewed gene: STIM1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 10 MIM612783; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2069 STK4 Zornitza Stark Marked gene: STK4 as ready
Genomic newborn screening: BabyScreen+ v0.2069 STK4 Zornitza Stark Gene: stk4 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2069 STK4 Zornitza Stark Classified gene: STK4 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2069 STK4 Zornitza Stark Gene: stk4 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2068 STK4 Zornitza Stark Tag treatable tag was added to gene: STK4.
Tag immunological tag was added to gene: STK4.
Genomic newborn screening: BabyScreen+ v0.2068 STK4 Zornitza Stark reviewed gene: STK4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM#614868; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inflammatory bowel disease v0.93 IL2RB Aimee Huynh gene: IL2RB was added
gene: IL2RB was added to Inflammatory bowel disease. Sources: Expert Review
Mode of inheritance for gene: IL2RB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL2RB were set to 31040184, 31040185
Phenotypes for gene: IL2RB were set to immunodeficiency; autoimmune enteropathy
Penetrance for gene: IL2RB were set to unknown
Review for gene: IL2RB was set to AMBER
gene: IL2RB was marked as current diagnostic
Added comment: 3 homozygous mutations in the IL2RB gene of 8 individuals from 4 consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and CMV disease. 4/5 children had severe diarrhea and infectious/autoimmune enteropathy. Endoscopy of patient B1 showed villous atrophy, and gastrointestinal biopsies revealed chronic inflammatory infiltration of the duodenum and rectum.
Sources: Expert Review
Genomic newborn screening: BabyScreen+ v0.2068 STX16 Zornitza Stark Marked gene: STX16 as ready
Genomic newborn screening: BabyScreen+ v0.2068 STX16 Zornitza Stark Gene: stx16 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2068 STX16 Zornitza Stark Classified gene: STX16 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2068 STX16 Zornitza Stark Gene: stx16 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2067 STX16 Zornitza Stark Tag treatable tag was added to gene: STX16.
Tag endocrine tag was added to gene: STX16.
Genomic newborn screening: BabyScreen+ v0.2067 SYT2 Zornitza Stark Marked gene: SYT2 as ready
Genomic newborn screening: BabyScreen+ v0.2067 SYT2 Zornitza Stark Gene: syt2 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2067 SYT2 Zornitza Stark Mode of inheritance for gene: SYT2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2066 SYT2 Zornitza Stark Classified gene: SYT2 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2066 SYT2 Zornitza Stark Gene: syt2 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2065 SYT2 Zornitza Stark Tag treatable tag was added to gene: SYT2.
Tag neurological tag was added to gene: SYT2.
Genomic newborn screening: BabyScreen+ v0.2065 TBL1X Zornitza Stark Marked gene: TBL1X as ready
Genomic newborn screening: BabyScreen+ v0.2065 TBL1X Zornitza Stark Gene: tbl1x has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2065 TBL1X Zornitza Stark Classified gene: TBL1X as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2065 TBL1X Zornitza Stark Gene: tbl1x has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2064 TBL1X Zornitza Stark Tag treatable tag was added to gene: TBL1X.
Tag endocrine tag was added to gene: TBL1X.
Inflammatory bowel disease v0.93 IL21 Aimee Huynh gene: IL21 was added
gene: IL21 was added to Inflammatory bowel disease. Sources: Expert Review
Mode of inheritance for gene: IL21 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL21 were set to 24746753
Phenotypes for gene: IL21 were set to immunodeficiency; inflammatory bowel disease
Penetrance for gene: IL21 were set to unknown
Review for gene: IL21 was set to AMBER
gene: IL21 was marked as current diagnostic
Added comment: IL-21 deficiency - a novel monogenetic cause of severe, early-onset IBD associated with a CVID-like primary immunodeficiency. One case of a turkish boy born to consanguinous parents, diagnosed with IBD in early years (diarrhea from 2 months of age, worsened over time, biopsy typical of Crohn's). This proband had 2 siblings who had early onset IBD before age 1 year and died.
Sources: Expert Review
Genomic newborn screening: BabyScreen+ v0.2064 TF Zornitza Stark Marked gene: TF as ready
Genomic newborn screening: BabyScreen+ v0.2064 TF Zornitza Stark Gene: tf has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2064 TF Zornitza Stark Classified gene: TF as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2064 TF Zornitza Stark Gene: tf has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2063 TF Zornitza Stark Tag treatable tag was added to gene: TF.
Tag haematological tag was added to gene: TF.
Inflammatory bowel disease v0.93 DKC1 Chris Richmond gene: DKC1 was added
gene: DKC1 was added to Inflammatory bowel disease. Sources: Expert Review
Mode of inheritance for gene: DKC1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DKC1 were set to 21284747
Phenotypes for gene: DKC1 were set to Dyskeratosis congenita
Penetrance for gene: DKC1 were set to unknown
Review for gene: DKC1 was set to GREEN
gene: DKC1 was marked as current diagnostic
Added comment: 2 unrelated infants with infant-onset DKC - the most prominent clinical finding was the presence of a severe, chronic, non-infectious enteropathy leading to malabsorption and nutrient deficiencies . Histological abnormalities included inflammation and mucosal apoptosis (identical to gut GVHD) in the esophagus, small bowel, or colon. Phenotypic overlap with IBD. Review with Dr. Peter McNaughton (immunologist QCH).
Sources: Expert Review
Stickler Syndrome v1.5 SLC29A3 Krithika Murali changed review comment from: Phenotypic features can overlap with Stickler syndrome (presentation VCGS Dysmorphology meeting 24.3.23)
Sources: Expert list, Literature; to: Phenotypic features can overlap with Stickler syndrome (presentation VCGS Dysmorphology meeting 24.3.23, suggested adding gene to Stickler panel)
Sources: Expert list, Literature
Stickler Syndrome v1.5 SLC29A3 Krithika Murali gene: SLC29A3 was added
gene: SLC29A3 was added to Stickler Syndrome. Sources: Expert list,Literature
Mode of inheritance for gene: SLC29A3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC29A3 were set to Histiocytosis-lymphadenopathy plus syndrome - MIM#602782
Review for gene: SLC29A3 was set to GREEN
Added comment: Phenotypic features can overlap with Stickler syndrome (presentation VCGS Dysmorphology meeting 24.3.23)
Sources: Expert list, Literature
Mendeliome v1.743 STX4 Achchuthan Shanmugasundram reviewed gene: STX4: Rating: AMBER; Mode of pathogenicity: None; Publications: 36355422; Phenotypes: Hearing impairment, HP:0000365; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.743 ARF1 Achchuthan Shanmugasundram edited their review of gene: ARF1: Changed publications: 36345169
Mendeliome v1.743 ARF1 Achchuthan Shanmugasundram reviewed gene: ARF1: Rating: ; Mode of pathogenicity: None; Publications: 3634516; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: BabyScreen+ v0.2063 SARS Lilian Downie gene: SARS was added
gene: SARS was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS were set to PMID:34570399, PMID: 34194004
Phenotypes for gene: SARS were set to Neurodevelopmental disorder with microcephaly, ataxia, and seizures MIM#617709
Review for gene: SARS was set to RED
Added comment: developmental delay, deafness, cardiomyopathy, epilepsy, and severe febrile decompensations
Rx serine supplementation - limited evidence and sounds supportive only
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2063 SCARB2 Lilian Downie gene: SCARB2 was added
gene: SCARB2 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SCARB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCARB2 were set to PMID: 34337151, PMID: 35346091, PMID: 26677510
Phenotypes for gene: SCARB2 were set to Epilepsy, progressive myoclonic 4, with or without renal failure MIM#254900
Review for gene: SCARB2 was set to RED
Added comment: Onset not <5
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2063 SERPING1 Lilian Downie gene: SERPING1 was added
gene: SERPING1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SERPING1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SERPING1 were set to PMID: 32898710
Phenotypes for gene: SERPING1 were set to Angioedema, hereditary, 1 and 2 MIM#106100
Review for gene: SERPING1 was set to RED
Added comment: episodic local subcutaneous edema and submucosal edema involving the upper respiratory and gastrointestinal tracts.

Age of onset not typically <5

Treatment Purified C1 inhibitor concentrate (Cinryze, Berinert, HAEGARDA, or Ruconest), Ecallantide (Kalbitor), Icatibant (Firazyr), Lanadelumab, Orladeyo (berotralstat), FFP or solvent-detergent treated plasma, antisense oligonucleotide treatment (donidalorsen)
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2063 SGPL1 Lilian Downie gene: SGPL1 was added
gene: SGPL1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SGPL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGPL1 were set to PMID: 28165343
Phenotypes for gene: SGPL1 were set to Nephrotic syndrome, type 14 MIM#617575
Review for gene: SGPL1 was set to RED
Added comment: infancy or early childhood with progressive renal dysfunction associated with focal segmental glomerulosclerosis (FSGS), resulting in end-stage renal disease within a few years. Other infants present with primary adrenal insufficiency. Some patients present in utero with fetal hydrops and fetal demise. Additional features of the disorder can include ichthyosis, acanthosis, adrenal insufficiency, immunodeficiency, and neurologic defects

Rx Hydrocortisone, kidney transplant (treatment doesn't fit screening model as would need to have ESRD before you had it?)
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2063 SLC1A3 Lilian Downie gene: SLC1A3 was added
gene: SLC1A3 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SLC1A3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC1A3 were set to PMID: 32754645
Phenotypes for gene: SLC1A3 were set to Episodic ataxia, type 6 MIM#612656
Review for gene: SLC1A3 was set to RED
Added comment: ataxia occurs with febrile illnesses
Episodic attacks lasted 2 to 3 hours and were often associated with nausea, vomiting, photophobia, phonophobia, vertigo, diplopia, and/or slurred speech
Not consistently in children <5 and variable severity

Suggested Rx acetazolamide
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2063 SMARCD2 Lilian Downie gene: SMARCD2 was added
gene: SMARCD2 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SMARCD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMARCD2 were set to PubMed: 28369036, 33279574, 33025377
Phenotypes for gene: SMARCD2 were set to Specific granule deficiency 2 MIM#617475
Review for gene: SMARCD2 was set to GREEN
Added comment: recurrent infections due to defective neutrophil development. Bone marrow findings include paucity of neutrophil granulocytes, absence of granule proteins in neutrophils, abnormal megakaryocytes, and features of progressive myelofibrosis with blasts. The disorder is apparent from infancy, and patients may die in early childhood unless they undergo hematopoietic stem cell transplantation. Most patients have additional findings, including delayed development, mild dysmorphic features, tooth abnormalities, and distal skeletal defects

Rx bone marrow transplant
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2063 SNX10 Lilian Downie gene: SNX10 was added
gene: SNX10 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SNX10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNX10 were set to PMID: 30885997, PMID: 22499339
Phenotypes for gene: SNX10 were set to Osteopetrosis, autosomal recessive 8 MIM#615085
Review for gene: SNX10 was set to GREEN
Added comment: macrocephaly
failure to thrive
osteopetrosis

Rx bone marrow tranplant
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2063 SORD Lilian Downie gene: SORD was added
gene: SORD was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SORD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SORD were set to PMID: 32367058
Phenotypes for gene: SORD were set to Sorbitol dehydrogenase deficiency with peripheral neuropathy MIM#618912
Review for gene: SORD was set to RED
Added comment: Slowly progressive, onset not consistently <5

Rx epalrestat and ranirestat
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2063 SOX3 Lilian Downie gene: SOX3 was added
gene: SOX3 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SOX3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SOX3 were set to PMID: 31678974, PMID: 15800844
Phenotypes for gene: SOX3 were set to Panhypopituitarism, X-linked MIM#312000
Review for gene: SOX3 was set to AMBER
Added comment: Amber in our mendeliome - reviewed for ID
Green in pituitary disorders

Xq27.1 duplication most common mechanism - inclusion might be a question of whether we can detect CNV's in this region

neonatal hypoglycemia and growth hormone deficiency in addition to variable deficiencies of other pituitary hormones. Brain hypoplasia of the anterior pituitary with hypoplasia or absence of the lower half of the infundibulum

Rx Growth hormone, levothyroxine, hydrocortisone
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2063 STAT1 Lilian Downie gene: STAT1 was added
gene: STAT1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: STAT1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: STAT1 were set to PMID: 31512162, PMID: 27117246
Phenotypes for gene: STAT1 were set to Immunodeficiency 31B, mycobacterial and viral infections, autosomal recessive MIM#613796
Review for gene: STAT1 was set to GREEN
Added comment: combined immunodeficiency
autosomal recessive (AR) complete STAT1 deficiency, AR partial STAT1 deficiency, autosomal dominant (AD) STAT1 deficiency, and AD STAT1 gain-of-function.
gain of function mutations - treat rituxomab
complete - treat BMT
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2063 STIM1 Lilian Downie gene: STIM1 was added
gene: STIM1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: STIM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STIM1 were set to PMID: 26469693, PMID: 30949876, PMID: 26560041
Phenotypes for gene: STIM1 were set to Immunodeficiency 10 MIM612783
Review for gene: STIM1 was set to GREEN
Added comment: recurrent infections in childhood due to defective T- and NK-cell function, although the severity is variable. Affected individuals may also have hypotonia, hypohidrosis, or dental enamel hypoplasia consistent with amelogenesis imperfecta

Rx bone marrow transpant

Age of onset is consistently <5 but the severity of infections is highly variable - treatment if the phenotype is severe
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2063 STK4 Lilian Downie gene: STK4 was added
gene: STK4 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: STK4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STK4 were set to PMID: 22294732
Phenotypes for gene: STK4 were set to T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM#614868
Review for gene: STK4 was set to GREEN
Added comment: primary T-cell immunodeficiency syndrome characterized by progressive loss of naive T cells, recurrent bacterial, viral, and fungal infections, warts, and abscesses, autoimmune manifestations, and cardiac malformations, including atrial septal defect

Rx bone marrow transplant
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2063 STX16 Lilian Downie gene: STX16 was added
gene: STX16 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: STX16 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: STX16 were set to PMID: 33247854, PMID: 34477200, PMID: 29072892
Phenotypes for gene: STX16 were set to Pseudohypoparathyroidism, type IB MIM#603233
Review for gene: STX16 was set to GREEN
Added comment: characterized clinically by isolated renal PTH resistance manifest as hypocalcemia, hyperphosphatemia, and increased serum PTH
without other features of Albright hereditary osteodystrophy
Rx Calcium, calcitriol, levothyroxine, growth hormone
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2063 SYT2 Lilian Downie gene: SYT2 was added
gene: SYT2 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SYT2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SYT2 were set to PMID: 32250532, 32776697
Phenotypes for gene: SYT2 were set to Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive MIM#619461
Review for gene: SYT2 was set to GREEN
Added comment: Bi-allelic disease: 32250532 and 32776697, 8 individuals from 6 families, with biallelic loss of function variants in SYT2, clinically manifesting with severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in 4 indviduals showed clinical improvement with increased strength and function.

