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Mendeliome v2.227 PREP chirag patel Classified gene: PREP as Amber List (moderate evidence)
Mendeliome v2.227 PREP chirag patel Gene: prep has been classified as Amber List (Moderate Evidence).
Mendeliome v2.226 PREP chirag patel Classified gene: PREP as Amber List (moderate evidence)
Mendeliome v2.226 PREP chirag patel Gene: prep has been classified as Amber List (Moderate Evidence).
Mendeliome v2.225 PREP chirag patel Marked gene: PREP as ready
Mendeliome v2.225 PREP chirag patel Gene: prep has been classified as Red List (Low Evidence).
Mendeliome v2.225 PREP chirag patel gene: PREP was added
gene: PREP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PREP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PREP were set to 42362369
Phenotypes for gene: PREP were set to Neurodevelopmental disorder (MONDO:0700092), PREP-related
Review for gene: PREP was set to AMBER
Added comment: PMID 42362369 reports 3 individuals from 2 unrelated families with homozygous loss-of-function PREP variants (c.1570_1573dup and c.1839-2A>G). Individuals presented with a syndromic neurodevelopmental disorder characterised by intellectual disability, epilepsy, hypotonia, dysmorphic features and behavioural abnormalities. Segregation analysis confirmed autosomal recessive inheritance. RNA‑seq and qRT‑PCR confirmed aberrant transcripts. Immunoblotting of patient‑derived lymphoblastoid cells showed complete loss of PREP protein for both variants, but no rescue experiments were performed. The precise physiological function of PREP remains largely elusive but other papers report Prep- KO mice show disturbed cone growth and synaptic function.
Sources: Literature
Mendeliome v2.18 PSMB8 Zornitza Stark edited their review of gene: PSMB8: Added comment: Preprints describing mono-allelic association now published. PMID 42167218 describes five families with monoallelic missense PSMB8 variants and PMID 41253591 adds eight families with the recurrent heterozygous p.G209R variant, together totalling 13 families with dominant‑negative disruption of immunoproteasome assembly.; Changed publications: 21129723, 21881205, 21852578, 21953331, 42167218, 41253591; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.4882 PDS5B chirag patel Tag preprint was removed from gene: PDS5B.
Mendeliome v1.4880 PDS5A chirag patel Tag preprint was removed from gene: PDS5A.
Mendeliome v1.4577 PDS5A chirag patel Tag preprint tag was added to gene: PDS5A.
Mendeliome v1.4577 PDS5B chirag patel Tag preprint tag was added to gene: PDS5B.
Mendeliome v1.4542 XPOT Zornitza Stark gene: XPOT was added
gene: XPOT was added to Mendeliome. Sources: Literature
preprint tags were added to gene: XPOT.
Mode of inheritance for gene: XPOT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: XPOT were set to 10.64898/2026.01.28.26344748
Phenotypes for gene: XPOT were set to Syndromic disease, MONDO:0002254
Review for gene: XPOT was set to GREEN
Added comment: Preprint by Von Hardenberg et al 2026 reports 8 individuals from 5 unrelated families with biallelic loss‑of‑function XPOT variants presenting with childhood‑onset severe sensorineural hearing loss, recurrent infections/bronchiectasis, developmental delay and growth retardation. Functional studies show absent XPOT protein in patient fibroblasts, reduced TNF‑α translation, and xpot‑deficient zebrafish recapitulating the multisystem phenotype.

