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| Intellectual disability v5.255 | PABPC1 |
Sarah Leigh edited their review of gene: PABPC1: Added comment: PABPC1 variants have not been associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35511136 reports four de novo PABPC1 variants in four unrelated cases with a phenotype of global DD, movement coordination disorders, seizures, behavioral disorders and mild facial dysmorphisms. Intellectual disability ranged in the cases from profound (1/4), IQ: 61 (1/4) and IQ: 79 (2/4). Seizures were apparent in the all of the three cases where it was assessed. Molecular modeling of the variants suggested that they would result in a reduced binding affinity to the messenger RNA metabolism-related protein - PAIP2. This predicted effect was seen in coimmunoprecipitation assays between variant PABPC1 and PAIP2 (PMID: 35511136). Further functional studies in PMID: 35511136, showed that the proliferation of neural progenitor cells in Pabpc1 knockdown mouse embryo brains were decreased, this effect was rescued by the wild-type Pabpc1, but not by the variants c.1691A>G (p.Glu564Gly) or c.1709T>C (p.Ile570Thr). Other variants were identified in 3/4 cases in PMID: 35511136, two of these had a ACMG VUS classification (RBBP4: c.845A>G, p.(Asn282Ser), IGF2R: c.1850G>A p.Cys617Tyr), while the third variant was monoallelic, whereas bialleic variants in this gene are associated with disease (KDM5B: c.2265dupA, p.(Tyr755*))(PMID: 35511136, table 1).; Changed rating: GREEN |
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| Intellectual disability v3.1562 | PABPC1 |
Konstantinos Varvagiannis gene: PABPC1 was added gene: PABPC1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PABPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PABPC1 were set to 35511136 Phenotypes for gene: PABPC1 were set to Global developmental delay; Expressive language delay; Intellectual disability; Behavioral abnormality; Seizures Penetrance for gene: PABPC1 were set to unknown Review for gene: PABPC1 was set to AMBER Added comment: Wegler et al (2022 - PMID: 35511136) describe the phenotype of 4 individuals with de novo variants in the PABP domain of PABPC1. Overlapping features included DD (4/4) with weak expressive language (4/4), learning disability/borderline intellectual functioning (in 2) to more severe ID (in 2 others), treatable/self-limiting seizures (in 3 for whom this information was available) as well as variable behavioral issues (impaired social skills, concentration/sleeping problems, ADHD, anxiety or autism). Other features involved feeding difficulties (3/4), hearing impairment (in 2/3) or variable other phenotypes. Contribution of de novo variants found in other genes was thought possible. All 4 were investigated by trio exome sequencing following negative previous routine diagnostic work-up. WES revealed heterozygous de novo PABPC1 variants, 3 of which were missense SNVs (c.1687G>A/p.Gly563Ser, c.1691A>C/p.Glu564Gly, c.1709T>C/p.Ile570Thr using NM_002568.3) and a fourth an in-frame deletion (c.1664_1666del/p.Pro555del). Additional de novo variants were reported in 3 cases (IGF2R missense SNV, htz KDM5B stopgain, RBBP4 - the latter not associated with any phenotype to date). PABPC1 encodes Polyadenylate-binding protein, cytoplasmic, 1 which as the authors summarize has an important role overall in regulation of gene expression (poly(A) tail length, mRNA formation, export of processed mRNAs to cytoplasm, translation initiation promotion and termination, mRNA stability, NMD). Translation is regulated by Polyadenylate-binding protein–interacting proteins (PAIPs) which control PABP activity. PAIP2 in particular, which is highly expressed in CNS, is known to inhibit translation via binding to the PABP domain of PABPC1 and is thought to play an important role through transcriptional regulation for synaptic plasticity and memory. To evaluate plausibility as a DD gene the authors performed analyses using publicly available data, with PABPC1 ranking high in terms of protein-protein interaction (PPI) and co-expression with known DD genes. Variants were absent from gnomAD with in silico predictions in favour of a deleterious effect. While PABPC1 is intolerant to both missense and LoF variants (z-score 4.49, pLI of 1), occurrence of these 4 dn variants and their clustering in the PABP domain appeared to be of statistical significance (p=0.002 and p=2.8x10-8) rather than being explained by random occurrence. Structural modeling of variants suggested that all were in close spatial vicinity within the PABP domain, likely influencing PAIP2 binding. In HeLa cells the variants were shown not to affect subcellular localization (to the cytoplasm) compared to wt. In addition, there were no significant differences upon stress conditions under which the protein localizes to stress granules. In