Only report biallelic for newborn screening ?
monoallelic causes a later onset distal weakness/neuropathy phenotype - still childhood but variable or not clear - not consistently <5yrs
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2063 TBL1X Lilian Downie gene: TBL1X was added
gene: TBL1X was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TBL1X was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: TBL1X were set to PMID: 27603907
Phenotypes for gene: TBL1X were set to Hypothyroidism, congenital, nongoitrous, 8 MIM#301033
Review for gene: TBL1X was set to GREEN
Added comment: Small thyroid gland
Detected on newborn screening
Can affect carrier females but more mildly
Association with deafness

Rx thyroxine
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2063 TF Lilian Downie gene: TF was added
gene: TF was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TF were set to PMID: 32028041, PMID: 19579082, PMID: 11110675
Phenotypes for gene: TF were set to Atransferrinemia MIM#209300
Review for gene: TF was set to GREEN
Added comment: Hypochromic microcytic anaemia from absent transferrin - presents in infancy


Rx Red cell transfusions, deferoxamine
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2063 SAR1B Zornitza Stark Marked gene: SAR1B as ready
Genomic newborn screening: BabyScreen+ v0.2063 SAR1B Zornitza Stark Gene: sar1b has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2063 SAR1B Zornitza Stark Classified gene: SAR1B as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2063 SAR1B Zornitza Stark Gene: sar1b has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2062 SAR1B Zornitza Stark gene: SAR1B was added
gene: SAR1B was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, gastrointestinal tags were added to gene: SAR1B.
Mode of inheritance for gene: SAR1B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SAR1B were set to Chylomicron retention disease, MIM# 246700
Review for gene: SAR1B was set to GREEN
Added comment: Chylomicron retention disease is an autosomal recessive disorder of severe fat malabsorption associated with failure to thrive in infancy. Well established gene-disease association.

Congenital onset.

Treatment: low-fat diet with supplementation of fat-soluble vitamins (A, D, E, and K) and oral essential fatty acid supplementation

Non-genetic confirmatory testing: total cholesterol, triglyceride, LDL-cholesterol, HDL-cholesterol
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2061 SAMD9L Zornitza Stark Marked gene: SAMD9L as ready
Genomic newborn screening: BabyScreen+ v0.2061 SAMD9L Zornitza Stark Gene: samd9l has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2061 SAMD9L Zornitza Stark Classified gene: SAMD9L as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2061 SAMD9L Zornitza Stark Gene: samd9l has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2060 SAMD9L Zornitza Stark gene: SAMD9L was added
gene: SAMD9L was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological, haematological tags were added to gene: SAMD9L.
Mode of inheritance for gene: SAMD9L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SAMD9L were set to 31306780
Phenotypes for gene: SAMD9L were set to Ataxia-pancytopenia syndrome, MIM# 159550
Review for gene: SAMD9L was set to GREEN
Added comment: At least three unrelated families reported, some postulate GoF whereas others postulate LoF as mechanism.

Ataxia-pancytopenia syndrome (ATXPC) is an autosomal dominant disorder characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to bone marrow failure and myeloid leukemia. The germline genetic defect is associated with somatic loss of chromosome 7 (monosomy 7) resulting in the deletion of several genes on chromosome 7 that may predispose to the development of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML).

Treatment: BMT.

Non-genetic confirmatory testing: no.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2059 SAMD9 Zornitza Stark Marked gene: SAMD9 as ready
Genomic newborn screening: BabyScreen+ v0.2059 SAMD9 Zornitza Stark Gene: samd9 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2059 SAMD9 Zornitza Stark Classified gene: SAMD9 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2059 SAMD9 Zornitza Stark Gene: samd9 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2058 SAMD9 Zornitza Stark gene: SAMD9 was added
gene: SAMD9 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SAMD9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SAMD9 were set to 31306780
Phenotypes for gene: SAMD9 were set to MIRAGE syndrome, MIM# 617053
Review for gene: SAMD9 was set to GREEN
Added comment: MIRAGE syndrome (MIRAGE) is a form of syndromic adrenal hypoplasia, characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. The condition is often fatal within the first decade of life, usually as a result of invasive infection.

Treatment: BMT.

Non-genetic confirmatory testing: no.
Sources: Expert list
Mendeliome v1.743 THAP11 Zornitza Stark Marked gene: THAP11 as ready
Mendeliome v1.743 THAP11 Zornitza Stark Gene: thap11 has been classified as Red List (Low Evidence).
Mendeliome v1.743 THAP11 Zornitza Stark gene: THAP11 was added
gene: THAP11 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: THAP11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THAP11 were set to 28449119
Phenotypes for gene: THAP11 were set to Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
Review for gene: THAP11 was set to RED
Added comment: Single individual reported with homozygous missense variant, supportive functional data.
Sources: Expert Review
Genomic newborn screening: BabyScreen+ v0.2057 THAP11 Zornitza Stark Marked gene: THAP11 as ready
Genomic newborn screening: BabyScreen+ v0.2057 THAP11 Zornitza Stark Gene: thap11 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2057 THAP11 Zornitza Stark Phenotypes for gene: THAP11 were changed from Combined methylmalonic acidemia and homocystinuria, cblX like 2 to Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
Genomic newborn screening: BabyScreen+ v0.2056 THAP11 Zornitza Stark Classified gene: THAP11 as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.2056 THAP11 Zornitza Stark Gene: thap11 has been classified as Red List (Low Evidence).
Miscellaneous Metabolic Disorders v1.26 THAP11 Zornitza Stark Marked gene: THAP11 as ready
Miscellaneous Metabolic Disorders v1.26 THAP11 Zornitza Stark Gene: thap11 has been classified as Red List (Low Evidence).
Miscellaneous Metabolic Disorders v1.26 THAP11 Zornitza Stark gene: THAP11 was added
gene: THAP11 was added to Miscellaneous Metabolic Disorders. Sources: Expert Review
Mode of inheritance for gene: THAP11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THAP11 were set to 28449119
Phenotypes for gene: THAP11 were set to Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
Review for gene: THAP11 was set to RED
Added comment: Single individual reported with homozygous missense variant, supportive functional data.
Sources: Expert Review
Genomic newborn screening: BabyScreen+ v0.2055 TMEM165 Zornitza Stark Marked gene: TMEM165 as ready
Genomic newborn screening: BabyScreen+ v0.2055 TMEM165 Zornitza Stark Gene: tmem165 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2055 TMEM165 Zornitza Stark Classified gene: TMEM165 as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.2055 TMEM165 Zornitza Stark Gene: tmem165 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2054 TMEM165 Zornitza Stark Tag metabolic tag was added to gene: TMEM165.
Genomic newborn screening: BabyScreen+ v0.2054 TMEM165 Zornitza Stark reviewed gene: TMEM165: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type IIk MIM#614727; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2054 TNFRSF13B Zornitza Stark Marked gene: TNFRSF13B as ready
Genomic newborn screening: BabyScreen+ v0.2054 TNFRSF13B Zornitza Stark Gene: tnfrsf13b has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2054 TNFRSF13B Zornitza Stark Classified gene: TNFRSF13B as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.2054 TNFRSF13B Zornitza Stark Gene: tnfrsf13b has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2053 TNFRSF13B Zornitza Stark Tag treatable tag was added to gene: TNFRSF13B.
Tag immunological tag was added to gene: TNFRSF13B.
Genomic newborn screening: BabyScreen+ v0.2053 TNFAIP3 Zornitza Stark Marked gene: TNFAIP3 as ready
Genomic newborn screening: BabyScreen+ v0.2053 TNFAIP3 Zornitza Stark Gene: tnfaip3 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2053 TNFAIP3 Zornitza Stark Classified gene: TNFAIP3 as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.2053 TNFAIP3 Zornitza Stark Gene: tnfaip3 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2052 TNFAIP3 Zornitza Stark Tag treatable tag was added to gene: TNFAIP3.
Tag immunological tag was added to gene: TNFAIP3.
Genomic newborn screening: BabyScreen+ v0.2052 THAP11 Lilian Downie gene: THAP11 was added
gene: THAP11 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: THAP11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THAP11 were set to PMID: 28449119, PMID: 31905202
Phenotypes for gene: THAP11 were set to Combined methylmalonic acidemia and homocystinuria, cblX like 2
Review for gene: THAP11 was set to RED
Added comment: Single patient?
Not in our mendeliome
Not enough gene disease validity
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2052 TMEM165 Lilian Downie gene: TMEM165 was added
gene: TMEM165 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TMEM165 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM165 were set to PMID: 28323990, PMID: 35693943, PMID: 22683087
Phenotypes for gene: TMEM165 were set to Congenital disorder of glycosylation, type IIk MIM#614727
Review for gene: TMEM165 was set to AMBER
Added comment: Affected individuals show psychomotor retardation and growth retardation, and most have short stature. Other features include dysmorphism, hypotonia, eye abnormalities, acquired microcephaly, hepatomegaly, and skeletal dysplasia. Serum transferrin analysis shows a CDG type II pattern

Rx D-galactose (single paper, 2 unrelated patients and an in vitro study) ?inadequete evidence for treatment? Might need to check with JC if we would offer it maybe include
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2052 TNFRSF13B Lilian Downie gene: TNFRSF13B was added
gene: TNFRSF13B was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TNFRSF13B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TNFRSF13B were set to PMID: 31681716, PMID: 18981294
Phenotypes for gene: TNFRSF13B were set to Immunodeficiency, common variable, 2 MIM#240500
Review for gene: TNFRSF13B was set to RED
Added comment: hypogammaglobulinemia with low serum IgG, IgM, and IgA, and recurrent infections, including otitis media, respiratory tract infections, and gastrointestinal tract infections. Serum IgG and IgA were low, and serum antibody response to immunization with pneumococcal vaccine was decreased, although T cell-dependent response to tetanus toxin was normal.

I think the age of onset is too variable .

Rx immunoglobulin
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2052 TNFAIP3 Lilian Downie gene: TNFAIP3 was added
gene: TNFAIP3 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TNFAIP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TNFAIP3 were set to PMID: 31587140, PMID: 33101300
Phenotypes for gene: TNFAIP3 were set to Autoinflammatory syndrome, familial, Behcet-like 1 MIM#616744
Review for gene: TNFAIP3 was set to RED
Added comment: Average age of onset 5yrs - too variable re age of onset.

painful and recurrent mucosal ulceration affecting the oral mucosa, gastrointestinal tract, and genital areas. The onset of symptoms is usually in the first decade, although later onset has been reported. Additional more variable features include skin rash, uveitis, and polyarthritis, consistent with a systemic hyperinflammatory state. Many patients have evidence of autoimmune disease. Rare patients may also have concurrent features of immunodeficiency, including recurrent infections with low numbers of certain white blood cells or impaired function of immune cells.

Treatment: Colchicine, glucocorticoid, mesalazine, cyclosporine, methotrexate, azathioprine, anakinra, rituximab, tocilizumab, infliximab
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2052 RNPC3 Zornitza Stark Marked gene: RNPC3 as ready
Genomic newborn screening: BabyScreen+ v0.2052 RNPC3 Zornitza Stark Gene: rnpc3 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2052 RNPC3 Zornitza Stark Classified gene: RNPC3 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2052 RNPC3 Zornitza Stark Gene: rnpc3 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2051 RNPC3 Zornitza Stark gene: RNPC3 was added
gene: RNPC3 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: RNPC3.
Mode of inheritance for gene: RNPC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNPC3 were set to 29866761; 32462814; 33650182
Phenotypes for gene: RNPC3 were set to Pituitary hormone deficiency, combined or isolated, 7, MIM# 618160
Review for gene: RNPC3 was set to GREEN
Added comment: Three unrelated individuals reported with combined and isolated pituitary hormone deficiencies, including GH and TSH.

Onset: congenital.

Treatment: GH, thyroxine.

Non-genetic confirmatory testing: hormone levels.
Sources: Expert list
Mendeliome v1.742 RNPC3 Zornitza Stark Phenotypes for gene: RNPC3 were changed from Growth hormone deficiency; Intellectual disability to Pituitary hormone deficiency, combined or isolated, 7, MIM# 618160
Mendeliome v1.741 RNPC3 Zornitza Stark edited their review of gene: RNPC3: Changed phenotypes: Pituitary hormone deficiency, combined or isolated, 7, MIM# 618160
Genomic newborn screening: BabyScreen+ v0.2050 RASGRP1 Zornitza Stark Marked gene: RASGRP1 as ready
Genomic newborn screening: BabyScreen+ v0.2050 RASGRP1 Zornitza Stark Gene: rasgrp1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2050 RASGRP1 Zornitza Stark Classified gene: RASGRP1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2050 RASGRP1 Zornitza Stark Gene: rasgrp1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2049 RASGRP1 Zornitza Stark gene: RASGRP1 was added
gene: RASGRP1 was added to Baby Screen+ newborn screening. Sources: Literature
treatable, immunological tags were added to gene: RASGRP1.
Mode of inheritance for gene: RASGRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: RASGRP1 were set to Immunodeficiency 64 (MIM#618534)
Review for gene: RASGRP1 was set to GREEN
Added comment: Immunodeficiency-64 with lymphoproliferation (IMD64) is an autosomal recessive primary immunodeficiency characterized by onset of recurrent bacterial, viral, and fungal infections in early childhood. Laboratory studies show variably decreased numbers of T cells, with lesser deficiencies of B and NK cells. There is impaired T-cell proliferation and activation; functional defects in B cells and NK cells may also be observed. Patients have increased susceptibility to EBV infection and may develop lymphoproliferation or EBV-associated lymphoma. Some patients may develop features of autoimmunity.

Severe disorder, fatal outcomes reported in childhood.

Treatment: BMT.

