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| Prepair 1000+ v1.1868 | POLR1D |
Andrew Coventry gene: POLR1D was added gene: POLR1D was added to Prepair 1000+. Sources: Literature Mode of inheritance for gene: POLR1D was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: POLR1D were set to 21131976; 24603435; 27448281; 25790162 Phenotypes for gene: POLR1D were set to Treacher Collins syndrome 2 MIM#613717 Review for gene: POLR1D was set to AMBER Added comment: Treacher Collins syndrome is a disorder of craniofacial development characterised by a combination of bilateral downward slanting of the palpebral fissures, colobomas of the lower eyelids with a paucity of eyelashes medial to the defect, hypoplasia of the facial bones, cleft palate, malformation of the external ears, atresia of the external auditory canals, and bilateral conductive hearing loss. Currently, only one study reporting AR TCS, 1 pathogenic variant in 4 affected individuals, across 2 unrelated consanguineous families. PMID: 24603435. Adding gene, requiring further evidence in humans for consideration for inclusion in screening of AR TCS. Sources: Literature |
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| Prepair 1000+ v1.1868 | COL11A2 |
Melanie Marty changed review comment from: The gene-disease association with otospondylomegaepiphyseal dysplasia is well established (DEFINITIVE) by ClinGen, and deafness is part of the phenotype, both mono-allelic and bi-allelic variants are reported. Otospondylomegaepiphyseal dysplasia AD (OSMED, MIM#184840) is also known as non-ocular Stickler syndrome or Type III Stickler syndrome. There are also a number of reports of mono-allelic and bi-allelic variants associated with isolated deafness (PMIDs: 10581026;25633957;16033917), and rated as MODERATE by ClinGen for AR and DEFINITIVE for AD. Bi-allelic variants are associated with severe pre lingual deafness. Fibrochondrogenesis 2 a severe skeletal dysplasia is associated with AD and AR.; to: The gene-disease association with otospondylomegaepiphyseal dysplasia is well established (DEFINITIVE) by ClinGen, and deafness is part of the phenotype, both mono-allelic and bi-allelic variants are reported. Otospondylomegaepiphyseal dysplasia AD (OSMED, MIM#184840) is also known as non-ocular Stickler syndrome or Type III Stickler syndrome. There are also a number of reports of mono-allelic and bi-allelic variants associated with isolated deafness (PMIDs: 10581026;25633957;16033917), and rated as MODERATE by ClinGen for AR and DEFINITIVE for AD. Bi-allelic variants are associated with severe pre lingual deafness. Fibrochondrogenesis 2 a severe skeletal dysplasia is associated with AD and AR. Only including the AR phenotypes for this screening panel. |
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| Prepair 1000+ v1.1811 | MTPAP |
Andrew Coventry gene: MTPAP was added gene: MTPAP was added to Prepair 1000+. Sources: Literature Mode of inheritance for gene: MTPAP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MTPAP were set to 20970105; 33340416; 32376682; 15769737; 31779033; 35235001; 27391121 Phenotypes for gene: MTPAP were set to Mitochondrial disease MONDO:0044970 Review for gene: MTPAP was set to GREEN Added comment: Definitive disease-gene classification by ClinGen - "Identified in five individuals from four publications (PMIDs: 20970105, 31779033, 35235001, 27391121). Supported by a biochemical function (mitochondrial translation) shared with other genes associated with primary mitochondrial disease, early embryonic lethality and failure of developmental progression in a knockout mouse model, and disrupted expression of mitochondrial proteins and mitochondrial dysfunction following gene knockdown in HeLa cells (PMIDs: 33340416, 32376682, 15769737)." Note that 6 individuals with spastic ataxia all had same founder variant and were traced as distantly related (Amish community - c.1432A>G (p.Asn478Asp). Further additional families reported with a much more severe phenotype of lethal encephalopathy. Phenotypes previous reported to be associated with MTPAP are likely to represent a continuum of severity associated with a mitochondrial disorder. Clingen "While various names have been given to the constellation of features seen in those with MTPAP-related disease, including autosomal recessive spastic ataxia 4 (SPAX4) (MIM 613672) in additional to other mitochondrial disorders, pathogenic variants in this gene cause a primary mitochondrial disease.... lumped into one disease entity..." Sources: Literature |