HeLa cells, co-immunoprecipitation assays using C-terminal HA tagged PABPC1, revealed that 3 variants (Gly563Ser, Glu564Gly, Ile570Thr) significantly reduced physical PABPC1-PAIP2 interaction compared with wt, which was also observed though to a not significant extent for Pro555del. (Other variants from literature also studied as discussed below). Pabpc1 is highly expressed in all regions of the developing mouse brain with remarkable decrease after birth, suggesting a critical role in prenatal brain development. Through electroporation with Pabpc1-directed shRNA the authors provided evidence that Pabpc1 LoF results in abnormal neural progenitor cell proliferation with rescue experiments using human WT or missense variants (Gly563Ser, Glu564Gly, Ile570Thr) showing that only the WT could rescue the proliferation phenotype. Overall a model whereby weakened PABPC1-PAIP2 interaction, leading to dysregulation to gene expression homeostasis and interference with proliferation of neural progenitors and the later to the NDD phenotype is proposed. Given previous reports in the literature for de novo PABPC1 variants, namely Lys138Glu, Asp204Val, Arg481His, Pro456Leu the authors noted that the phenotypes reported in the respective individuals were rather explained by other variants (16p11.2 dup, ARID1A dn, TBL1XR1 dn variants). These PABPC1 variants do not lie in the PABP domain, have lower in silico pathogenicity scores (MPC/CADD), with structural modelling suggestive of no significant effect. Importantly, upon co-immunoprecipitation studies with PAIP2 which were here performed, these variants had no effect. Pathogenicity of these variants - not located within the PABP domain - through another mechanism cannot be however ruled out. (PMIDs cited, though not reviewed based on this discussion: De Rubeis et al, 2014 - PMID: 25363760, Guo et al, 2019 - PMID: 30504930, Kaplanis et al, 2020 - PMID: 33057194). Currently there is no PABPC1-related phenotype in other databases (incl. OMIM, G2P, SysID, PanelApp Australia). Consider inclusion in the gene panels for ID and epilepsy with amber / green rating (DD with or without ID in >= 3 individuals/families/variants – also the case for seizures, role of the gene, statistical evidence for the gene/occurrence and clustering of variants, functional studies with strong evidence for at least 3 variants || learning difficulties/borderline intellectual functioning in 2 affected individuals, phenotype in few might be "blended" due to additional de novo variants). Sources: Literature |
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| Intellectual disability v3.1544 | KDM5B | Arina Puzriakova Phenotypes for gene: KDM5B were changed from neurodevelopment delay and autism spectrum disorder; Mental retardation, autosomal recessive 65, 618109 to Intellectual developmental disorder, autosomal recessive 65, OMIM:618109 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.0 | TET3 |
Konstantinos Varvagiannis gene: TET3 was added gene: TET3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: TET3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: TET3 were set to https://doi.org/10.1016/j.ajhg.2019.12.007 Phenotypes for gene: TET3 were set to Global developmental delay; Intellectual disability; Macrocephaly; Growth abnormality; Seizures; Autistic behavior; Abnormality of movement; Abnormality of the face Penetrance for gene: TET3 were set to Complete Review for gene: TET3 was set to GREEN Added comment: Beck et al (2020 - DOI: https://doi.org/10.1016/j.ajhg.2019.12.007) report on individuals with monoallelic de novo or biallelic pathogenic TET3 variants. For both inheritance modes (AR/AD) DD/ID were among the observed features (mild-severe - individuals from families 2, 4 and 6 for whom presence of ID was not commented, relevance to the current panel is suggested from the developmental milestones in the supplement. One individual presented DD without ID). Other features included hypotonia (in 8), ASD/autistic features (in 5), seizures (2 unrelated subjects for each inheritance mode). Postnatal growth abnormalities were observed in many, in most cases involving head size (with/without abnormal stature) and few presented abnormal prenatal growth. Variable movement disorders were observed in some. Some facial features appeared to be more common (eg. long face, tall forehead, etc). Most were referred for their DD. Extensive prior genetic investigations had (mostly) come out normal (with possible contribution of a 16p11.2 dup in an individual with monoallelic variant or a 16q22 dup in another with biallelic TET3 variants). Monoallelic / biallelic variants in all subjects were identified following exome sequencing. TET3 encodes a methylcytosine dioxygenase (the TET family consisting of 3 enzymes, TET1, TET2, TET3). These enzymes are involved in DNA demethylation through a series of reactions beginning with the conversion of 5-methyl cytosine [5mc] to 5-hydromethylcytosine [5hmC]. 