All reported variants are homozygous.
Sources: Literature
Mendeliome v1.4537 WAPL Zornitza Stark gene: WAPL was added
gene: WAPL was added to Mendeliome. Sources: Literature
preprint tags were added to gene: WAPL.
Mode of inheritance for gene: WAPL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WAPL were set to 10.64898/2026.02.23.26346364; 30158690
Phenotypes for gene: WAPL were set to complex neurodevelopmental disorder, MONDO:0100038
Review for gene: WAPL was set to GREEN
Added comment: PMID 30158690 reports a single de novo missense WAPL variant in a patient with mild CdLS‑like cohesinopathy, while a preprint (Boone et al 2026) describes 27 unrelated individuals with heterozygous loss‑of‑function or damaging missense WAPL variants presenting with a neurodevelopmental syndrome (developmental delay/intellectual disability, facial dysmorphism, congenital anomalies such as clubfoot). Combined, the two studies provide 28 unrelated families supporting WAPL haploinsufficiency as a cause of a complex neurodevelopmental disorder, with mouse and iPSC functional data corroborating pathogenicity.
Sources: Literature
Mendeliome v1.4258 CTNND2 Zornitza Stark edited their review of gene: CTNND2: Added comment: PMID 41502569 (preprint) reports phenotypic and molecular information for 57 individuals, 42 previously unpublished, with heterozygous CTNND2 variants. The 41 CTNND2 variants included 12 previously reported loss-of-function- and one missense variant, and 28 novel variants comprising 10 missense and 18 predicted loss-of-function changes. Eight of the novel variants occurred de novo, and 12 were inherited from a parent with a neurodevelopmental phenotype. The most common clinical features were developmental delay (90%), intellectual disability (74%), and behavioral abnormalities (79%). Functional studies revealed impaired early neurogenesis in one patient-derived line, characterized by aberrant neural rosette formation. Transcriptome analysis showed dysregulated WNT signaling, and partial rescue of these defects was achieved by modulating the WNT pathway, highlighting δ-catenin's role in early neural development.

Note several of the reported missense variants in this gene have high gnomAD counts so these should be interpreted with caution. Nevertheless, large number of individuals reported now with LoF variants and NDD phenotype.; Changed rating: GREEN; Changed publications: 25839933, 29127138, 25807484, 41502569; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, CTNND2-related
Mendeliome v1.4087 RNU4-2 Zornitza Stark edited their review of gene: RNU4-2: Added comment: PMID 39830270: Reports 36 individuals from 13 unrelated families with heterozygous dominant variants n.18_19insA and n.56T>C in RNU4-2 presenting with autosomal dominant retinitis pigmentosa (adRP). Night‑blindness and progressive peripheral vision loss start in late adolescence/early adulthood, with classic RP fundus changes, cystoid macular edema, and cataracts. Both inherited and de novo cases are observed. Immunoprecipitation assays demonstrate increased association of mutant U4 snRNA with di‑snRNP proteins SART3 and PRPF31, indicating a gain‑of‑function/dominant‑negative effect on snRNP biogenesis. PREPRINT; Changed publications: 38991538, 40297424, 39830270; Changed phenotypes: Neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language, MIM# 620851, Retinitis pigmentosa, MONDO:0019200, RNU4-2 related
Mendeliome v1.4061 RNU4-2 Zornitza Stark edited their review of gene: RNU4-2: Added comment: PMID 40297424: preprint reporting 16 individuals from 10 families with balletic variants and presenting with global developmental delay, intellectual disability, speech delay or absence, hypotonia, spasticity, microcephaly, ophthalmologic and visual impairment, seizures, and variable genital, skin, hair and limb anomalies; brain MRI shows distinctive white‑matter abnormalities and cerebellar atrophy.; Changed publications: 38991538, 40297424; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.3877 RNU6-1 Zornitza Stark gene: RNU6-1 was added
gene: RNU6-1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNU6-1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNU6-1 were set to 39830270
Phenotypes for gene: RNU6-1 were set to retinitis pigmentosa MONDO:0019200, RNU6-1-related
Review for gene: RNU6-1 was set to GREEN
Added comment: RNU6-1 encodes the U6 small nuclear RNA, a core spliceosomal component involved in pre-mRNA splicing. PMID 39830270 reports 99 individuals with autosomal dominant adolescent-onset progressive retinitis pigmentosa caused by heterozygous insertion variants (n.55_56insG and n.56_57insG). The disease follows a dominant inheritance pattern with de novo events confirmed in seven individuals, and functional assays demonstrate a dominant‑negative effect via increased binding of mutant U6 snRNA to SART3 and PRPF31.

Preprint.
Sources: Literature
Mendeliome v1.3867 NUBP2 Zornitza Stark gene: NUBP2 was added
gene: NUBP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NUBP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUBP2 were set to 39867373
Phenotypes for gene: NUBP2 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: NUBP2 was set to AMBER
Added comment: PMID 39867373 reports 2 individuals from 2 unrelated families with biallelic missense variants in NUBP2 presenting with congenital primary microcephaly, intrauterine growth restriction, severe joint contractures and facial dysmorphism. A forebrain‑specific conditional Nubp2 knockout mouse recapitulates the severe microcephaly, and rescue assays show patient alleles fail to restore growth, supporting a loss‑of‑function mechanism.