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| Prepair 1000+ v1.1566 | SCNN1A |
Lauren Thomas changed review comment from: Well established gene-disease association. Childhood onset, potentially lethal salt wasting condition characterised by excess loss of salt in the urine and high concentrations of sodium in sweat, stool, and saliva. Treatment for this condition involves aggressive salt replacement and control of hyperkalemia. HGNC approved symbol/name: SCNN1A Is the phenotype(s) severe and onset <18yo? Yes Treatments available: Yes, supplementary sodium, but not mineralocorticoids Known technical challenges? No Gene reported in 3 independent families: Yes; to: Well established gene-disease association. Childhood onset, potentially lethal salt wasting condition characterised by excess loss of salt in the urine and high concentrations of sodium in sweat, stool, and saliva. Treatment for this condition involves aggressive salt replacement and control of hyperkalemia. HGNC approved symbol/name: SCNN1A Is the phenotype(s) severe and onset <18yo? Yes Treatments available: Yes, supplementary sodium, but not mineralocorticoids Known technical challenges? No Gene reported in 3 independent families: Yes NOTE: Limited evidence for association between mono-allelic variants and disease (bronchiectasis with or without elevated sweat chloride 2, MIM# 613021; Liddle syndrome 3, MIM# 618126) |
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| Prepair 1000+ v1.1566 | PLEC |
Lauren Thomas changed review comment from: PLEC was first reported in relation to autosomal recessive limb-girdle muscular dystrophy which is typically characterized by early childhood onset of proximal muscle weakness and atrophy, notably without skin involvement. PLEC has also been noted to be associated with epidermolysis bullosa 5A-5D. ClinGen: The molecular mechanisms underlying EBS with muscular dystrophy (EBS5B) has primarily been nonsense, out-of-frame insertions or deletions within exon 31 and 32, leading to premature protein termination. The mechanism underlying autosomal recessive limb-girdle muscular dystrophy appears to be recessive truncating variants in exon 1f. HGNC approved symbol/name: PLEC Is the phenotype(s) severe and onset <18yo? Yes Known technical challenges? For AR limb-girdle muscular dystrophy, a 9-bp deletion has been reported in seven probands in two publications (PMIDs: 21109228, 32605089) Gene reported in 3 independent families: Yes NOTE: AD phenotype - Epidermolysis bullosa simplex 5A, Ogna type MIM# 131950; to: PLEC was first reported in relation to autosomal recessive limb-girdle muscular dystrophy which is typically characterized by early childhood onset of proximal muscle weakness and atrophy, notably without skin involvement. PLEC has also been noted to be associated with epidermolysis bullosa 5A-5D. ClinGen: The molecular mechanisms underlying EBS with muscular dystrophy (EBS5B) has primarily been nonsense, out-of-frame insertions or deletions within exon 31 and 32, leading to premature protein termination. The mechanism underlying autosomal recessive limb-girdle muscular dystrophy appears to be recessive truncating variants in exon 1f. HGNC approved symbol/name: PLEC Is the phenotype(s) severe and onset <18yo? Yes Known technical challenges? For AR limb-girdle muscular dystrophy, a 9-bp deletion has been reported in seven probands in two publications (PMIDs: 21109228, 32605089) Gene reported in 3 independent families: Yes NOTE: AD phenotype - Epidermolysis bullosa simplex 5A, Ogna type MIM# 131950 |
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| Prepair 1000+ v1.1566 | PLEC |
Lauren Thomas changed review comment from: PLEC was first reported in relation to autosomal recessive limb-girdle muscular dystrophy which is typically characterized by early childhood onset of proximal muscle weakness and atrophy, notably without skin involvement. PLEC has also been noted to be associated with epidermolysis bullosa 5A-5D. ClinGen: The molecular mechanisms underlying EBS with muscular dystrophy (EBS5B) has primarily been nonsense, out-of-frame insertions or deletions within exon 31 and 32, leading to premature protein termination. The mechanism underlying autosomal recessive limb-girdle muscular dystrophy appears to be recessive truncating variants in exon 1f. HGNC approved symbol/name: PLEC Is the phenotype(s) severe and