Non-genetic confirmatory testing: no.
Sources: Literature
Arthrogryposis v0.392 NALCN Zornitza Stark Marked gene: NALCN as ready
Arthrogryposis v0.392 NALCN Zornitza Stark Gene: nalcn has been classified as Green List (High Evidence).
Arthrogryposis v0.392 SLC35A3 Zornitza Stark Marked gene: SLC35A3 as ready
Arthrogryposis v0.392 SLC35A3 Zornitza Stark Gene: slc35a3 has been classified as Green List (High Evidence).
Arthrogryposis v0.392 LIFR Zornitza Stark Marked gene: LIFR as ready
Arthrogryposis v0.392 LIFR Zornitza Stark Gene: lifr has been classified as Green List (High Evidence).
Arthrogryposis v0.392 KY Zornitza Stark Marked gene: KY as ready
Arthrogryposis v0.392 KY Zornitza Stark Gene: ky has been classified as Green List (High Evidence).
Arthrogryposis v0.392 KIF5C Zornitza Stark Marked gene: KIF5C as ready
Arthrogryposis v0.392 KIF5C Zornitza Stark Gene: kif5c has been classified as Green List (High Evidence).
Arthrogryposis v0.392 CNTN1 Zornitza Stark Marked gene: CNTN1 as ready
Arthrogryposis v0.392 CNTN1 Zornitza Stark Gene: cntn1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.392 CNTN1 Zornitza Stark Classified gene: CNTN1 as Amber List (moderate evidence)
Arthrogryposis v0.392 CNTN1 Zornitza Stark Gene: cntn1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.391 CNTN1 Zornitza Stark reviewed gene: CNTN1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital myopathy 12, OMIM #612540; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v0.391 CACNA1S Zornitza Stark Marked gene: CACNA1S as ready
Arthrogryposis v0.391 CACNA1S Zornitza Stark Gene: cacna1s has been classified as Green List (High Evidence).
Arthrogryposis v0.391 B3GALT6 Zornitza Stark Marked gene: B3GALT6 as ready
Arthrogryposis v0.391 B3GALT6 Zornitza Stark Gene: b3galt6 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.391 VRK1 Zornitza Stark Marked gene: VRK1 as ready
Arthrogryposis v0.391 VRK1 Zornitza Stark Gene: vrk1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.391 PPP3CA Zornitza Stark Marked gene: PPP3CA as ready
Arthrogryposis v0.391 PPP3CA Zornitza Stark Gene: ppp3ca has been classified as Green List (High Evidence).
Arthrogryposis v0.391 PMM2 Zornitza Stark Marked gene: PMM2 as ready
Arthrogryposis v0.391 PMM2 Zornitza Stark Gene: pmm2 has been classified as Green List (High Evidence).
Arthrogryposis v0.391 LMNA Zornitza Stark Marked gene: LMNA as ready
Arthrogryposis v0.391 LMNA Zornitza Stark Gene: lmna has been classified as Green List (High Evidence).
Arthrogryposis v0.391 FLVCR2 Zornitza Stark Marked gene: FLVCR2 as ready
Arthrogryposis v0.391 FLVCR2 Zornitza Stark Gene: flvcr2 has been classified as Green List (High Evidence).
Arthrogryposis v0.391 BIN1 Zornitza Stark Marked gene: BIN1 as ready
Arthrogryposis v0.391 BIN1 Zornitza Stark Gene: bin1 has been classified as Green List (High Evidence).
Arthrogryposis v0.391 TMEM5 Zornitza Stark Marked gene: TMEM5 as ready
Arthrogryposis v0.391 TMEM5 Zornitza Stark Gene: tmem5 has been classified as Red List (Low Evidence).
Arthrogryposis v0.391 TMEM5 Zornitza Stark Phenotypes for gene: TMEM5 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 10, MIM# 615041
Arthrogryposis v0.390 TMEM5 Zornitza Stark Mode of inheritance for gene: TMEM5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v0.389 FAM20C Zornitza Stark Marked gene: FAM20C as ready
Arthrogryposis v0.389 FAM20C Zornitza Stark Gene: fam20c has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.389 FAM20C Zornitza Stark Mode of inheritance for gene: FAM20C was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v0.388 FAM20C Zornitza Stark Phenotypes for gene: FAM20C were changed from to Raine syndrome, MIM# 259775
Arthrogryposis v0.387 DAG1 Zornitza Stark Marked gene: DAG1 as ready
Arthrogryposis v0.387 DAG1 Zornitza Stark Gene: dag1 has been classified as Red List (Low Evidence).
Arthrogryposis v0.387 DAG1 Zornitza Stark Phenotypes for gene: DAG1 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 9 (MIM#616538)
Arthrogryposis v0.386 B3GALNT2 Zornitza Stark Marked gene: B3GALNT2 as ready
Arthrogryposis v0.386 B3GALNT2 Zornitza Stark Gene: b3galnt2 has been classified as Red List (Low Evidence).
Arthrogryposis v0.386 B3GALNT2 Zornitza Stark Phenotypes for gene: B3GALNT2 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 11, MIM# 615181
Arthrogryposis v0.385 SLC35A3 Chirag Patel Classified gene: SLC35A3 as Green List (high evidence)
Arthrogryposis v0.385 SLC35A3 Chirag Patel Gene: slc35a3 has been classified as Green List (High Evidence).
Arthrogryposis v0.384 LIFR Chirag Patel Classified gene: LIFR as Green List (high evidence)
Arthrogryposis v0.384 LIFR Chirag Patel Gene: lifr has been classified as Green List (High Evidence).
Arthrogryposis v0.384 SLC35A3 Chirag Patel gene: SLC35A3 was added
gene: SLC35A3 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: SLC35A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC35A3 were set to PMID: 28777481, 24031089, 28328131, 33416188
Phenotypes for gene: SLC35A3 were set to Arthrogryposis, impaired intellectual development, and seizures, OMIM #615553
Review for gene: SLC35A3 was set to GREEN
Added comment: Arthrogryposis, impaired intellectual development, and seizures (AMRS) is an autosomal recessive disorder characterized by skeletal abnormalities, including arthrogryposis, short limbs, and vertebral malformations, impaired intellectual development, and seizures consistent with early-onset epileptic encephalopathy in some patients. Other features may include cleft palate, micrognathia, posterior embryotoxon, talipes valgus, rocker-bottom feet, and dysmorphic facies.

4 families with 12 affected individuals reported with biallelic variants in SLC35A3 gene. Functional studies in one family showed patient cells showed no normal transcript, indicating that they had no functional SLC35A3 protein. Golgi vesicles derived from patient fibroblasts showed significantly reduced transport of UDP-GlcNAc compared to controls.
Sources: Expert list
Arthrogryposis v0.383 LIFR Chirag Patel gene: LIFR was added
gene: LIFR was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: LIFR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIFR were set to PMID: 9674905, 9674906, 14740318, 24988918, 35663789
Phenotypes for gene: LIFR were set to Stuve-Wiedemann syndrome/Schwartz-Jampel type 2 syndrome, OMIM #601559
Review for gene: LIFR was set to GREEN
Added comment: Patients reported as having either neonatal SJS or STWS presented a combination of a severe, prenatal-onset neuromuscular disorder with congenital joint contractures, respiratory and feeding difficulties, tendency to hyperthermia, and frequent death in infancy and a distinct campomelic-metaphyseal skeletal dysplasia. Multiple families with biallelic variants in LIFR gene reported.
Sources: Expert list
Arthrogryposis v0.382 KY Chirag Patel Classified gene: KY as Green List (high evidence)
Arthrogryposis v0.382 KY Chirag Patel Gene: ky has been classified as Green List (High Evidence).
Arthrogryposis v0.381 KIF5C Chirag Patel Classified gene: KIF5C as Green List (high evidence)
Arthrogryposis v0.381 KIF5C Chirag Patel Gene: kif5c has been classified as Green List (High Evidence).
Arthrogryposis v0.381 KY Chirag Patel gene: KY was added
gene: KY was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: KY was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KY were set to PMID: 27484770, 27485408, 30591934, 35752288
Phenotypes for gene: KY were set to Myopathy, myofibrillar, 7, OMIM #617114
Review for gene: KY was set to GREEN
Added comment: Myofibrillar myopathy-7 (MFM7) is an autosomal recessive muscle disorder characterized by early childhood onset of slowly progressive muscle weakness that primarily affects the lower limbs and is associated with joint contractures. 4 families with 6 affected individuals, with homozygous variants in KY gene. Immunostaining showed absence of the KY protein in patient muscle, consistent with a loss of function in one family.
Sources: Expert list
Arthrogryposis v0.380 KIF5C Chirag Patel gene: KIF5C was added
gene: KIF5C was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: KIF5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: KIF5C were set to Cortical dysplasia, complex, with other brain malformations 2, OMIM #615282
Review for gene: KIF5C was set to GREEN
Added comment: 2 families with 5 affecteds with severe malformations of cortical development. One family with 4 siblings with severe arthrogryposis. Same heterozygous missense variant found in both families (E237V) in KIF5C gene.

Family 1: unaffected mother was determined to be germline mosaic for the mutation. In vitro functional expression studies in E. coli and COS-7 cells showed that the mutant protein had a complete loss of ATP hydrolysis activity. In COS-7 cells, mutant KIF5C heavily colocalized with microtubules throughout the cell, but did not appear as puncta or accumulate in cortical clusters as did the wildtype protein. Poirier et al. (2013) postulated a dominant-negative effect. The findings extended the association between microtubule-based cellular processes and proper cortical development.
Sources: Expert list
Arthrogryposis v0.379 CACNA1S Chirag Patel Classified gene: CACNA1S as Green List (high evidence)
Arthrogryposis v0.379 CACNA1S Chirag Patel Gene: cacna1s has been classified as Green List (High Evidence).
Arthrogryposis v0.378 CNTN1 Chirag Patel gene: CNTN1 was added
gene: CNTN1 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: CNTN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNTN1 were set to PMID:19026398
Phenotypes for gene: CNTN1 were set to Congenital myopathy 12, OMIM #612540
Review for gene: CNTN1 was set to RED
Added comment: Congenital myopathy-12 (CMYP12) is an autosomal recessive disorder characterized by severe neonatal hypotonia resulting in feeding difficulties and respiratory failure within the first months of life. There is evidence of the disorder in utero, with decreased fetal movements and polyhydramnios. Additional features may include high-arched palate and contractures. Skeletal muscle biopsy shows myopathic changes with disrupted sarcomeres and minicore-like structures. One family reported with homozygous mutation in the CNTN1 gene.
Sources: Expert list
Arthrogryposis v0.377 CACNA1S Chirag Patel gene: CACNA1S was added
gene: CACNA1S was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: CACNA1S was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA1S were set to PMID: 33060286, 31227654, 28012042
Phenotypes for gene: CACNA1S were set to Congenital myopathy 18 due to dihydropyridine receptor defect, OMIM #620246
Review for gene: CACNA1S was set to GREEN
Added comment: Congenital myopathy-18 (CMYP18) is a disorder of the skeletal muscle characterized by the onset of symptoms of muscle weakness in early childhood, including in utero and infancy. There is clinical heterogeneity in the manifestations and severity, ranging from fetal akinesia sequence causing early death to onset of symptoms in adulthood.
Sources: Expert list
Arthrogryposis v0.376 B3GALT6 Chirag Patel Classified gene: B3GALT6 as Amber List (moderate evidence)
Arthrogryposis v0.376 B3GALT6 Chirag Patel Gene: b3galt6 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.376 VRK1 Chirag Patel Classified gene: VRK1 as Amber List (moderate evidence)
Arthrogryposis v0.376 VRK1 Chirag Patel Gene: vrk1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.375 B3GALT6 Chirag Patel gene: B3GALT6 was added
gene: B3GALT6 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: B3GALT6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: B3GALT6 were set to PMID: 29443383, 25149931
Phenotypes for gene: B3GALT6 were set to Al-Gazali syndrome, OMIM #609465
Review for gene: B3GALT6 was set to AMBER
Added comment: Al-Gazali syndrome (ALGAZ) is characterized by prenatal growth retardation, skeletal anomalies including joint contractures, camptodactyly, and bilateral talipes equinovarus, small mouth, anterior segment eye anomalies, and early lethality.

In an infant with Al-Gazali syndrome, Sellars et al. (2014) identified compound heterozygous missense mutations in the B3GALT6 gene. The mutation, which was found by exome sequencing, segregated with the disorder in the family.

In 1 of the Palestinian infants with Al-Gazali syndrome reported by al-Gazali et al. (1999), Ben-Mahmoud et al. (2018) identified homozygosity for a missense mutation in the B3GALT6 gene. The parents were heterozygous for the mutation.
Sources: Expert list
Arthrogryposis v0.374 VRK1 Chirag Patel gene: VRK1 was added
gene: VRK1 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: VRK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VRK1 were set to PMID: 21937992, 21937992
Phenotypes for gene: VRK1 were set to Pontocerebellar hypoplasia type 1A, OMIM# 607596
Review for gene: VRK1 was set to AMBER
Added comment: contractures reported and mutation found in 2 families
Sources: Expert list
Arthrogryposis v0.373 PPP3CA Chirag Patel Classified gene: PPP3CA as Green List (high evidence)
Arthrogryposis v0.373 PPP3CA Chirag Patel Gene: ppp3ca has been classified as Green List (High Evidence).
Arthrogryposis v0.372 PMM2 Chirag Patel Classified gene: PMM2 as Green List (high evidence)
Arthrogryposis v0.372 PMM2 Chirag Patel Gene: pmm2 has been classified as Green List (High Evidence).
Arthrogryposis v0.372 PPP3CA Chirag Patel gene: PPP3CA was added
gene: PPP3CA was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: PPP3CA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPP3CA were set to PMID: 29432562
Phenotypes for gene: PPP3CA were set to Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development, OMIM #618265
Review for gene: PPP3CA was set to GREEN
Added comment: 2 unrelated patients with arthrogryposis, cleft palate, craniosynostosis, micrognathia, short stature, and impaired intellectual development. Whole-exome sequencing (+ Sanger confirmation) found de novo heterozygous mutations in the autoinhibitory domain of PPP3CA gene. Using a yeast model, the mutations were found to be constitutively activating.
Sources: Expert list
Arthrogryposis v0.371 PMM2 Chirag Patel gene: PMM2 was added
gene: PMM2 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: PMM2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PMM2 were set to Congenital disorder of glycosylation, type Ia, OMIM #212065
Review for gene: PMM2 was set to GREEN
Added comment: Arthrogryposis reported
Sources: Expert list
Arthrogryposis v0.370 LMNA Chirag Patel Classified gene: LMNA as Green List (high evidence)
Arthrogryposis v0.370 LMNA Chirag Patel Gene: lmna has been classified as Green List (High Evidence).
Arthrogryposis v0.369 LMNA Chirag Patel gene: LMNA was added
gene: LMNA was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: LMNA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMNA were set to PMID:18551513
Phenotypes for gene: LMNA were set to Muscular dystrophy, congenital, OMIM #613205
Review for gene: LMNA was set to GREEN
Added comment: Arthrogryposis reported
Sources: Expert list
Arthrogryposis v0.368 FLVCR2 Chirag Patel Classified gene: FLVCR2 as Green List (high evidence)
Arthrogryposis v0.368 FLVCR2 Chirag Patel Gene: flvcr2 has been classified as Green List (High Evidence).
Arthrogryposis v0.367 FLVCR2 Chirag Patel gene: FLVCR2 was added
gene: FLVCR2 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: FLVCR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLVCR2 were set to PMID: 20206334, 20014121, 20014121
Phenotypes for gene: FLVCR2 were set to Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome, OMIM #225790
Review for gene: FLVCR2 was set to GREEN
Added comment: Severe arthrogryposis disorder
Sources: Expert list
Arthrogryposis v0.366 BIN1 Chirag Patel Classified gene: BIN1 as Green List (high evidence)
Arthrogryposis v0.366 BIN1 Chirag Patel Gene: bin1 has been classified as Green List (High Evidence).
Arthrogryposis v0.366 BIN1 Chirag Patel Classified gene: BIN1 as Green List (high evidence)
Arthrogryposis v0.366 BIN1 Chirag Patel Gene: bin1 has been classified as Green List (High Evidence).
Arthrogryposis v0.366 BIN1 Chirag Patel Classified gene: BIN1 as Green List (high evidence)
Arthrogryposis v0.366 BIN1 Chirag Patel Gene: bin1 has been classified as Green List (High Evidence).
Arthrogryposis v0.365 BIN1 Chirag Patel gene: BIN1 was added
gene: BIN1 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: BIN1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: BIN1 were set to Centronuclear myopathy 2; OMIM #255200
Review for gene: BIN1 was set to GREEN
Added comment: Arthrogryposis reported
Sources: Expert list
Arthrogryposis v0.364 TMEM5 Chirag Patel Classified gene: TMEM5 as Red List (low evidence)
Arthrogryposis v0.364 TMEM5 Chirag Patel Gene: tmem5 has been classified as Red List (Low Evidence).
Arthrogryposis v0.364 TMEM5 Chirag Patel Classified gene: TMEM5 as Red List (low evidence)
Arthrogryposis v0.364 TMEM5 Chirag Patel Gene: tmem5 has been classified as Red List (Low Evidence).
Arthrogryposis v0.364 TMEM5 Chirag Patel Classified gene: TMEM5 as Red List (low evidence)
Arthrogryposis v0.364 TMEM5 Chirag Patel Gene: tmem5 has been classified as Red List (Low Evidence).
Arthrogryposis v0.363 TMEM5 Chirag Patel reviewed gene: TMEM5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v0.363 FAM20C Chirag Patel Classified gene: FAM20C as Amber List (moderate evidence)
Arthrogryposis v0.363 FAM20C Chirag Patel Gene: fam20c has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.362 FAM20C Chirag Patel reviewed gene: FAM20C: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v0.362 DAG1 Chirag Patel Classified gene: DAG1 as Red List (low evidence)
Arthrogryposis v0.362 DAG1 Chirag Patel Gene: dag1 has been classified as Red List (Low Evidence).
Arthrogryposis v0.361 DAG1 Chirag Patel reviewed gene: DAG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v0.361 B4GAT1 Chirag Patel Classified gene: B4GAT1 as Red List (low evidence)
Arthrogryposis v0.361 B4GAT1 Chirag Patel Gene: b4gat1 has been classified as Red List (Low Evidence).
Arthrogryposis v0.360 B4GAT1 Chirag Patel reviewed gene: B4GAT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v0.360 B3GALNT2 Chirag Patel Classified gene: B3GALNT2 as Red List (low evidence)
Arthrogryposis v0.360 B3GALNT2 Chirag Patel Gene: b3galnt2 has been classified as Red List (Low Evidence).
Arthrogryposis v0.359 B3GALNT2 Chirag Patel reviewed gene: B3GALNT2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Genomic newborn screening: BabyScreen+ v0.2048 RAC2 Zornitza Stark Marked gene: RAC2 as ready
Genomic newborn screening: BabyScreen+ v0.2048 RAC2 Zornitza Stark Gene: rac2 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2048 RAC2 Zornitza Stark Phenotypes for gene: RAC2 were changed from Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia MIM# 618986 to Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopenia MIM# 618986
Genomic newborn screening: BabyScreen+ v0.2047 RAC2 Zornitza Stark Classified gene: RAC2 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2047 RAC2 Zornitza Stark Gene: rac2 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2046 RAC2 Zornitza Stark gene: RAC2 was added
gene: RAC2 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: RAC2.
Mode of inheritance for gene: RAC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RAC2 were set to Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia MIM# 618986
Review for gene: RAC2 was set to GREEN
Added comment: Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia
13 individuals from 8 unrelated families; mono-allelic; gain of function; multiple mouse models

Mono-allelic missense variants were reported in each individual (5 x De Novo) and resulted in a gain-of -function. (E62K, P34H, N92T, G12R)

These individuals typically presented in infancy with frequent infections, profound leukopaenia, lymphopaenia diarrhoea and hypogammaglobulinaemia.