Preprint.
Sources: Literature
Mendeliome v1.3233 AP2S1 Zornitza Stark edited their review of gene: AP2S1: Added comment: Association with NDD: Several isolated cases with de novo missense variants in large NDD cohorts PMID: 31981491;33057194;35982160;35982159.

26 unrelated NDD in a preprint with 5 recurring de novo missenses p.Arg10Trp, p.Arg10Gln, p.Lys18Glu, p.Lys18Asn and p.Arg61His https://doi.org/10.1101/2024.07.22.24310683. 70% had epilepsy, 50% brain anomalies.; Changed publications: 23222959, 33729479, 33168530, 3204769, 31723423, 29479578, 31981491, 33057194, 35982160, 35982159; Changed phenotypes: Hypocalciuric hypercalcaemia, type III, MIM# 600740, MONDO:0010926, Neurodevelopmental disorder, MONDO:0700092, AP2S1-related
Mendeliome v1.2967 RNF2 Zornitza Stark edited their review of gene: RNF2: Added comment: PMID 40831499 is a preprint which identifies additional individuals with de novo variants. p.S82R is recurrent. Functional data to support gene-disease association.; Changed rating: GREEN; Changed publications: 40831499
Mendeliome v1.2926 BORCS5 Zornitza Stark gene: BORCS5 was added
gene: BORCS5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 40385417
Phenotypes for gene: BORCS5 were set to Lysosomal storage disease, MONDO:0002561, BORCS5-related
Review for gene: BORCS5 was set to GREEN
Added comment: preprint PMID 40385417, describing 12 individuals from 7 families with a spectrum of abnormalities (osteopetrosis not mentioned), suggestive of lysosomal disorder.

Homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy. Individuals with missense variants presented differently, with microcephaly, developmental epileptic encephalopathy, intellectual disability, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 knockout in zebrafish exhibited microcephaly, motor deficits, and seizures, mirroring the patients' clinical presentation. At the cellular level, BORCS5 loss-of-function but not missense variants, resulted in lower protein expression and impaired BORC assembly, paralleled by perinuclear lysosomal clustering. However, both loss-of-function and missense BORCS5 variants were associated with reduced total lysosomal proteolysis, reduced activity of the lysosomal hydrolases glucocerebrosidase and cathepsin B, and presence of multilamellar bodies, indicating lysosomal dysfunction.
Sources: Literature
Mendeliome v1.2817 BLOC1S1 Rylee Peters changed review comment from: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.; to: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy, and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.
Mendeliome v1.2817 BLOC1S1 Rylee Peters changed review comment from: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy (in some cases), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.; to: De Pace et al. 2025 [preprint] doi: https://doi.org/10.1101/2025.07.17.25331211
11 individuals from seven unrelated families (includes 4 individuals from 3 families described in Bertoli-Avella PMID: 33875846), with severe neurodevelopmental disorder and harbour biallelic variants of BLOC1S1.

The disorder presents with early infantile onset and is characterised by deficient myelination, global developmental delay, intellectual disability, hypotonia, epilepsy), and visual impairment (bilateral optic atrophy in most). The severity ranged from early death to a milder form with preserved ambulation and single-word communication. All individuals harbouring BLOC1S1 variants with available neuroimaging exhibit hypomyelinating leukodystrophy.

Functional analyses show that BLOC1S1 KO impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Missense variants displayed various combinations of defective expression, assembly, lysosome dispersal and/or autophagy. The frameshift variant showed the most severe deficiencies in tested assays.
Mendeliome v1.2089 IRAK2 chirag patel changed review comment from: 2 individuals with sequential or repeated invasive infections with 2 different variants in IRAK2 gene found on WES testing. The IRAK kinases function as downstream signal transductors following the activation of pathogen recognition receptors. IRAK4 gene has been associated with susceptibility to severe infections by common pyogenic bacteria.

Individual 1 had herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and a homozygous missense variant (L78P). There are no homozygous individuals in gnomAD (MAF 0.003%). No segregation testing reported.

Individual 2 had Streptococcus pneumoniae bacteremia with candidemia, and a heterozygous missense variant (R506W) which straddles between the kinase and TRAF6-binding CTD of IRAK2. There are 15 heterozygous individuals in gnomAD for this rare variant with no homozygotes (MAF 0.012%). No segregation testing reported.