5 individuals from 3 families (1/3 consanguineous) harbored biallelic missense variants. 5 different missense variants were observed. Heterozygous parents appeared to be mildly affected (eg. having learning difficulties, etc). 6 individuals from 5 families harbored monoallelic variants [3 truncating (of which 2 localizing in the last exon), 2 missense SNVs]. In one family the variant was inherited from a similarly affected parent. In all other cases the variant had occured de novo. No additional TET3 variants were identified, with the limitations of WES. All missense mutations, whether observed in individuals with biallelic or monoallelic variants, were located within the catalytic domain or - for a single variant (NM_001287491.1:c.2254C>T / p.Arg752Cys) - adjacent to it. Functional studies were carried out only for (all) missense variants observed in individuals with biallelic variants. Conversion of 5mC to 5hmC is the first step in DNA demethylation. In HEK293 cells overexpressing either wt or variants, production of 5hmc was measured. 4/5 missense variants evaluated demonstrated a defect in converting 5mC to 5hmC, Arg752Cys being an exception (as also predicted by its localization). DD/ID and abnormal growth are also features of disorders of the epigenetic machinery (DNA methylation machinery, histone machinery, chromatin remodelers, other chromatin-associated proteins). Similarly to TET3, both monoallelic and biallelic variants in KDM5B, encoding for another component of the epigenetic machinery, have been identified in individuals with ID. Mouse models discussed by the authors [several Refs provided though not here reviewed] : The gene has been shown to be highly expressed in oocytes, zygotes and neurons and to play a role in demethylation of the paternal genome after fertilization. (From the MGI: 'mice inheriting a null allele from a germ cell conditional null mother display impaired reprogramming of the paternal genome resulting in reduced embryo viability'). Beck et al also note that Tet3 inhibition or depletion in differentiated neurons can impact synaptic function [PMIDs cited: 25915473, 24757058, 26711116]. Sources: Literature |
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| Intellectual disability v2.780 | KDM5B | Ivone Leong Added comment: Comment on mode of inheritance: Changed mode of inheritance from Monoallelic to Both monoallelic and biallelic based on evidence provided by expert review. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.780 | KDM5B | Ivone Leong Mode of inheritance for gene: KDM5B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.779 | KDM5B |
Ivone Leong Added comment: Comment on publications: PMID: 30217758 reports on 2 de novo splice variants found in 3 patients from 2 unrelated families who have ID and ASD. One variant was found in a boy with mild ID and autism traits. In vitro studies found that this variant reduced KDM5B mRNA production. The sister of this affected patient did not have carry this splice variant but she also presented with mild ID and epilepsy. The authors suggest that a variant in another gene may be linked to these phenotypes and that KDM5B haploinsufficiency cannot explain the ID/ASD phenotype. The other variant was found in a pair of monozygotic twins who both presented with global developmental delay, poor language and ASD. In vitro studies of this second variant showed that it causes the production of an abnormal transcript which is degraded by nonsense-mediated decay. |
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| Intellectual disability v2.779 | KDM5B | Ivone Leong Publications for gene: KDM5B were set to 25363768; 24307393; 29276005; 30409806; 25529582 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.742 | KDM5B | Ivone Leong Phenotypes for gene: KDM5B were changed from neurodevelopment delay and autism spectrum disorder to neurodevelopment delay and autism spectrum disorder; Mental retardation, autosomal recessive 65, 618109 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.741 | KDM5B | Ivone Leong Publications for gene: KDM5B were set to http://www.nature.com/nature/journal/v515/n7526/pdf/nature13908.pdf; 24307393 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.535 | KDM5B | Konstantinos Varvagiannis reviewed gene: KDM5B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29276005, 30409806; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.468 | KDM5B | Louise Daugherty Source Victorian Clinical Genetics Services was added to KDM5B. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | KDM5B | BRIDGE consortium edited their review of KDM5B | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | KDM5B | BRIDGE consortium reviewed KDM5B | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||