SCID-like phenotype.

Treatment: IVIG, BMT

Note evidence for the other two immunodeficiency disorders associated with this gene is limited.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2045 PLS3 Zornitza Stark Marked gene: PLS3 as ready
Genomic newborn screening: BabyScreen+ v0.2045 PLS3 Zornitza Stark Gene: pls3 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2045 PLS3 Zornitza Stark Classified gene: PLS3 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2045 PLS3 Zornitza Stark Gene: pls3 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2044 PLS3 Zornitza Stark Tag treatable tag was added to gene: PLS3.
Tag skeletal tag was added to gene: PLS3.
Genomic newborn screening: BabyScreen+ v0.2044 PLS3 Zornitza Stark gene: PLS3 was added
gene: PLS3 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: PLS3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PLS3 were set to 32655496; 25209159; 29736964; 29884797; 28777485; 24088043
Phenotypes for gene: PLS3 were set to Bone mineral density QTL18, osteoporosis - MIM#300910
Review for gene: PLS3 was set to GREEN
Added comment: Females mildly affected: exclude from screening.

Presentation in males similar to OI, though also variable in severity.

Treatment: safe handling techniques, bisphosphonates, pamidronate, zoledronic acid, teriparatide, denosumab, alendronate

Non-genetic confirmatory testing: skeletal survey
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2043 OTULIN Zornitza Stark Marked gene: OTULIN as ready
Genomic newborn screening: BabyScreen+ v0.2043 OTULIN Zornitza Stark Gene: otulin has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2043 OTULIN Zornitza Stark Classified gene: OTULIN as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2043 OTULIN Zornitza Stark Gene: otulin has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2042 OTULIN Zornitza Stark gene: OTULIN was added
gene: OTULIN was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: OTULIN.
Mode of inheritance for gene: OTULIN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: OTULIN were set to Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099
Review for gene: OTULIN was set to GREEN
Added comment: Autoinflammation, panniculitis, and dermatosis syndrome (AIPDS) is an autosomal recessive autoinflammatory disease characterized by neonatal onset of recurrent fever, erythematous rash with painful nodules, painful joints, and lipodystrophy. Additional features may include diarrhea, increased serum C-reactive protein (CRP), leukocytosis, and neutrophilia in the absence of any infection.

Onset is generally in infancy.

Treatment: inflixiimab, anakinra, etanercept, corticosteroids.

Non-genetic confirmatory testing: no.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2041 OAS1 Zornitza Stark Marked gene: OAS1 as ready
Genomic newborn screening: BabyScreen+ v0.2041 OAS1 Zornitza Stark Gene: oas1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2041 OAS1 Zornitza Stark Classified gene: OAS1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2041 OAS1 Zornitza Stark Gene: oas1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2040 OAS1 Zornitza Stark gene: OAS1 was added
gene: OAS1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: OAS1.
Mode of inheritance for gene: OAS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: OAS1 were set to 34145065; 29455859
Phenotypes for gene: OAS1 were set to Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinaemia, MIM#618042
Review for gene: OAS1 was set to GREEN
Added comment: Immunodeficiency-100 with pulmonary alveolar proteinosis and hypogammaglobulinemia (IMD100) is primarily a lung disorder characterized by onset of respiratory insufficiency due to pulmonary alveolar proteinosis (PAP) in the first months of life. Affected individuals may have normal respiratory function at birth. Development of the disorder appears to be influenced or triggered by viral infection, manifest as progressive respiratory insufficiency, confluent consolidations on lung imaging, and diffuse collection of periodic acid-Schiff (PAS)-positive material in pulmonary alveoli associated with small and nonfoamy alveolar macrophages. Patients also have hypogammaglobulinemia, leukocytosis, and splenomegaly. Many patients die of respiratory failure in infancy or early childhood.

Treatment: IVIG; BMT is curative.

Non-genetic confirmatory testing: immunoglobulin levels.
Sources: Expert list
Inflammatory bowel disease v0.93 NLRC4 Zornitza Stark Marked gene: NLRC4 as ready
Inflammatory bowel disease v0.93 NLRC4 Zornitza Stark Gene: nlrc4 has been classified as Amber List (Moderate Evidence).
Inflammatory bowel disease v0.93 NLRC4 Zornitza Stark Phenotypes for gene: NLRC4 were changed from Infantile onset enterocolitis and autoinflammation to Autoinflammation with infantile enterocolitis, MIM# 616050
Inflammatory bowel disease v0.92 NLRC4 Zornitza Stark Publications for gene: NLRC4 were set to PMID: 25217960
Inflammatory bowel disease v0.91 NLRC4 Zornitza Stark edited their review of gene: NLRC4: Changed publications: 25217959, 25217960
Inflammatory bowel disease v0.91 NLRC4 Zornitza Stark edited their review of gene: NLRC4: Changed publications: 25217959
Inflammatory bowel disease v0.91 NLRC4 Zornitza Stark Classified gene: NLRC4 as Amber List (moderate evidence)
Inflammatory bowel disease v0.91 NLRC4 Zornitza Stark Gene: nlrc4 has been classified as Amber List (Moderate Evidence).
Inflammatory bowel disease v0.90 NLRC4 Zornitza Stark reviewed gene: NLRC4: Rating: AMBER; Mode of pathogenicity: None; Publications: 25217960; Phenotypes: Autoinflammation with infantile enterocolitis 616050; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5192 TAB2 Lucy Spencer gene: TAB2 was added
gene: TAB2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TAB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TAB2 were set to 35971781
Phenotypes for gene: TAB2 were set to Congenital heart defects, multiple types, 2 MONDO:0014000
Review for gene: TAB2 was set to GREEN
Added comment: PMID: 35971781 - expansion of the phenotype, 14 patients with TAB2 variants 6 have dev delay and 4 are also listed as having ID along with other phenotype features associated with this gene.

Note- there is a previous review of this paper in the mendeilome as amber
Sources: Literature
Genomic newborn screening: BabyScreen+ v0.2039 NFKBIA Zornitza Stark Marked gene: NFKBIA as ready
Genomic newborn screening: BabyScreen+ v0.2039 NFKBIA Zornitza Stark Gene: nfkbia has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2039 NFKBIA Zornitza Stark Classified gene: NFKBIA as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2039 NFKBIA Zornitza Stark Gene: nfkbia has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2038 NFKBIA Zornitza Stark gene: NFKBIA was added
gene: NFKBIA was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: NFKBIA.
Mode of inheritance for gene: NFKBIA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: NFKBIA were set to Ectodermal dysplasia and immunodeficiency 2 MIM# 612132
Review for gene: NFKBIA was set to GREEN
Added comment: 12 heterozygous variants were identified in 15 unrelated individuals (de novo in 14 individuals and somatic mosaicism in 1 individual).

Functional studies & two mouse models; demonstrate reported NFKBIA gain-of-function variants resulting in impaired NFKB1 activity.

The majority of individuals displayed recurrent infections, chronic diarrhoea, agammaglobulinaemia, increased IgM, and defects in teeth (hair, nail, sweat glands).

Onset is generally in infancy.

Treatment: BMT.

Non-genetic confirmatory testing: no
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2037 NAXE Zornitza Stark Marked gene: NAXE as ready
Genomic newborn screening: BabyScreen+ v0.2037 NAXE Zornitza Stark Gene: naxe has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2037 NAXE Zornitza Stark gene: NAXE was added
gene: NAXE was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, metabolic tags were added to gene: NAXE.
Mode of inheritance for gene: NAXE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAXE were set to 27122014; 27616477; 31758406
Phenotypes for gene: NAXE were set to Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, MIM# 617186
Review for gene: NAXE was set to RED
Added comment: Early-onset progressive encephalopathy with brain oedema and/or leukoencephalopathy-1 (PEBEL1) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, respiratory insufficiency, and seizures, resulting in coma and death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions. More than 5 unrelated families reported.

Treatment: niacin

However, single case reported. Treatment not established.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2036 NAXD Zornitza Stark Marked gene: NAXD as ready
Genomic newborn screening: BabyScreen+ v0.2036 NAXD Zornitza Stark Gene: naxd has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2036 NAXD Zornitza Stark Classified gene: NAXD as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.2036 NAXD Zornitza Stark Gene: naxd has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2035 NAXD Zornitza Stark gene: NAXD was added
gene: NAXD was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, metabolic tags were added to gene: NAXD.
Mode of inheritance for gene: NAXD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAXD were set to 30576410; 31755961; 32462209; 35231119
Phenotypes for gene: NAXD were set to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 MIM#618321
Review for gene: NAXD was set to AMBER
Added comment: Seven unrelated cases, episodes of fever/infection prior to deterioration reported. Variable phenotype: one patient reported with neurodevelopmental disorder, autism spectrum disorder and a muscular-dystrophy-like myopathy; another with progressive encephalopathy with brain oedema. Patient cells and muscle biopsies also showed impaired mitochondrial function, higher sensitivity to metabolic stress, and decreased mitochondrial reactive oxygen species production. In vitro functional assays also conducted.

Treatment: niacin

However, only two cases reported. Treatment not established.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2034 MYD88 Zornitza Stark Marked gene: MYD88 as ready
Genomic newborn screening: BabyScreen+ v0.2034 MYD88 Zornitza Stark Gene: myd88 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2034 MYD88 Zornitza Stark Classified gene: MYD88 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2034 MYD88 Zornitza Stark Gene: myd88 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2033 MYD88 Zornitza Stark gene: MYD88 was added
gene: MYD88 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: MYD88.
Mode of inheritance for gene: MYD88 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYD88 were set to 18669862; 20538326; 31301515
Phenotypes for gene: MYD88 were set to Immunodeficiency 68, MIM# 612260
Review for gene: MYD88 was set to GREEN
Added comment: Immunodeficiency-68 (IMD68) is an autosomal recessive primary immunodeficiency characterized by severe systemic and invasive bacterial infections beginning in infancy or early childhood. The most common organisms implicated are Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas, although other organisms may be observed.

At least 7 families and a mouse model.

Treatment: Prophylactic antibiotic treatment, pneumococcal, meningococcal, haemophilus influenzae vaccines, and immunoglobulin replacement.

Non-genetic confirmatory testing: toll-like receptor function
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2032 MTHFS Zornitza Stark Marked gene: MTHFS as ready
Genomic newborn screening: BabyScreen+ v0.2032 MTHFS Zornitza Stark Gene: mthfs has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2032 MTHFS Zornitza Stark gene: MTHFS was added
gene: MTHFS was added to Baby Screen+ newborn screening. Sources: Expert list
metabolic tags were added to gene: MTHFS.
Mode of inheritance for gene: MTHFS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTHFS were set to 30031689; 31844630; 22303332
Phenotypes for gene: MTHFS were set to Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, 618367
Review for gene: MTHFS was set to RED
Added comment: Established gene-disease association.

Onset in infancy. Severe disorder.

Treatment: single report of some improvement with combination of oral L-5- methyltetrahydrofolate and intramuscular methylcobalamin
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2031 MTHFD1 Zornitza Stark Marked gene: MTHFD1 as ready
Genomic newborn screening: BabyScreen+ v0.2031 MTHFD1 Zornitza Stark Gene: mthfd1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2031 MTHFD1 Zornitza Stark Classified gene: MTHFD1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2031 MTHFD1 Zornitza Stark Gene: mthfd1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2030 MTHFD1 Zornitza Stark gene: MTHFD1 was added
gene: MTHFD1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological, haematological tags were added to gene: MTHFD1.
Mode of inheritance for gene: MTHFD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTHFD1 were set to 32414565; 19033438
Phenotypes for gene: MTHFD1 were set to Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinaemia MIM # 617780
Review for gene: MTHFD1 was set to GREEN
Added comment: 8 individuals from 4 unrelated families have been reported; multiple mouse models

7 individuals were Compound heterozygous (nonsense & missense) and 1 was homozygous (missense) for MTHFD1 variants often resulting in alteration of highly conserved residues in binding-sites.

Individuals typically present with megaloblastic anaemia, atypical hemolytic uremic syndrome, hyperhomocysteinaemia, microangiopathy, recurrent infections and autoimmune diseases.

Treatment: hydroxocobalamin, folinic acid and betaine

Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile, complete blood count with MCV, plasma homocysteine and methylmalonic acid levels, CSF
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.5192 UBE3C Zornitza Stark Phenotypes for gene: UBE3C were changed from Neurodevelopmental disorder, MONDO:0700092, UBE3C-related to Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Intellectual disability syndromic and non-syndromic v0.5191 UBE3C Zornitza Stark edited their review of gene: UBE3C: Changed phenotypes: Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Mendeliome v1.741 UBE3C Zornitza Stark Phenotypes for gene: UBE3C were changed from Neurodevelopmental disorder, MONDO:0700092, UBE3C-related to Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Mendeliome v1.740 UBE3C Zornitza Stark edited their review of gene: UBE3C: Changed phenotypes: Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Angelman Rett like syndromes v1.8 UBE3C Zornitza Stark Phenotypes for gene: UBE3C were changed from Neurodevelopmental disorder, MONDO:0700092, UBE3C-related to Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Angelman Rett like syndromes v1.7 UBE3C Zornitza Stark edited their review of gene: UBE3C: Changed phenotypes: Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Mendeliome v1.740 MS4A1 Zornitza Stark Publications for gene: MS4A1 were set to 20038800
Mendeliome v1.739 MS4A1 Zornitza Stark Classified gene: MS4A1 as Amber List (moderate evidence)
Mendeliome v1.739 MS4A1 Zornitza Stark Gene: ms4a1 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.2029 MNX1 Zornitza Stark Marked gene: MNX1 as ready
Genomic newborn screening: BabyScreen+ v0.2029 MNX1 Zornitza Stark Gene: mnx1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2029 MNX1 Zornitza Stark Classified gene: MNX1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2029 MNX1 Zornitza Stark Gene: mnx1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2028 MNX1 Zornitza Stark gene: MNX1 was added
gene: MNX1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: MNX1.
Mode of inheritance for gene: MNX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MNX1 were set to 36586106
Phenotypes for gene: MNX1 were set to Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related
Review for gene: MNX1 was set to GREEN
Added comment: Three unrelated families reported. Presentation is in newborn period.