Both patients’ peripheral blood mononuclear cells showed tendencies for TNFα hypo-responsiveness to representative bacterial, fungal and viral ligands, in line with subjects with IRAK defects. Immunoprecipitation platform assay to pull down TRAF6 revealed that possession of L78P or R506W variants led to reduced TRAF6 ubiquitination. The led to TRAF6 accumulation and in turn decreased TNFα production (an inflammatory cytokine to invading pathogens).

Paper does not comment on reasons for disease in biallelic and mono-allelic form.
Sources: Literature; to: PMID: 39299377
2 individuals with sequential or repeated invasive infections with 2 different variants in IRAK2 gene found on WES testing. The IRAK kinases function as downstream signal transductors following the activation of pathogen recognition receptors. IRAK4 gene has been associated with susceptibility to severe infections by common pyogenic bacteria.

Individual 1 had herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and a homozygous missense variant (L78P). There are no homozygous individuals in gnomAD (MAF 0.003%). No segregation testing reported. Individual 2 had Streptococcus pneumoniae bacteremia with candidemia, and a heterozygous missense variant (R506W) which straddles between the kinase and TRAF6-binding CTD of IRAK2. There are 15 heterozygous individuals in gnomAD for this rare variant with no homozygotes (MAF 0.012%). No segregation testing reported.

Both patients’ peripheral blood mononuclear cells showed tendencies for TNFα hypo-responsiveness to representative bacterial, fungal and viral ligands, in line with subjects with IRAK defects. Immunoprecipitation platform assay to pull down TRAF6 revealed that possession of L78P or R506W variants led to reduced TRAF6 ubiquitination. The led to TRAF6 accumulation and in turn decreased TNFα production (an inflammatory cytokine to invading pathogens). Paper does not comment on reasons for disease in biallelic and mono-allelic form.


Preprint paper:
2 individuals with immune dysregulation (1 x systemic lupus erythematosus and 1 x autoinflammatory disease) with same homozgyous exon 2 deletion in IRAK2 gene found on WES testing and confirmed with Sanger sequencing. Unaffected family members in trio were heterozygous for variant. Exon 2 encodes a proportion of the death domain, a critical protein domain for Myddosome assembly.

The patients exhibited aberrantly upregulated type I interferon (IFN) response following LPS stimulation, which was further confirmed in bone marrow-derived macrophages (BMDMs) in mice. RNA sequencing analysis indicated that PBMCs from the two patients consistently exhibited defects in activating NFkb signaling in response to LPS or R848 stimulation, as well as impaired activation of the MAPK signaling pathway. RNA sequencing demonstrated that BMDMs from Irak2 ∆ex2/∆ex2 mice exhibited defects in NFkb and MAPK signaling pathways, similar to patients’ PBMCs.
Mendeliome v1.2076 RNU5B-1 Zornitza Stark gene: RNU5B-1 was added
gene: RNU5B-1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNU5B-1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU5B-1 were set to https://www.medrxiv.org/content/10.1101/2024.10.04.24314692v1.full.pdf; https://www.medrxiv.org/content/10.1101/2024.10.07.24314689v1
Phenotypes for gene: RNU5B-1 were set to Neurodevelopmental disorder, MONDO:0700092, RNU5B-1 related
Review for gene: RNU5B-1 was set to GREEN
Added comment: 20 individuals reported in two preprints with de novo variants in this gene and a neurodevelopmental phenotype.
Sources: Literature
Mendeliome v1.34 TRIM47 Zornitza Stark gene: TRIM47 was added
gene: TRIM47 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRIM47 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRIM47 were set to 35511193
Phenotypes for gene: TRIM47 were set to Genetic cerebral small vessel disease MONDO:0018787
Review for gene: TRIM47 was set to RED
Added comment: GWAS data: Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. Observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology.
Sources: Literature
Mendeliome v0.13784 KCNH5 Elena Savva gene: KCNH5 was added
gene: KCNH5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNH5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNH5 were set to https://www.medrxiv.org/content/10.1101/2022.04.26.22274147v1
Phenotypes for gene: KCNH5 were set to Neurodevelopmental disorders
Mode of pathogenicity for gene: KCNH5 was set to Other
Review for gene: KCNH5 was set to GREEN
Added comment: Happ (2022), preprint: Screen of 893 patients with DEE found 17 patients with missense variants (16/17 de novo, 1/17 inherited). GOF mechanism suggested.
Patient phenotypes included focal/generalized seizures, Cognitive outcome for the ten individuals >5 years ranged from normal (3/10) to mild (3/10), moderate (2/10), severe (1/10) and profound (1/10) intellectual disability (ID)

p.Arg327His (7 probands), p.Arg333His (4 probands) were recurring
Sources: Literature
Mendeliome v0.13782 STX1A Ain Roesley changed review comment from: Preprint:
8 individuals - 2x hom (related) and 6x hets (all de novo except 1x unknown)