onset <18yo? Yes Known technical challenges? For AR limb-girdle muscular dystrophy, a 9-bp deletion has been reported in seven probands in two publications (PMIDs: 21109228, 32605089) Gene reported in 3 independent families: Yes NOTE: AD phenotype - Epidermolysis bullosa simplex 5A, Ogna type MIM# 131950; to: PLEC was first reported in relation to autosomal recessive limb-girdle muscular dystrophy which is typically characterized by early childhood onset of proximal muscle weakness and atrophy, notably without skin involvement. PLEC has also been noted to be associated with epidermolysis bullosa 5A-5D. ClinGen: The molecular mechanisms underlying EBS with muscular dystrophy (EBS5B) has primarily been nonsense, out-of-frame insertions or deletions within exon 31 and 32, leading to premature protein termination. The mechanism underlying autosomal recessive limb-girdle muscular dystrophy appears to be recessive truncating variants in exon 1f. HGNC approved symbol/name: PLEC Is the phenotype(s) severe and onset <18yo? Yes Known technical challenges? For AR limb-girdle muscular dystrophy, a 9-bp deletion has been reported in seven probands in two publications (PMIDs: 21109228, 32605089) Gene reported in 3 independent families: Yes NOTE: AD phenotype - Epidermolysis bullosa simplex 5A, Ogna type MIM# 131950 |
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| Prepair 1000+ v1.761 | TPRKB |
Lucy Spencer changed review comment from: Gene is red on Mackenzie's mission panel but the review itself is green and says "Three unrelated families reported with renal-neurologic disease characterized by early-onset nephrotic syndrome associated with microcephaly." this is refering to 3 families all with homozygous missense, p.Lys65Met, p.Tyr149Cys, and p.Leu136Pro. There has been at least one more individual reported PMID: 38628357: a three-year-old male with developmental delay, regression, microcephaly, distinctive facial features, skeletal abnormalities, and epilepsy. He also had relapsing nephrotic proteinuria exacerbated by upper respiratory tract infections and progressive renal function decline. He was compound heterozygous for p.(Ser76IlefsTer3) and c.247C>T, p.(Leu83Phe). Severe early-onset and reported in at least 4 individuals (also green on mendeliome), upgrading to green here.; to: Gene is red on Mackenzie's mission panel but the review itself is green and says "Three unrelated families reported with renal-neurologic disease characterized by early-onset nephrotic syndrome associated with microcephaly." this is refering to 3 families all with homozygous missense, p.Lys65Met, p.Tyr149Cys, and p.Leu136Pro (PMIDs: 28805828, 30053862). There has been at least one more individual reported PMID: 38628357: a three-year-old male with developmental delay, regression, microcephaly, distinctive facial features, skeletal abnormalities, and epilepsy. He also had relapsing nephrotic proteinuria exacerbated by upper respiratory tract infections and progressive renal function decline. He was compound heterozygous for p.(Ser76IlefsTer3) and c.247C>T, p.(Leu83Phe). Severe early-onset and reported in at least 4 individuals (also green on mendeliome), upgrading to green here. |
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| Prepair 1000+ v1.648 | IDS | Zornitza Stark Marked gene: IDS as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.648 | IDS | Zornitza Stark Gene: ids has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.648 | IDS | Zornitza Stark Phenotypes for gene: IDS were changed from Mucopolysaccharidosis II, 309900 (3) to Mucopolysaccharidosis II, MIM# 309900; Hunter syndrome, MONDO:0010674 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.647 | IDS | Zornitza Stark Publications for gene: IDS were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.633 | IDS | Ee Ming Wong reviewed gene: IDS: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 20301451; Phenotypes: Mucopolysaccharidosis II, MIM# 309900, Hunter syndrome, MONDO:0010674; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v1.384 | TSPYL1 |
Lilian Downie Added comment: Comment when marking as ready: Originally reported only in Amish community, founder variant subsequently reported in 3 unrelated families, non amish - GREEN AT UPGRADE 2 cohort studies looking for variants in this gene in SIDS cohorts but it's very rare and presents with more of a progressive neurological phenotype in the non Amish families |