Treatment: insulin.

Non-genetic confirmatory testing: glucose tolerance test, hemoglobin A1C, insulin level, glucose level
Sources: Expert list
Mendeliome v1.738 MNX1 Zornitza Stark Phenotypes for gene: MNX1 were changed from Currarino syndrome, MIM# 176450 to Currarino syndrome, MIM# 176450; Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related
Mendeliome v1.737 MNX1 Zornitza Stark Mode of inheritance for gene: MNX1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic Diabetes v0.38 MNX1 Zornitza Stark Marked gene: MNX1 as ready
Monogenic Diabetes v0.38 MNX1 Zornitza Stark Gene: mnx1 has been classified as Green List (High Evidence).
Monogenic Diabetes v0.38 MNX1 Zornitza Stark Phenotypes for gene: MNX1 were changed from to Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related
Monogenic Diabetes v0.37 MNX1 Zornitza Stark reviewed gene: MNX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36586106; Phenotypes: Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.736 MNX1 Zornitza Stark reviewed gene: MNX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36586106; Phenotypes: Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.2027 MALT1 Zornitza Stark Marked gene: MALT1 as ready
Genomic newborn screening: BabyScreen+ v0.2027 MALT1 Zornitza Stark Gene: malt1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2027 MALT1 Zornitza Stark Classified gene: MALT1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2027 MALT1 Zornitza Stark Gene: malt1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2026 MALT1 Zornitza Stark gene: MALT1 was added
gene: MALT1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: MALT1.
Mode of inheritance for gene: MALT1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MALT1 were set to Immunodeficiency 12 MIM# 615468
Review for gene: MALT1 was set to GREEN
Added comment: 5 individuals from 3 unrelated families with immunodeficiency phenotype have reported variants in MALT1; two MALT1-knockout mouse models displaying primary T- and B-cell lymphocyte deficiency.

Variants identified were homozygous missense variants resulting in the alteration of highly conserved residue domains.

All individuals reported onset in infancy of recurrent bacterial/ fungal/ viral infections leading to bronchiectasis and poor T-cell proliferation.

Treatment: prophylactic antibiotics, IVIG, BMT.

Non-genetic confirmatory testing: no
Sources: Expert list
Ectodermal Dysplasia v0.81 RIPK4 Bryony Thompson Marked gene: RIPK4 as ready
Ectodermal Dysplasia v0.81 RIPK4 Bryony Thompson Gene: ripk4 has been classified as Green List (High Evidence).
Ectodermal Dysplasia v0.81 RIPK4 Bryony Thompson Classified gene: RIPK4 as Green List (high evidence)
Ectodermal Dysplasia v0.81 RIPK4 Bryony Thompson Gene: ripk4 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2025 MAGT1 Zornitza Stark Marked gene: MAGT1 as ready
Genomic newborn screening: BabyScreen+ v0.2025 MAGT1 Zornitza Stark Gene: magt1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2025 MAGT1 Zornitza Stark Classified gene: MAGT1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2025 MAGT1 Zornitza Stark Gene: magt1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2024 MAGT1 Zornitza Stark gene: MAGT1 was added
gene: MAGT1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: MAGT1.
Mode of inheritance for gene: MAGT1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: MAGT1 were set to 31036665; 31714901
Phenotypes for gene: MAGT1 were set to Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia (MIM# 300853)
Review for gene: MAGT1 was set to GREEN
Added comment: XMEN is an X-linked recessive immunodeficiency characterized by CD4 lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation. Affected individuals have chronic Epstein-Barr virus (EBV) infection and are susceptible to the development of EBV-associated B-cell lymphoproliferative disorders.

Variable age of onset, including in early childhood.

Treatment: Mg supplementation; IVIG, BMT.

Non-genetic confirmatory testing: immunoglobulin levels, T and B Lymphocyte and Natural Killer Cell Profile, Carbohydrate deficient glycosylation profile
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2023 LRBA Zornitza Stark Marked gene: LRBA as ready
Genomic newborn screening: BabyScreen+ v0.2023 LRBA Zornitza Stark Gene: lrba has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2023 LRBA Zornitza Stark Classified gene: LRBA as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2023 LRBA Zornitza Stark Gene: lrba has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2022 LRBA Zornitza Stark gene: LRBA was added
gene: LRBA was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: LRBA.
Mode of inheritance for gene: LRBA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRBA were set to 22608502; 22721650; 25468195; 26206937; 33155142; 31887391
Phenotypes for gene: LRBA were set to Immunodeficiency, common variable, 8, with autoimmunity MIM# 614700
Review for gene: LRBA was set to GREEN
Added comment: Well established gene-disease association.

Generally childhood onset with recurrent infections and autoimmune phenomena.

Treatment: abatacept, BMT.

Non-genetic confirmatory testing: immunoglobulin levels.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2021 LIG1 Zornitza Stark Marked gene: LIG1 as ready
Genomic newborn screening: BabyScreen+ v0.2021 LIG1 Zornitza Stark Gene: lig1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2021 LIG1 Zornitza Stark Classified gene: LIG1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2021 LIG1 Zornitza Stark Gene: lig1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2020 LIG1 Zornitza Stark gene: LIG1 was added
gene: LIG1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: LIG1.
Mode of inheritance for gene: LIG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG1 were set to 30395541
Phenotypes for gene: LIG1 were set to Immunodeficiency 96, MIM# 619774
Review for gene: LIG1 was set to GREEN
Added comment: Established gene-disease association.

Onset is generally in early childhood.

Presents with recurrent severe infections.

Treatment: IVIG, BMT.

Non-genetic confirmatory testing: immunoglobulin levels, T and B Lymphocyte and Natural Killer Cell Profile, complete blood count
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2019 LEP Zornitza Stark Marked gene: LEP as ready
Genomic newborn screening: BabyScreen+ v0.2019 LEP Zornitza Stark Gene: lep has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2019 LEP Zornitza Stark Classified gene: LEP as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2019 LEP Zornitza Stark Gene: lep has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2018 LEP Zornitza Stark gene: LEP was added
gene: LEP was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: LEP.
Mode of inheritance for gene: LEP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LEP were set to 26567097
Phenotypes for gene: LEP were set to Obesity, morbid, due to leptin deficiency (MIM#614962)
Review for gene: LEP was set to GREEN
Added comment: Established gene-disease association.

Onset is in infancy/early childhood. Similar disorders included.

Treatment: metreleptin.

Non-genetic confirmatory testing: leptin level.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2017 JAGN1 Zornitza Stark Marked gene: JAGN1 as ready
Genomic newborn screening: BabyScreen+ v0.2017 JAGN1 Zornitza Stark Gene: jagn1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2017 JAGN1 Zornitza Stark Classified gene: JAGN1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2017 JAGN1 Zornitza Stark Gene: jagn1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2016 JAGN1 Zornitza Stark gene: JAGN1 was added
gene: JAGN1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: JAGN1.
Mode of inheritance for gene: JAGN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JAGN1 were set to 25129144
Phenotypes for gene: JAGN1 were set to Neutropenia, severe congenital, 6, autosomal recessive, MIM# 616022
Review for gene: JAGN1 was set to GREEN
Added comment: Established gene-disease association.

Typically presents in early childhood with severe infections.

Treatment: G-CSF, BMT.

Non-genetic confirmatory testing: complete blood count, bone marrow aspiration and biopsy
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2015 TNFRSF13C Zornitza Stark Marked gene: TNFRSF13C as ready
Genomic newborn screening: BabyScreen+ v0.2015 TNFRSF13C Zornitza Stark Gene: tnfrsf13c has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2015 TNFRSF13C Zornitza Stark Classified gene: TNFRSF13C as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.2015 TNFRSF13C Zornitza Stark Gene: tnfrsf13c has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.2014 ITK Zornitza Stark Marked gene: ITK as ready
Genomic newborn screening: BabyScreen+ v0.2014 ITK Zornitza Stark Gene: itk has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2014 ITK Zornitza Stark Classified gene: ITK as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2014 ITK Zornitza Stark Gene: itk has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2013 ITK Zornitza Stark gene: ITK was added
gene: ITK was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: ITK.
Mode of inheritance for gene: ITK was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ITK were set to Lymphoproliferative syndrome 1, MIM# 613011
Review for gene: ITK was set to GREEN
Added comment: 7 individuals from 5 unrelated families reported homozygous (missense/ nonsense) ITK variants consistent with Lymphoproliferative syndrome phenotype. Triggered by EBV infection.

Two ITK-deficient mouse models demonstrated reduced T cells (CD4+), causing decreased CD4 to CD8 ratio.

Patients displayed early onset of features typically including fever, lymphadenopathy, autoimmune disorders, low immunoglobulins and high EBV viral load.

Fatal without BMT.

Non-genetic confirmatory testing: immunoglobulin levels, T and B Lymphocyte and Natural Killer Cell Profile.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2012 IRS4 Zornitza Stark changed review comment from: Nongoitrous congenital hypothyroidism-9 (CHNG9) is characterized by a small thyroid gland with low free T4 (FT4) levels and inappropriately normal levels of thyroid-stimulating hormone (TSH). Five unrelated families reported.

Most identified through standard NBS.
Sources: Expert list; to: Nongoitrous congenital hypothyroidism-9 (CHNG9) is characterized by a small thyroid gland with low free T4 (FT4) levels and inappropriately normal levels of thyroid-stimulating hormone (TSH). Five unrelated families reported.

Most identified through standard NBS.

Treatment: thyroxine.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2012 IRS4 Zornitza Stark Marked gene: IRS4 as ready
Genomic newborn screening: BabyScreen+ v0.2012 IRS4 Zornitza Stark Gene: irs4 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2012 IRS4 Zornitza Stark Classified gene: IRS4 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2012 IRS4 Zornitza Stark Gene: irs4 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2011 IRS4 Zornitza Stark gene: IRS4 was added
gene: IRS4 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: IRS4.
Mode of inheritance for gene: IRS4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: IRS4 were set to 30061370
Phenotypes for gene: IRS4 were set to Hypothyroidism, congenital, nongoitrous, 9, MIM# 301035
Review for gene: IRS4 was set to GREEN
Added comment: Nongoitrous congenital hypothyroidism-9 (CHNG9) is characterized by a small thyroid gland with low free T4 (FT4) levels and inappropriately normal levels of thyroid-stimulating hormone (TSH). Five unrelated families reported.

Most identified through standard NBS.
Sources: Expert list
Mendeliome v1.736 IRS4 Zornitza Stark Marked gene: IRS4 as ready
Mendeliome v1.736 IRS4 Zornitza Stark Gene: irs4 has been classified as Green List (High Evidence).
Mendeliome v1.736 IRS4 Zornitza Stark Classified gene: IRS4 as Green List (high evidence)
Mendeliome v1.736 IRS4 Zornitza Stark Gene: irs4 has been classified as Green List (High Evidence).
Mendeliome v1.735 IRS4 Zornitza Stark gene: IRS4 was added
gene: IRS4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IRS4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: IRS4 were set to 30061370
Phenotypes for gene: IRS4 were set to Hypothyroidism, congenital, nongoitrous, 9, MIM# 301035
Review for gene: IRS4 was set to GREEN
Added comment: Nongoitrous congenital hypothyroidism-9 (CHNG9) is characterized by a small thyroid gland with low free T4 (FT4) levels and inappropriately normal levels of thyroid-stimulating hormone (TSH). Five unrelated families reported.
Sources: Expert Review
Congenital hypothyroidism v0.38 IRS4 Zornitza Stark Marked gene: IRS4 as ready
Congenital hypothyroidism v0.38 IRS4 Zornitza Stark Gene: irs4 has been classified as Green List (High Evidence).
Congenital hypothyroidism v0.38 IRS4 Zornitza Stark Phenotypes for gene: IRS4 were changed from Congenital central hypothyroidism to Hypothyroidism, congenital, nongoitrous, 9, MIM# 301035
Congenital hypothyroidism v0.37 IRS4 Zornitza Stark reviewed gene: IRS4: Rating: GREEN; Mode of pathogenicity: None; Publications: 30061370; Phenotypes: Hypothyroidism, congenital, nongoitrous, 9, MIM# 301035; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genomic newborn screening: BabyScreen+ v0.2010 TNFRSF13C Lilian Downie gene: TNFRSF13C was added
gene: TNFRSF13C was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TNFRSF13C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNFRSF13C were set to PMID: 19666484, PMID: 27250108, PMID: 18025937
Phenotypes for gene: TNFRSF13C were set to Immunodeficiency, common variable, 4 MIM#613494
Review for gene: TNFRSF13C was set to RED
Added comment: Amber in our mendeliome
Later childhood or adult onset.
BAFFR deficiency in humans is characterized by very few circulating B cells, very low IgM and IgG serum concentrations but normal or high IgA levels.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2010 IL36RN Zornitza Stark Marked gene: IL36RN as ready
Genomic newborn screening: BabyScreen+ v0.2010 IL36RN Zornitza Stark Gene: il36rn has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2010 IL36RN Zornitza Stark Classified gene: IL36RN as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2010 IL36RN Zornitza Stark Gene: il36rn has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2009 IL36RN Zornitza Stark gene: IL36RN was added
gene: IL36RN was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: IL36RN.
Mode of inheritance for gene: IL36RN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL36RN were set to 31286990
Phenotypes for gene: IL36RN were set to Psoriasis 14, pustular, MIM# 614204
Review for gene: IL36RN was set to GREEN
Added comment: Generalized pustular psoriasis (GPP) is a life-threatening disease characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein.

Variable age of onset but predominantly in infancy/early childhood.

Treatment: ustekinumab, secukinumab, etanercept.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2008 IL2RA Zornitza Stark Marked gene: IL2RA as ready
Genomic newborn screening: BabyScreen+ v0.2008 IL2RA Zornitza Stark Gene: il2ra has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2008 IL2RA Zornitza Stark Classified gene: IL2RA as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2008 IL2RA Zornitza Stark Gene: il2ra has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2007 IL2RA Zornitza Stark gene: IL2RA was added
gene: IL2RA was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: IL2RA.
Mode of inheritance for gene: IL2RA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IL2RA were set to Immunodeficiency 41 with lymphoproliferation and autoimmunity, MIM# 606367
Review for gene: IL2RA was set to GREEN
Added comment: Immunodeficiency-41 is a disorder of immune dysregulation. Affected individuals present in infancy with recurrent viral, fungal, and bacterial infections, lymphadenopathy, and variable autoimmune features, such as autoimmune enteropathy and eczematous skin lesions. Immunologic studies show a defect in T-cell regulation.

At least 4 unrelated families reported.

Treatment: rapamycin, bone marrow transplant.

Confirmatory non-genetic testing: flow cytometric analysis.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2006 IL21R Zornitza Stark Marked gene: IL21R as ready
Genomic newborn screening: BabyScreen+ v0.2006 IL21R Zornitza Stark Gene: il21r has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2006 IL21R Zornitza Stark Classified gene: IL21R as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2006 IL21R Zornitza Stark Gene: il21r has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2005 IL21R Zornitza Stark gene: IL21R was added
gene: IL21R was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: IL21R.
Mode of inheritance for gene: IL21R was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IL21R were set to Immunodeficiency 56, MIM# 615207
Review for gene: IL21R was set to GREEN
Added comment: Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections.

More than 20 individuals reported. Recent series of 13 individuals: the main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinaemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients.