7 unrelated since the 2 siblings share similar features:
7/7 ID, 7/7 motor delay, 4/7 epilepsy, 5/7 neonatal hypotonia 2/7 regression, 2/7 ASD excluding 1 with features but did not meet criteria
Sources: Literature; to: Preprint: https://www.medrxiv.org/content/10.1101/2022.04.20.22274073v1
8 individuals - 2x hom (related) and 6x hets (all de novo except 1x unknown)

7 unrelated since the 2 siblings share similar features:
7/7 ID, 7/7 motor delay, 4/7 epilepsy, 5/7 neonatal hypotonia 2/7 regression, 2/7 ASD excluding 1 with features but did not meet criteria
Sources: Literature
Mendeliome v0.13778 STX1A Ain Roesley gene: STX1A was added
gene: STX1A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: STX1A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Review for gene: STX1A was set to GREEN
gene: STX1A was marked as current diagnostic
Added comment: Preprint:
8 individuals - 2x hom (related) and 6x hets (all de novo except 1x unknown)

7 unrelated since the 2 siblings share similar features:
7/7 ID, 7/7 motor delay, 4/7 epilepsy, 5/7 neonatal hypotonia 2/7 regression, 2/7 ASD excluding 1 with features but did not meet criteria
Sources: Literature
Mendeliome v0.13017 PREPL Zornitza Stark Marked gene: PREPL as ready
Mendeliome v0.13017 PREPL Zornitza Stark Gene: prepl has been classified as Green List (High Evidence).
Mendeliome v0.13017 PREPL Zornitza Stark Phenotypes for gene: PREPL were changed from to Myasthenic syndrome, congenital, 22 MIM#616224; hypotonia-cystinuria syndrome; Disorders of amino acid transport
Mendeliome v0.13016 PREPL Zornitza Stark Publications for gene: PREPL were set to
Mendeliome v0.13015 PREPL Zornitza Stark Mode of inheritance for gene: PREPL was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9899 POLR3H Bryony Thompson gene: POLR3H was added
gene: POLR3H was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLR3H was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3H were set to 34794894; 30830215
Phenotypes for gene: POLR3H were set to Primary ovarian insufficiency
Review for gene: POLR3H was set to AMBER
Added comment: A homozygous missense variant (p.Asp50Gly) was identified homozygous in 2 unrelated families. A mull mouse model was embryonic lethal, but a mouse model homozygous for the missense were viable and showed delayed pubertal development, characterised by late first oestrus or preputial separation.
Sources: Literature
Mendeliome v0.5229 PRKAR1B Konstantinos Varvagiannis gene: PRKAR1B was added
gene: PRKAR1B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRKAR1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 25414040
Phenotypes for gene: PRKAR1B were set to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure
Penetrance for gene: PRKAR1B were set to unknown
Review for gene: PRKAR1B was set to AMBER
Added comment: Please consider inclusion of this gene with amber rating pending publication of the preprint and/or additional evidence.

Marbach et al. (2020 - medRxiv : https://doi.org/10.1101/2020.09.10.20190314 - last author : C. Schaaf) report 6 unrelated individuals with heterozygous missense PRKAR1B variants.

All presented formal ASD diagnosis (6/6), global developmental delay (6/6) and intellectual disability (all - formal evaluations were lacking though). Additional features included neurologic anomalies (movement disorders : dyspraxia, apraxia, clumsiness in all, with tremor/dystonia or involuntary movements as single occurrences). Three displayed high pain tolerance. Regression in speech was a feature in two. Additional behavior anomalies included ADHD (4-5/6) or aggression (3/6). There was no consistent pattern of malformations, physical anomalies or facial features (with the exception of uplsanted palpebral fissures reported in 4).

3 different missense variants were identified (NM_00116470:c.1003C>T - p.Arg335Trp, c.586G>A - p.Glu196Lys, c.500_501delAAinsTT - p.Gln167Leu) with Arg355Trp being a recurrent one within this cohort (4/6 subjects). A possible splicing effect may apply for the MNV. All variants are absent from gnomAD and the SNVs had CADD scores > 24.