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| Prepair 1000+ v1.187 | COLQ |
Marta Cifuentes Ochoa changed review comment from: Patients with congenital myasthenic syndromes present clinically with onset of variable muscle weakness between infancy and adulthood. Well established gene-disease association, more than 10 families reported. HGNC approved symbol/name: COLQ Is the phenotype(s) severe and onset <18yo ? Y Known technical challenges?N; to: Patients with congenital myasthenic syndromes present clinically with onset of variable muscle weakness between infancy and adulthood. Presentations: -neonatal: respiratory insufficiency, multiple joint contractures (often described as arthrogryposis multiplex congenita) resulting from a lack of fetal movement in utero. Feeding difficulties, poor suck and cry, choking spells, eyelid ptosis, and facial, bulbar, and generalized weakness.In some individuals, long face, narrow jaw, and a high-arched palate have been reported -childhood: delayed motr milestones, fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness. Ptosis may involve one or both eyelids. Facial and bulbar weakness with nasal speech and difficulties in coughing and swallowing may be present.Spinal deformity or muscle atrophy may occur -limb-girdle Well established gene-disease association, more than 10 families reported. HGNC approved symbol/name: COLQ Is the phenotype(s) severe and onset <18yo ? Y Known technical challenges?N |
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| Prepair 1000+ v1.143 | CSMD1 |
Krithika Murali gene: CSMD1 was added gene: CSMD1 was added to Prepair 1000+. Sources: Literature Mode of inheritance for gene: CSMD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CSMD1 were set to PMID:38816421 Phenotypes for gene: CSMD1 were set to complex neurodevelopmental disorder MONDO:0100038 Review for gene: CSMD1 was set to GREEN Added comment: PMID 38816421 Werren et al 2024 report 8 individuals from 6 families with biallelic missense CSMD1 variants identified through exome sequencing and subsequent gene-sharing efforts. Shared phenotypic features included: GDD, ID, microcephaly and polymicrogyria. Other features included dysmorphism, IUGR, hypotonia, arthrogryposis, seizures, opthalmological anomalies and other brain white matter anomalies Heterozygous parents were unaffected. Loss of function is the postulated mechanism based on experimental data involving early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells. ClinGen haploinsufficiency score of 1, however, this curation was last reviewed in 2018. This gene is within the scope of review for the ClinGen Autism and ID GCEP. Sources: Literature |
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| Prepair 1000+ v1.65 | CLCNKB |
Lucy Spencer changed review comment from: Is the phenotype(s) severe and onset <18yo? YES. CLCNKB mutations cause Bartter syndrome type 3 also called classic Bartter syndrome with renal salt wasting, hypokalemia, metabolic alkalosis, polyuria, polydipsia, and failure to thrive. It typically manifests in early childhood but late childhood or adulthood onset cases have been reported. Classic Bartter syndrome has a heterogeneous presentation from severe to very mild (PMIDs: 25810436, 24965226) There is also a digenic inheritance known for this gene with variants in CLCNKA causing Bartter syndrome type 4b.; to: Is the phenotype(s) severe and onset <18yo? YES. CLCNKB mutations cause Bartter syndrome type 3 also called classic Bartter syndrome with renal salt wasting, hypokalemia, metabolic alkalosis, polyuria, polydipsia, and failure to thrive. It typically manifests in early childhood but late childhood or adulthood onset cases have been reported. Classic Bartter syndrome has a heterogeneous presentation from severe to very mild (PMIDs: 25810436, 24965226) There is also a digenic inheritance known for this gene with variants in CLCNKA causing Bartter syndrome type 4b. |
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| Prepair 1000+ v1.3 | IDS | Seb Lunke Added phenotypes Mucopolysaccharidosis II, 309900 (3) for gene: IDS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prepair 1000+ v0.0 | IDS |
Zornitza Stark gene: IDS was added gene: IDS was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green Mode of inheritance for gene: IDS was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: IDS were set to Mucopolysaccharidosis II, 309900 (3) |
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