Onset: infancy/early childhood.

Treatment: BMT.

Non-genetic confirmatory testing: immunoglobulin levels.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2004 IL1RN Zornitza Stark Marked gene: IL1RN as ready
Genomic newborn screening: BabyScreen+ v0.2004 IL1RN Zornitza Stark Gene: il1rn has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2004 IL1RN Zornitza Stark Classified gene: IL1RN as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2004 IL1RN Zornitza Stark Gene: il1rn has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2003 IL1RN Zornitza Stark gene: IL1RN was added
gene: IL1RN was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: IL1RN.
Mode of inheritance for gene: IL1RN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IL1RN were set to Interleukin 1 receptor antagonist deficiency, MIM# 612852
Review for gene: IL1RN was set to GREEN
Added comment: Severe immunodeficiency, onset in infancy. Multi-system involvement, can be fatal if untreated.

Treatment: anakinra, etanercept, methotrexate, corticosteroid
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2002 IKZF1 Zornitza Stark Marked gene: IKZF1 as ready
Genomic newborn screening: BabyScreen+ v0.2002 IKZF1 Zornitza Stark Gene: ikzf1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2002 IKZF1 Zornitza Stark Classified gene: IKZF1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2002 IKZF1 Zornitza Stark Gene: ikzf1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2001 IKZF1 Zornitza Stark Tag treatable tag was added to gene: IKZF1.
Tag immunological tag was added to gene: IKZF1.
Genomic newborn screening: BabyScreen+ v0.2001 IKZF1 Zornitza Stark edited their review of gene: IKZF1: Changed rating: GREEN
Genomic newborn screening: BabyScreen+ v0.2001 IKZF1 Zornitza Stark gene: IKZF1 was added
gene: IKZF1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: IKZF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: IKZF1 were set to Immunodeficiency, common variable, 13 MIM# 616873
Added comment: Over 25 individuals from 9 unrelated families with variants in IKZF1 displaying Immunodeficiency; three mouse models Heterozygous missense, frameshift and deletion variants in IKZF1 gene resulting in loss or alteration of a zinc finger DNA contact site cause LoF. Typically presents with recurrent bacterial respiratory infections, hypogammaglobulinaemia and low Ig levels; variable age of onset.

PMID 35333544: Eight individuals harboring heterozygous IKZF1R183H or IKZF1R183C variants associated with GOF effects reported. The clinical phenotypes and pathophysiology associated with IKZF1R183H/C differ from those of previously reported patients with IKZF1HI, IKZF1DN, and IKZF1DD and should therefore be considered as a novel IKAROS-associated disease entity. This condition is characterized by immune dysregulation manifestations including inflammation, autoimmunity, atopy, and polyclonal PC proliferation.

Included primarily for LoF phenotype.

Treatment: IVIG and BMT.

Non-genetic confirmatory testing: immunoglobulin levels
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2000 IKBKB Zornitza Stark changed review comment from: Primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinaemia with relatively normal numbers of B and T cells.

Treatment: bone marrow transplant.
Sources: Expert list; to: Primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinaemia with relatively normal numbers of B and T cells.

Treatment: bone marrow transplant.

Limited evidence for mono-allelic disease.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.2000 IKBKB Zornitza Stark Marked gene: IKBKB as ready
Genomic newborn screening: BabyScreen+ v0.2000 IKBKB Zornitza Stark Gene: ikbkb has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.2000 IKBKB Zornitza Stark Classified gene: IKBKB as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.2000 IKBKB Zornitza Stark Gene: ikbkb has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1999 IKBKB Zornitza Stark gene: IKBKB was added
gene: IKBKB was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: IKBKB.
Mode of inheritance for gene: IKBKB was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IKBKB were set to Immunodeficiency 15B, MIM# 615592
Review for gene: IKBKB was set to GREEN
Added comment: Primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinaemia with relatively normal numbers of B and T cells.

Treatment: bone marrow transplant.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1998 IFNGR2 Zornitza Stark Marked gene: IFNGR2 as ready
Genomic newborn screening: BabyScreen+ v0.1998 IFNGR2 Zornitza Stark Gene: ifngr2 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.1998 IFNGR2 Zornitza Stark Classified gene: IFNGR2 as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.1998 IFNGR2 Zornitza Stark Gene: ifngr2 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.1997 IFNGR2 Zornitza Stark gene: IFNGR2 was added
gene: IFNGR2 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: IFNGR2.
Mode of inheritance for gene: IFNGR2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IFNGR2 were set to Immunodeficiency 28, mycobacteriosis, MIM# 614889
Review for gene: IFNGR2 was set to AMBER
Added comment: At least 5 unrelated families reported.

Commonest trigger is BCG vaccination, which is not part of the routine schedule in Australia, therefore exclude.

Treatment: BMT; avoidance of BCG.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1996 IFNGR1 Zornitza Stark Marked gene: IFNGR1 as ready
Genomic newborn screening: BabyScreen+ v0.1996 IFNGR1 Zornitza Stark Gene: ifngr1 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.1996 IFNGR1 Zornitza Stark Classified gene: IFNGR1 as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.1996 IFNGR1 Zornitza Stark Gene: ifngr1 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.1995 IFNGR1 Zornitza Stark Tag treatable tag was added to gene: IFNGR1.
Tag immunological tag was added to gene: IFNGR1.
Genomic newborn screening: BabyScreen+ v0.1995 IFNGR1 Zornitza Stark gene: IFNGR1 was added
gene: IFNGR1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: IFNGR1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: IFNGR1 were set to Immunodeficiency 27A, mycobacteriosis, AR, MIM# 209950; Immunodeficiency 27B, mycobacteriosis, AD, MIM# 615978
Review for gene: IFNGR1 was set to AMBER
Added comment: Variable age of onset. Most common precipitant is BCG vaccination, which is not part of the routine schedule in Australia, therefore exclude.

Treatment: BMT; avoidance of BCG.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1994 IFITM5 Zornitza Stark Marked gene: IFITM5 as ready
Genomic newborn screening: BabyScreen+ v0.1994 IFITM5 Zornitza Stark Gene: ifitm5 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1994 IFITM5 Zornitza Stark Classified gene: IFITM5 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.1994 IFITM5 Zornitza Stark Gene: ifitm5 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1993 IFITM5 Zornitza Stark gene: IFITM5 was added
gene: IFITM5 was added to Baby Screen+ newborn screening. Sources: Expert list
5'UTR, treatable, skeletal tags were added to gene: IFITM5.
Mode of inheritance for gene: IFITM5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IFITM5 were set to 22863190; 22863195; 32383316; 24519609
Phenotypes for gene: IFITM5 were set to Osteogenesis imperfecta, type V MIM#610967
Review for gene: IFITM5 was set to GREEN
Added comment: A recurrent c.-14C>T variant has been reported in many patients with type V OI. It introduces an alternative in-frame start codon upstream that is stronger than the reference start codon in transfected HEK cells (PMIDs: 22863190, 22863195). However, the effect of mutant protein (5 amino acids longer) remains unknown but neomorphic mechanism is a widely accepted hypothesis (PMIDs: 25251575, 32383316).

Variable severity, including within families. However, severe perinatal presentations reported.

Treatment: bisphosphanates.

Non-genetic confirmatory testing: skeletal survey.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1992 ICOS Zornitza Stark Marked gene: ICOS as ready
Genomic newborn screening: BabyScreen+ v0.1992 ICOS Zornitza Stark Gene: icos has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1992 ICOS Zornitza Stark Classified gene: ICOS as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.1992 ICOS Zornitza Stark Gene: icos has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1991 ICOS Zornitza Stark gene: ICOS was added
gene: ICOS was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: ICOS.
Mode of inheritance for gene: ICOS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ICOS were set to Immunodeficiency, common variable, 1 MIM# 607594
Review for gene: ICOS was set to GREEN
Added comment: 15 affected individuals from 8 unrelated families reported with ICOS variants and displayed immunodeficiency, common variable, 1 phenotype; three mouse models.

Homozygous and compound heterozygous deletion and missense variants, with the most frequent variant being a 442 nucleotide deletion.

Patients typically presented with recurrent bacterial respiratory & gastrointestinal infections and low IgG/IgA.

Congenital onset.

Treatment: replacement immunoglobulin treatment, bone marrow transplant.

Non-genetic confirmatory testing: immunoglobulin levels.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1990 IARS Zornitza Stark Marked gene: IARS as ready
Genomic newborn screening: BabyScreen+ v0.1990 IARS Zornitza Stark Gene: iars has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.1990 IARS Zornitza Stark Classified gene: IARS as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.1990 IARS Zornitza Stark Gene: iars has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.1989 IARS Zornitza Stark Tag treatable tag was added to gene: IARS.
Tag metabolic tag was added to gene: IARS.
Genomic newborn screening: BabyScreen+ v0.1989 IARS Zornitza Stark gene: IARS was added
gene: IARS was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: IARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IARS were set to 27426735; 34194004
Phenotypes for gene: IARS were set to Growth retardation, impaired intellectual development, hypotonia, and hepatopathy, MIM#617093
Review for gene: IARS was set to AMBER
Added comment: Established gene-disease association.

Congenital, multi-system metabolic disorder.

N=1 study of Isoleucine supplementation and protein fortification (2.5mg/kg/day, during illness 3.5 g/kg/day) with some clinical improvement.
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.5191 HECTD4 Zornitza Stark Phenotypes for gene: HECTD4 were changed from Neurodevelopmental disorder, MONDO:0700092, HECTD4-related to Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250
Intellectual disability syndromic and non-syndromic v0.5190 HECTD4 Zornitza Stark edited their review of gene: HECTD4: Changed phenotypes: Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250
Mendeliome v1.734 HECTD4 Zornitza Stark Marked gene: HECTD4 as ready
Mendeliome v1.734 HECTD4 Zornitza Stark Gene: hectd4 has been classified as Green List (High Evidence).
Mendeliome v1.734 HECTD4 Zornitza Stark Phenotypes for gene: HECTD4 were changed from Neurodevelopmental disorder overlapping Angelman syndrome, no OMIM# to Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250
Mendeliome v1.733 HECTD4 Zornitza Stark reviewed gene: HECTD4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Angelman Rett like syndromes v1.7 HECTD4 Zornitza Stark Phenotypes for gene: HECTD4 were changed from Neurodevelopmental disorder, MONDO:0700092, HECTD4-related to Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250
Angelman Rett like syndromes v1.6 HECTD4 Zornitza Stark edited their review of gene: HECTD4: Changed phenotypes: Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250
Disorders of immune dysregulation v0.167 TNFRSF9 Zornitza Stark Phenotypes for gene: TNFRSF9 were changed from EBV lymphoproliferation; B-cell lymphoma; Chronic active EBV infection to Immunodeficiency 109 with lymphoproliferation, MIM# 620282; EBV lymphoproliferation; B-cell lymphoma; Chronic active EBV infection
Disorders of immune dysregulation v0.166 TNFRSF9 Zornitza Stark edited their review of gene: TNFRSF9: Changed phenotypes: Immunodeficiency 109 with lymphoproliferation, MIM# 620282, EBV lymphoproliferation, B-cell lymphoma, Chronic active EBV infection
Mendeliome v1.733 TNFRSF9 Zornitza Stark Phenotypes for gene: TNFRSF9 were changed from EBV lymphoproliferation; B-cell lymphoma; Chronic active EBV infection to Immunodeficiency 109 with lymphoproliferation, MIM# 620282; EBV lymphoproliferation; B-cell lymphoma; Chronic active EBV infection
Mendeliome v1.732 TNFRSF9 Zornitza Stark edited their review of gene: TNFRSF9: Changed phenotypes: Immunodeficiency 109 with lymphoproliferation, MIM# 620282, EBV lymphoproliferation, B-cell lymphoma, Chronic active EBV infection
Genomic newborn screening: BabyScreen+ v0.1988 TNFRSF1A Zornitza Stark Marked gene: TNFRSF1A as ready
Genomic newborn screening: BabyScreen+ v0.1988 TNFRSF1A Zornitza Stark Gene: tnfrsf1a has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.1988 TNFRSF1A Zornitza Stark Classified gene: TNFRSF1A as Red List (low evidence)
Genomic newborn screening: BabyScreen+ v0.1988 TNFRSF1A Zornitza Stark Gene: tnfrsf1a has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.1987 TOP2B Zornitza Stark Marked gene: TOP2B as ready
Genomic newborn screening: BabyScreen+ v0.1987 TOP2B Zornitza Stark Gene: top2b has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.1987 TOP2B Zornitza Stark Classified gene: TOP2B as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.1987 TOP2B Zornitza Stark Gene: top2b has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.1986 TOP2B Zornitza Stark reviewed gene: TOP2B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: B-cell immunodeficiency, distal limb anomalies, and urogenital malformations MIM#609296; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: BabyScreen+ v0.1986 TPK1 Zornitza Stark Marked gene: TPK1 as ready
Genomic newborn screening: BabyScreen+ v0.1986 TPK1 Zornitza Stark Gene: tpk1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1986 TPK1 Zornitza Stark Classified gene: TPK1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.1986 TPK1 Zornitza Stark Gene: tpk1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1985 TPK1 Zornitza Stark Tag treatable tag was added to gene: TPK1.
Tag metabolic tag was added to gene: TPK1.
Genomic newborn screening: BabyScreen+ v0.1985 TRNT1 Zornitza Stark Marked gene: TRNT1 as ready
Genomic newborn screening: BabyScreen+ v0.1985 TRNT1 Zornitza Stark Gene: trnt1 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.1985 TRNT1 Zornitza Stark Classified gene: TRNT1 as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.1985 TRNT1 Zornitza Stark Gene: trnt1 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.1984 TRNT1 Zornitza Stark Tag treatable tag was added to gene: TRNT1.
Tag immunological tag was added to gene: TRNT1.
Genomic newborn screening: BabyScreen+ v0.1984 TRNT1 Zornitza Stark reviewed gene: TRNT1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay MIM#616084; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.1984 TRPM6 Zornitza Stark Marked gene: TRPM6 as ready
Genomic newborn screening: BabyScreen+ v0.1984 TRPM6 Zornitza Stark Gene: trpm6 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1984 TRPM6 Zornitza Stark Classified gene: TRPM6 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.1984 TRPM6 Zornitza Stark Gene: trpm6 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1983 TRPM6 Zornitza Stark Tag treatable tag was added to gene: TRPM6.
Tag endocrine tag was added to gene: TRPM6.
Genomic newborn screening: BabyScreen+ v0.1983 UCP2 Zornitza Stark Marked gene: UCP2 as ready
Genomic newborn screening: BabyScreen+ v0.1983 UCP2 Zornitza Stark Gene: ucp2 has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.1983 UCP2 Zornitza Stark Publications for gene: UCP2 were set to
Genomic newborn screening: BabyScreen+ v0.1982 TNFRSF1A Lilian Downie gene: TNFRSF1A was added
gene: TNFRSF1A was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TNFRSF1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TNFRSF1A were set to PMID: 11175303, PMID: 32066461, PMID: 29773275, PMID: 32831641
Phenotypes for gene: TNFRSF1A were set to Periodic fever, familial MIM#142680
Penetrance for gene: TNFRSF1A were set to Incomplete
Review for gene: TNFRSF1A was set to RED
Added comment: Strong gene disease association
Childhood onset but age not consistently under 5 and cases of adult onset
reports of variable penetrance
Rx
NSAIDs, corticosteroids, Etanercept , anakinra, canakinumab, tocilizumab

because there is no non-molecular confirmatory test I think should be red for variability of age of onset and severity of symptoms.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1982 TOP2B Lilian Downie gene: TOP2B was added
gene: TOP2B was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TOP2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TOP2B were set to PMID: 31409799, PMID: 35063500, PMID: 32128574, PMID: 33459963
Phenotypes for gene: TOP2B were set to B-cell immunodeficiency, distal limb anomalies, and urogenital malformations MIM#609296
Review for gene: TOP2B was set to AMBER
Added comment: congenital onset
humoral immunodeficiency with undetectable B cells, distal limb anomalies, dysmorphic facial features, and urogenital malformations

Treatment immunoglobulin (only partially treats phenotype) no literature for evidence around immunoglobulin treatment.