In all cases were parental samples were available (5/6), the variant had occurred as a de novo event.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes. As the authors comment, the RIβ subunit is primarily expressed in brain with higher expression in cortex and hypothalamus.

The functional consequences of the variants at cellular level were not studied.

Previous studies have demonstrated that downregulation of RIβ in murine hippocampal cultures, reduced phosphorylation of CREB, a transcription factor involved in long-term memory formation. The authors speculate that a similar effect on cAMP/PKA/CREB cascade may mediate the cognitive effects in humans. RIβ deficient mice also display diminished nociceptive pain, similar to the human phenotype. [Several refs provided].

The authors cite the study by Kaplanis et al (2020 - PMID: 33057194), where in a large sample of 31,058 trio exomes of children with developmental disorders, PRKAR1B was among the genes with significant enrichment for de novo missense variants. [The gene has a pLI score of 0.18 in gnomAD / o/e = 0.26 - so pLoF variants may not be deleterious].

Please note that a specific PRKAR1B variant (NM_002735.2:c.149T>G - p.Leu50Arg) has been previous reported to segregate with a late-onset neurodegenerative disorder characterized by dementia and/or parkinsonism within a large pedigree with 12 affected individuals [Wong et al 2014 - PMID: 25414040].
Sources: Literature
Mendeliome v0.3872 LMBRD2 Zornitza Stark gene: LMBRD2 was added
gene: LMBRD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LMBRD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMBRD2 were set to 32820033; https://doi.org/10.1101/797787
Phenotypes for gene: LMBRD2 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye
Mode of pathogenicity for gene: LMBRD2 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: LMBRD2 was set to GREEN
Added comment: 13 individuals with dn missense SNVs overall, overlapping features for 10 with available phenotype / a recurring variant has been identified in 2 different studies.

► Malhotra et al (2020 - PMID: 32820033) report on 10 unrelated individuals with de novo missense LMBRD2 variants. Features included DD (9/10), ID (6/8 of relevant age), microcephaly (7/10), seizures (5/10 - >=3 different variants), structural brain abnormalities (e.g. thin CC in 6/9), highly variable ocular abnormalities (5/10) and dysmorphic features in some (7/10 - nonspecific). All had variable prior non-diagnostic genetic tests (CMA, gene panel, mendeliome, karyotype). WES/WGS revealed LMBRD2 missense variants, in all cases de novo. A single individual had additional variants with weaker evidence of pathogenicity. 5 unique missense SNVs and 2 recurrent ones (NM_001007527:c.367T>C - p.Trp123Arg / c.1448G>A - p.Arg483His) were identified. These occurred in different exons. Variants were not present in gnomAD and all had several in silico predictions in favor of a deleterious effect. There was phenotypic variability among individuals with the same variant (e.g. seizures in 1/3 and microchephaly in 2/3 of those harboring R483H). The gene has a pLI of 0 (although o/e ranges from 0.23 to 0.55), %HI of 15.13 and z-score of 2.27. The authors presume that haploinsufficiency may not apply, and consider a gain-of-function/dominant-negative effect more likely. As the authors comment LMBRD2 (LMBR1 domain containing 2) encodes a membrane bound protein with poorly described function. It is widely expressed across tissues with notable expression in human brain (also in Drosophila, or Xenopus laevis). It displays high interspecies conservation. It has been suggested (Paek et al - PMID: 28388415) that LMBRD2 is a potential regulator of β2 adrenoreceptor signalling through involvement in GPCR signalling.

► Kaplanis et al (2020 - https://doi.org/10.1101/797787) in a dataset of 31058 parent-offspring trios (WES) previously identified 3 individuals with developmental disorder, harboring c.1448G>A - p.Arg483His. These individuals (1 from the DDD study, and 2 GeneDx patients) appear in Decipher. [ https://decipher.sanger.ac.uk/ddd/research-variant/40e17c78cc9655a6721006fc1e0c98db/overview ]. The preprint by Kaplanis et al is cited by Malhotra et al, with Arg483His reported in 6 patients overall in both studies.
Sources: Literature
Mendeliome v0.0 PREPL Zornitza Stark gene: PREPL was added
gene: PREPL was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: PREPL was set to Unknown