Suggest RED but maybe discuss with immunologist?
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1982 TPK1 Lilian Downie gene: TPK1 was added
gene: TPK1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TPK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPK1 were set to PMID: 33086386, 32679198, 22152682, PMID: 33231275
Phenotypes for gene: TPK1 were set to Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type) MIM#614458
Review for gene: TPK1 was set to GREEN
Added comment: Strong gene disease association
Variable age of onset but always under 5years

Thiamine metabolism dysfunction syndrome-5 (THMD5) is an autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes result in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases may result in loss of ability to walk. Cognitive function is usually preserved, although mildly delayed development has been reported. These episodes are usually associated with infection and metabolic decompensation. Some patients may have recovery of some neurologic deficits (Mayr et al., 2011).

Biotin and thiamine therapy - newer evidence (2021) suggests early thiamine therapy may prevent any neurologic deficits.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1982 TRNT1 Lilian Downie gene: TRNT1 was added
gene: TRNT1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TRNT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRNT1 were set to PMID: 25193871, PMID: 23553769, PMID: 33936027, PMID: 26494905
Phenotypes for gene: TRNT1 were set to Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay MIM#616084
Review for gene: TRNT1 was set to AMBER
Added comment: Onset infancy
Strong gene disease association

Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndromic disorder characterized by onset of severe sideroblastic anemia in the neonatal period or infancy. Affected individuals show delayed psychomotor development with variable neurodegeneration. Recurrent periodic fevers without an infectious etiology occur throughout infancy and childhood; immunologic work-up shows B-cell lymphopenia and hypogammaglobulinemia. Other more variable features include sensorineural hearing loss, retinitis pigmentosa, nephrocalcinosis, and cardiomyopathy. Death in the first decade may occur (summary by Wiseman et al., 2013).

Bone marrow transplant (hematopoietic stem cell transplantation (HSCT)), replacement immunoglobulin treatment

Allelic disease: Retinitis pigmentosa and erythrocytic microcytosis MIM#616959. Also AR.
DeLuca et al. (2016) concluded that hypomorphic TRNT1 mutations can cause a recessive disease that is almost entirely limited to the retina - this has teenage onset and is not treatable. can we exclude these variants?
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1982 TRPM6 Lilian Downie gene: TRPM6 was added
gene: TRPM6 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TRPM6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRPM6 were set to PMID: 35903165, PMID: 18818955
Phenotypes for gene: TRPM6 were set to Hypomagnesemia 1, intestinal MIM#602014
Review for gene: TRPM6 was set to GREEN
Added comment: Hypomagnaesemia and hypocalcaemia
Hypocalcemia is a secondary consequence of parathyroid failure and parathyroid hormone resistance as a result of severe magnesium deficiency. The disease typically manifests during the first months of life with generalized convulsions or signs of increased neuromuscular excitability, such as muscle spasms or tetany. Untreated, the disease may be fatal or lead to severe neurologic damage. Treatment includes immediate administration of magnesium, usually intravenously, followed by life-long high-dose oral magnesium (review by Knoers, 2009).
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1982 UCP2 Lilian Downie reviewed gene: UCP2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 28681398, PMID: 27967291; Phenotypes: UCP2 associated hyperinsulinism; Mode of inheritance: None
Mendeliome v1.732 SPTLC1 Zornitza Stark Phenotypes for gene: SPTLC1 were changed from Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400; Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis) to Juvenile amyotrophic lateral sclerosis-27, MIM#620285; Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400; Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis)
Mendeliome v1.731 SPTLC1 Zornitza Stark edited their review of gene: SPTLC1: Changed phenotypes: Juvenile amyotrophic lateral sclerosis-27, MIM#620285, Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400, Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis)
Hyperinsulinism v1.9 GLUD1 Zornitza Stark Mode of inheritance for gene: GLUD1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hyperinsulinism v1.8 GLUD1 Zornitza Stark edited their review of gene: GLUD1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fatty Acid Oxidation Defects v1.10 GLUD1 Zornitza Stark Mode of inheritance for gene: GLUD1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fatty Acid Oxidation Defects v1.9 GLUD1 Zornitza Stark edited their review of gene: GLUD1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.731 GLUD1 Zornitza Stark Mode of inheritance for gene: GLUD1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.730 GLUD1 Zornitza Stark edited their review of gene: GLUD1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.730 GLUD1 Zornitza Stark edited their review of gene: GLUD1: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.1982 UNG Zornitza Stark Marked gene: UNG as ready
Genomic newborn screening: BabyScreen+ v0.1982 UNG Zornitza Stark Gene: ung has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.1982 UNG Zornitza Stark Classified gene: UNG as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.1982 UNG Zornitza Stark Gene: ung has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.1981 UNG Zornitza Stark Tag treatable tag was added to gene: UNG.
Tag immunological tag was added to gene: UNG.
Genomic newborn screening: BabyScreen+ v0.1981 UNG Zornitza Stark reviewed gene: UNG: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency with hyper IgM, type 5 MIM#608106; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.1981 UMPS Zornitza Stark Marked gene: UMPS as ready
Genomic newborn screening: BabyScreen+ v0.1981 UMPS Zornitza Stark Gene: umps has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1981 UMPS Zornitza Stark Classified gene: UMPS as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.1981 UMPS Zornitza Stark Gene: umps has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1980 UMPS Zornitza Stark Tag for review tag was added to gene: UMPS.
Tag treatable tag was added to gene: UMPS.
Tag metabolic tag was added to gene: UMPS.
Neurodegeneration with brain iron accumulation v0.22 BCAS3 Zornitza Stark Marked gene: BCAS3 as ready
Neurodegeneration with brain iron accumulation v0.22 BCAS3 Zornitza Stark Gene: bcas3 has been classified as Green List (High Evidence).
Neurodegeneration with brain iron accumulation v0.22 BCAS3 Zornitza Stark Phenotypes for gene: BCAS3 were changed from spasticity; intellectual disability; global developmental delay; microcephaly; short stature to Hengel-Maroofian-Schols syndrome, MIM# 619641
Neurodegeneration with brain iron accumulation v0.21 BCAS3 Zornitza Stark Publications for gene: BCAS3 were set to DOI:10.1002/mds.28915 Corpus ID: 245670502
Neurodegeneration with brain iron accumulation v0.20 BCAS3 Zornitza Stark Classified gene: BCAS3 as Green List (high evidence)
Neurodegeneration with brain iron accumulation v0.20 BCAS3 Zornitza Stark Gene: bcas3 has been classified as Green List (High Evidence).
Neurodegeneration with brain iron accumulation v0.19 BCAS3 Zornitza Stark reviewed gene: BCAS3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34981858; Phenotypes: Hengel-Maroofian-Schols syndrome, MIM# 619641; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neurodegeneration with brain iron accumulation v0.19 AFG3L2 Zornitza Stark Marked gene: AFG3L2 as ready
Neurodegeneration with brain iron accumulation v0.19 AFG3L2 Zornitza Stark Gene: afg3l2 has been classified as Red List (Low Evidence).
Neurodegeneration with brain iron accumulation v0.19 AFG3L2 Zornitza Stark Phenotypes for gene: AFG3L2 were changed from ataxia; visual impairment; neuroregression to Spastic ataxia 5, autosomal recessive, MIM# 614487; Spinocerebellar ataxia 28, MIM# 610246
Neurodegeneration with brain iron accumulation v0.18 AFG3L2 Zornitza Stark Classified gene: AFG3L2 as Red List (low evidence)
Neurodegeneration with brain iron accumulation v0.18 AFG3L2 Zornitza Stark Gene: afg3l2 has been classified as Red List (Low Evidence).
Neurodegeneration with brain iron accumulation v0.17 AFG3L2 Zornitza Stark reviewed gene: AFG3L2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic ataxia 5, autosomal recessive, MIM# 614487, Spinocerebellar ataxia 28, MIM# 610246; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neurodegeneration with brain iron accumulation v0.17 GTPBP2 Zornitza Stark Marked gene: GTPBP2 as ready
Neurodegeneration with brain iron accumulation v0.17 GTPBP2 Zornitza Stark Gene: gtpbp2 has been classified as Amber List (Moderate Evidence).
Neurodegeneration with brain iron accumulation v0.17 GTPBP2 Zornitza Stark Phenotypes for gene: GTPBP2 were changed from dystonia; ataxia; cognitive dysfunction; motor neuropathy; retinal abnormalities; sparse thin and brittle hair to Jaberi-Elahi syndrome, MIM# 617988
Neurodegeneration with brain iron accumulation v0.16 GTPBP2 Zornitza Stark Classified gene: GTPBP2 as Amber List (moderate evidence)
Neurodegeneration with brain iron accumulation v0.16 GTPBP2 Zornitza Stark Gene: gtpbp2 has been classified as Amber List (Moderate Evidence).
Neurodegeneration with brain iron accumulation v0.15 GTPBP2 Zornitza Stark reviewed gene: GTPBP2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Jaberi-Elahi syndrome, MIM# 617988; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.1980 NLGN4X Zornitza Stark Marked gene: NLGN4X as ready
Genomic newborn screening: BabyScreen+ v0.1980 NLGN4X Zornitza Stark Gene: nlgn4x has been classified as Red List (Low Evidence).
Genomic newborn screening: BabyScreen+ v0.1980 NLGN4X Zornitza Stark Phenotypes for gene: NLGN4X were changed from Autism to Intellectual developmental disorder, X-linked MIM#300495
Genomic newborn screening: BabyScreen+ v0.1979 NLGN4X Zornitza Stark Mode of inheritance for gene: NLGN4X was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Genomic newborn screening: BabyScreen+ v0.1978 NLGN4X Zornitza Stark reviewed gene: NLGN4X: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, X-linked MIM#300495; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.730 NLGN4X Zornitza Stark Classified gene: NLGN4X as Green List (high evidence)
Mendeliome v1.730 NLGN4X Zornitza Stark Gene: nlgn4x has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5190 Zornitza Stark removed gene:MTSS1 from the panel
Microcephaly v1.195 Zornitza Stark removed gene:MTSS1 from the panel
Mendeliome v1.729 Zornitza Stark removed gene:MTSS1 from the panel
Autism v0.188 NLGN4X Elena Savva commented on gene: NLGN4X
Autism v0.188 NLGN4X Elena Savva Classified gene: NLGN4X as Green List (high evidence)
Autism v0.188 NLGN4X Elena Savva Gene: nlgn4x has been classified as Green List (High Evidence).
Mendeliome v1.728 TAB2 Achchuthan Shanmugasundram reviewed gene: TAB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35971781; Phenotypes: intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genomic newborn screening: BabyScreen+ v0.1978 HSD11B2 Zornitza Stark Marked gene: HSD11B2 as ready
Genomic newborn screening: BabyScreen+ v0.1978 HSD11B2 Zornitza Stark Gene: hsd11b2 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1978 HSD11B2 Zornitza Stark Classified gene: HSD11B2 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.1978 HSD11B2 Zornitza Stark Gene: hsd11b2 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1977 HSD11B2 Zornitza Stark gene: HSD11B2 was added
gene: HSD11B2 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: HSD11B2.
Mode of inheritance for gene: HSD11B2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: HSD11B2 were set to Apparent mineralocorticoid excess, MIM# 218030; MONDO:0009025
Review for gene: HSD11B2 was set to GREEN
Added comment: Apparent mineralocorticoid excess (AME) is an autosomal recessive form of low-renin hypertension associated with low aldosterone, metabolic alkalosis, hypernatremia, and hypokalemia. The disorder is due to a congenital defect in 11-beta-hydroxysteroid dehydrogenase type II (HSD11B2) activity, resulting in decreased conversion of biologically active cortisol to inactive cortisone; this defect allows cortisol to act as a ligand for the mineralocorticoid receptor, resulting in sodium retention and volume expansion. There is a favorable therapeutic response to spironolactone. More than 10 unrelated families reported.

Onset is usually in infancy or early childhood.

Non-genetic confirmatory testing: aldosterone, renin, potassium levels
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1976 HOGA1 Zornitza Stark Marked gene: HOGA1 as ready
Genomic newborn screening: BabyScreen+ v0.1976 HOGA1 Zornitza Stark Gene: hoga1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1976 HOGA1 Zornitza Stark Classified gene: HOGA1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.1976 HOGA1 Zornitza Stark Gene: hoga1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1975 HOGA1 Zornitza Stark gene: HOGA1 was added
gene: HOGA1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, metabolic tags were added to gene: HOGA1.
Mode of inheritance for gene: HOGA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HOGA1 were set to 20797690; 21896830; 22391140
Phenotypes for gene: HOGA1 were set to Hyperoxaluria, primary, type III MIM#613616
Review for gene: HOGA1 was set to GREEN
Added comment: Well-established association with primary hyperoxaluria type III. c.700+5G>T is a recurrent pathogenic variant in European populations (possibly founder) and has high frequency in gnomad (0.2-0.3%).

Onset in infancy, progressive multi-system disorder.

Treatment: pyridoxine, drinking large volumes, alkalinzation of urine, pyrophosphate-containing solutions, liver-kidney transplant

Non-genetic confirmatory testing: urinary oxalate
Sources: Expert list
Neurodegeneration with brain iron accumulation v0.15 GTPBP2 Shekeeb Mohammad gene: GTPBP2 was added
gene: GTPBP2 was added to Neuroferritinopathies. Sources: Literature
Mode of inheritance for gene: GTPBP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTPBP2 were set to 26675814; 29449720
Phenotypes for gene: GTPBP2 were set to dystonia; ataxia; cognitive dysfunction; motor neuropathy; retinal abnormalities; sparse thin and brittle hair
Review for gene: GTPBP2 was set to GREEN
gene: GTPBP2 was marked as current diagnostic
Added comment: Sources: Literature
Neurodegeneration with brain iron accumulation v0.15 BCAS3 Shekeeb Mohammad gene: BCAS3 was added
gene: BCAS3 was added to Neuroferritinopathies. Sources: Expert Review,Literature
Mode of inheritance for gene: BCAS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCAS3 were set to DOI:10.1002/mds.28915 Corpus ID: 245670502
Phenotypes for gene: BCAS3 were set to spasticity; intellectual disability; global developmental delay; microcephaly; short stature
Penetrance for gene: BCAS3 were set to unknown
Review for gene: BCAS3 was set to GREEN
gene: BCAS3 was marked as current diagnostic
Added comment: Sources: Expert Review, Literature
Neurodegeneration with brain iron accumulation v0.15 AFG3L2 Shekeeb Mohammad gene: AFG3L2 was added
gene: AFG3L2 was added to Neuroferritinopathies. Sources: Literature
Mode of inheritance for gene: AFG3L2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: AFG3L2 were set to 32237276
Phenotypes for gene: AFG3L2 were set to ataxia; visual impairment; neuroregression
Review for gene: AFG3L2 was set to GREEN
gene: AFG3L2 was marked as current diagnostic
Added comment: Sources: Literature
Neurodegeneration with brain iron accumulation v0.15 SCP2 Shekeeb Mohammad edited their review of gene: SCP2: Changed rating: AMBER
Neurodegeneration with brain iron accumulation v0.15 SCP2 Shekeeb Mohammad reviewed gene: SCP2: Rating: RED; Mode of pathogenicity: None; Publications: 35996156; Phenotypes: progressive bulbar dysfunction, dementia, azoospermia, cardiac dysrhythmia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Genomic newborn screening: BabyScreen+ v0.1974 UMPS Lilian Downie changed review comment from: megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001).

Treat uridine
Very rare only 20 cases but treatable.
Sources: Expert list; to: megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001).

Better check with John who wrote the paper!! PMID: 25030255

Treat uridine
Very rare only 20 cases but treatable.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1974 UMPS Lilian Downie gene: UMPS was added
gene: UMPS was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: UMPS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UMPS were set to PMID: 9042911, PMID: 28205048, PMID: 25757096, PMID: 33489760
Phenotypes for gene: UMPS were set to Orotic aciduria MIM#258900
Review for gene: UMPS was set to GREEN
Added comment: megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001).

Treat uridine
Very rare only 20 cases but treatable.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1974 UNG Lilian Downie gene: UNG was added
gene: UNG was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: UNG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNG were set to PubMed: 12958596, PMID: 15967827, PMID: 19202054, PMID: 16860315
Phenotypes for gene: UNG were set to Immunodeficiency with hyper IgM, type 5 MIM#608106
Review for gene: UNG was set to RED
Added comment: normal or increased serum IgM concentrations associated with low or absent serum IgG, IgA, and IgE concentrations.
susceptibility to bacterial infections, lymphoid hyperplasia
only 3 patients reported in a single paper ?
Rx immunoglobulin replacement according to Rx genes but I can't find actual papers - i don't think there is enough evidence regarding age of onset or treatability.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1974 HELLS Zornitza Stark Marked gene: HELLS as ready
Genomic newborn screening: BabyScreen+ v0.1974 HELLS Zornitza Stark Gene: hells has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1974 HELLS Zornitza Stark Classified gene: HELLS as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.1974 HELLS Zornitza Stark Gene: hells has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1973 HELLS Zornitza Stark Tag treatable tag was added to gene: HELLS.
Tag immunological tag was added to gene: HELLS.
Genomic newborn screening: BabyScreen+ v0.1973 HELLS Zornitza Stark gene: HELLS was added
gene: HELLS was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: HELLS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: HELLS were set to Immunodeficiency-centromeric instability-facial anomalies syndrome 4, MIM# 616911
Review for gene: HELLS was set to GREEN
Added comment: Congenital onset.

Immunodeficiency-centromeric instability-facial anomalies syndrome-4 is characterized by recurrent infections in childhood and variable dysmorphic facial features. Laboratory studies show hypomethylation of certain chromosomal regions. Additional features, including delayed development, are variable. At least 4 unrelated families reported.

Treatment: bone marrow transplant.
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1972 USP18 Zornitza Stark Marked gene: USP18 as ready
Genomic newborn screening: BabyScreen+ v0.1972 USP18 Zornitza Stark Gene: usp18 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.1972 USP18 Zornitza Stark Classified gene: USP18 as Amber List (moderate evidence)
Genomic newborn screening: BabyScreen+ v0.1972 USP18 Zornitza Stark Gene: usp18 has been classified as Amber List (Moderate Evidence).
Genomic newborn screening: BabyScreen+ v0.1971 USP18 Zornitza Stark reviewed gene: USP18: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Pseudo-TORCH syndrome 2 MIM#617397; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.1971 VKORC1 Zornitza Stark Marked gene: VKORC1 as ready
Genomic newborn screening: BabyScreen+ v0.1971 VKORC1 Zornitza Stark Gene: vkorc1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1971 VKORC1 Zornitza Stark Mode of inheritance for gene: VKORC1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.1970 VKORC1 Zornitza Stark Classified gene: VKORC1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.1970 VKORC1 Zornitza Stark Gene: vkorc1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1969 VKORC1 Zornitza Stark Tag treatable tag was added to gene: VKORC1.
Tag haematological tag was added to gene: VKORC1.
Genomic newborn screening: BabyScreen+ v0.1969 VKORC1 Zornitza Stark reviewed gene: VKORC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Vitamin K-dependent clotting factors, combined deficiency of, 2 MIM#607473; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genomic newborn screening: BabyScreen+ v0.1969 WDR1 Zornitza Stark Marked gene: WDR1 as ready
Genomic newborn screening: BabyScreen+ v0.1969 WDR1 Zornitza Stark Gene: wdr1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1969 WDR1 Zornitza Stark Classified gene: WDR1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.1969 WDR1 Zornitza Stark Gene: wdr1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1968 WDR1 Zornitza Stark Tag treatable tag was added to gene: WDR1.
Tag immunological tag was added to gene: WDR1.
Tag haematological tag was added to gene: WDR1.
Mendeliome v1.728 ACTA1 Zornitza Stark Phenotypes for gene: ACTA1 were changed from Myopathy, actin, congenital, with cores, MIM#161800; Myopathy, actin, congenital, with excess of thin myofilaments, MIM#161800; Myopathy, congenital, with fiber-type disproportion 1, MIM#255310; Nemaline myopathy 3, MIM#161800; ?Myopathy, scapulohumeroperoneal to Congenital myopathy 2C, severe infantile, autosomal dominant, MIM# 620278; Myopathy, actin, congenital, with cores, MIM#161800; Myopathy, actin, congenital, with excess of thin myofilaments, MIM#161800; Myopathy, congenital, with fiber-type disproportion 1, MIM#255310; Nemaline myopathy 3, MIM#161800; ?Myopathy, scapulohumeroperoneal
Mendeliome v1.727 ACTA1 Zornitza Stark reviewed gene: ACTA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital myopathy 2C, severe infantile, autosomal dominant, MIM# 620278; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genomic newborn screening: BabyScreen+ v0.1968 GPIHBP1 Zornitza Stark Marked gene: GPIHBP1 as ready
Genomic newborn screening: BabyScreen+ v0.1968 GPIHBP1 Zornitza Stark Gene: gpihbp1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1968 GPIHBP1 Zornitza Stark Classified gene: GPIHBP1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.1968 GPIHBP1 Zornitza Stark Gene: gpihbp1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1967 GPIHBP1 Zornitza Stark Tag treatable tag was added to gene: GPIHBP1.
Tag metabolic tag was added to gene: GPIHBP1.
Genomic newborn screening: BabyScreen+ v0.1967 GPIHBP1 Zornitza Stark gene: GPIHBP1 was added
gene: GPIHBP1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GPIHBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPIHBP1 were set to 31390500
Phenotypes for gene: GPIHBP1 were set to Hyperlipoproteinemia, type 1D MIM#615947; familial chylomicronemia syndrome
Review for gene: GPIHBP1 was set to GREEN
Added comment: Well-established gene-disease association.

Usually presents in childhood with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly.

Approximately 25% of affected children develop symptoms before age one year and the majority develop symptoms before age ten years; however, some individuals present for the first time during pregnancy.

Treatment: volanesorsen, dietary fat restriction

Non-genetic confirmatory testing: triglyceride level
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1966 GHRHR Zornitza Stark Marked gene: GHRHR as ready
Genomic newborn screening: BabyScreen+ v0.1966 GHRHR Zornitza Stark Gene: ghrhr has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1966 GHRHR Zornitza Stark Classified gene: GHRHR as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.1966 GHRHR Zornitza Stark Gene: ghrhr has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1965 GHRHR Zornitza Stark Tag treatable tag was added to gene: GHRHR.
Tag endocrine tag was added to gene: GHRHR.
Genomic newborn screening: BabyScreen+ v0.1965 GHRHR Zornitza Stark gene: GHRHR was added
gene: GHRHR was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GHRHR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GHRHR were set to 8528260; 10084571; 11232012
Phenotypes for gene: GHRHR were set to Growth hormone deficiency, isolated, type IV, MIM# 618157
Review for gene: GHRHR was set to GREEN
Added comment: IGHD type IV is characterized by early and severe growth failure (height SDS up to -7.4), a blunted growth hormone (GH) response to different provocation tests and low insulin-like growth factor-I and IGF-binding protein-3 concentrations, and a good response to growth hormone treatment. At least three unrelated families reported.

Non-genetic confirmatory testing: growth hormone stimulation test
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1964 GHR Zornitza Stark Marked gene: GHR as ready
Genomic newborn screening: BabyScreen+ v0.1964 GHR Zornitza Stark Gene: ghr has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1964 GHR Zornitza Stark Classified gene: GHR as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.1964 GHR Zornitza Stark Gene: ghr has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1963 GHR Zornitza Stark Tag treatable tag was added to gene: GHR.
Tag endocrine tag was added to gene: GHR.
Genomic newborn screening: BabyScreen+ v0.1963 GHR Zornitza Stark gene: GHR was added
gene: GHR was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GHR was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: GHR were set to Growth hormone insensitivity, partial, MIM# 604271; Laron dwarfism, MIM# 262500
Review for gene: GHR was set to GREEN
Added comment: Well established gene-disease association.

Congenital onset.

Treatment: growth hormone.

Non-genetic confirmatory testing: growth hormone stimulation test
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1962 GH1 Zornitza Stark Marked gene: GH1 as ready
Genomic newborn screening: BabyScreen+ v0.1962 GH1 Zornitza Stark Gene: gh1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1962 GH1 Zornitza Stark Classified gene: GH1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.1962 GH1 Zornitza Stark Gene: gh1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1961 GH1 Zornitza Stark Tag treatable tag was added to gene: GH1.
Tag endocrine tag was added to gene: GH1.
Genomic newborn screening: BabyScreen+ v0.1961 GH1 Zornitza Stark gene: GH1 was added
gene: GH1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GH1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: GH1 were set to Growth hormone deficiency, isolated, type IA, MIM# 262400; Growth hormone deficiency, isolated, type II, MIM# 173100; Kowarski syndrome, MIM# 262650
Review for gene: GH1 was set to GREEN
Added comment: Well established gene-disease association. Congenital onset.

Treatment: growth hormone.

Non-genetic confirmatory test: growth hormone stimulation test
Sources: Expert list
Genomic newborn screening: BabyScreen+ v0.1960 GFI1 Zornitza Stark Marked gene: GFI1 as ready
Genomic newborn screening: BabyScreen+ v0.1960 GFI1 Zornitza Stark Gene: gfi1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1960 GFI1 Zornitza Stark Classified gene: GFI1 as Green List (high evidence)
Genomic newborn screening: BabyScreen+ v0.1960 GFI1 Zornitza Stark Gene: gfi1 has been classified as Green List (High Evidence).
Genomic newborn screening: BabyScreen+ v0.1959 GFI1 Zornitza Stark gene: GFI1 was added
gene: GFI1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GFI1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GFI1 were set to 12778173; 20560965; 11810106; 22684987
Phenotypes for gene: GFI1 were set to Neutropenia, severe congenital 2, autosomal dominant, MIM# 613107
Review for gene: GFI1 was set to GREEN
Added comment: At least three unrelated families reported, and supportive functional data.

Severe congenital immunodeficiency.

Treatment: granulocyte colony-stimulating factor (G-CSF), Bone marrow transplant

Non-genetic confirmatory testing: FBE.
Sources: Expert list
Neurodegeneration with brain iron accumulation v0.15 Zornitza Stark Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease
Neurodegeneration with brain iron accumulation v0.14 SCP2 Zornitza Stark Phenotypes for gene: SCP2 were changed from Neurodegeneration with brain iron accumulation; ataxia to Leukoencephalopathy with dystonia and motor neuropathy, MIM#613724; Neurodegeneration with brain iron accumulation; ataxia
Neurodegeneration with brain iron accumulation v0.13 SCP2 Zornitza Stark Publications for gene: SCP2 were set to 26497993
Neurodegeneration with brain iron accumulation v0.12 SCP2 Zornitza Stark Classified gene: SCP2 as Amber List (moderate evidence)
Neurodegeneration with brain iron accumulation v0.12 SCP2 Zornitza Stark Gene: scp2 has been classified as Amber List (Moderate Evidence).
Neurodegeneration with brain iron accumulation v0.11 SCP2 Zornitza Stark reviewed gene: SCP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 26497993; Phenotypes: Leukoencephalopathy with dystonia and motor neuropathy, MIM#613724; Mode of inheritance: None
Mendeliome v1.727 REPS1 Zornitza Stark Marked gene: REPS1 as ready
Mendeliome v1.727 REPS1 Zornitza Stark Gene: reps1 has been classified as Red List (Low Evidence).
Mendeliome v1.727 REPS1 Zornitza Stark gene: REPS1 was added
gene: REPS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: REPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: REPS1 were set to 29395073
Phenotypes for gene: REPS1 were set to Neurodegeneration with brain iron accumulation 7 , MIM# 617916
Review for gene: REPS1 was set to RED
Added comment: Two siblings reported with compound het missense variants in this gene and a neurodegenerative course in childhood.
Sources: Literature
Neurodegeneration with brain iron accumulation v0.11 REPS1 Zornitza Stark Marked gene: REPS1 as ready
Neurodegeneration with brain iron accumulation v0.11 REPS1 Zornitza Stark Gene: reps1 has been classified as Red List (Low Evidence).
Neurodegeneration with brain iron accumulation v0.11 REPS1 Zornitza Stark gene: REPS1 was added
gene: REPS1 was added to Neuroferritinopathies. Sources: Literature
Mode of inheritance for gene: REPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: REPS1 were set to 29395073
Phenotypes for gene: REPS1 were set to Neurodegeneration with brain iron accumulation 7 , MIM# 617916
Review for gene: REPS1 was set to RED
Added comment: Two siblings reported with compound het missense variants in this gene and a neurodegenerative course in childhood.
Sources: Literature
Hydrops fetalis v0.298 GLA Zornitza Stark Marked gene: GLA as ready
Hydrops fetalis v0.298 GLA Zornitza Stark Gene: gla has been classified as Red List (Low Evidence).
Hydrops fetalis v0.298 GLA Zornitza Stark Phenotypes for gene: GLA were changed from to Fabry disease, MIM# 301500
Hydrops fetalis v0.297 GLA Zornitza Stark Mode of inheritance for gene: GLA was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Hydrops fetalis v0.296 GLA Zornitza Stark Classified gene: GLA as Red List (low evidence)
Hydrops fetalis v0.296 GLA Zornitza Stark Gene: gla has been classified as Red List (Low Evidence).
Hydrops fetalis v0.295 GLA Zornitza Stark reviewed gene: GLA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Fabry disease, MIM# 301500; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.726 MCF2L Zornitza Stark Mode of inheritance for gene: MCF2L was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.276 MCF2L Zornitza Stark Marked gene: MCF2L as ready
Congenital Heart Defect v0.276 MCF2L Zornitza Stark Gene: mcf2l has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.276 MCF2L Zornitza Stark Mode of inheritance for gene: MCF2L was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.275 MCF2L Zornitza Stark Classified gene: MCF2L as Red List (low evidence)
Congenital Heart Defect v0.275 MCF2L Zornitza Stark Gene: mcf2l has been classified as Red List (Low Evidence).
Mendeliome v1.725 FTH1 Zornitza Stark Phenotypes for gene: FTH1 were changed from Hemochromatosis, type 5, MIM# 615517 to Hemochromatosis, type 5, MIM# 615517; Neuroferritinopathy (MONDO:0011638)
Mendeliome v1.724 FTH1 Zornitza Stark Publications for gene: FTH1 were set to 11389486
Mendeliome v1.723 FTH1 Zornitza Stark Classified gene: FTH1 as Amber List (moderate evidence)