| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Intellectual disability v3.1562 | CTR9 |
Konstantinos Varvagiannis gene: CTR9 was added gene: CTR9 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CTR9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CTR9 were set to 35499524; 2815719; 25363760; 27479843; 25099282; 29292210 Phenotypes for gene: CTR9 were set to Delayed speech and language development; Motor delay; Intellectual disability; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system Penetrance for gene: CTR9 were set to unknown Mode of pathogenicity for gene: CTR9 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: CTR9 was set to AMBER Added comment: Meuwissen, Verstraeten, Ranza et al (2022 - PMID: 35499524) describe the phenotype of 13 unrelated individuals harboring heterozygous - predominantly de novo - CTR9 missense variants. Overlapping features included delayed speech and/or motor development (each in 9 cases) with the latter complicated by hypotonia or hyperlaxity in some cases. Balance or coordination problems were also reported in some. Variable degrees of ID ranging from mild to severe were observed in all individuals of relevant age except for 3 who however experienced impairment in other domains and/or learning difficulties (8/11 - 2 individuals were too young for evaluation). Few had evidence of regression. Other features included behavioral abnormalities (incl. ASD in 4), FTT/feeding problems (in 5), cardiovascular findings (in 4 - incl. infantile thoracic aortic aneurysm, VSD, pulm. valve stenosis, SVAS). The authors reported variable/nonspecific dysmorphic features. WES revealed heterozygous CTR9 missense variants in all cases (NM_014633.5 as RefSeq). The variants occurred de novo in most (11/13) individuals with a one proband having inherited the variant from his affected parent. For one case, a single parental sample was available. Most SNVs were absent from gnomAD with the exception of c.1364A>G/p.Asn455Ser and c.2633G>A/p.Arg878Gln present once in the database (Z-score for CTR9: 4.3 / pLI : 1). The variants affected highly conserved residues with in silico predictions mostly in favor of a deleterious effect. CTR9 encodes a subunit of the PAF1 complex (PAF1C) with the other subunits encoded by PAF1, LEO1, CDC73, RTF1 and WDR61/SKI8. The complex acts as a transcriptional regulator with CTR9 binding RNA polymerase II. The complex influences gene expression by promoting H2BK123 ubiquitylation, H3K4 and H3K36 methylation. In yeast, Paf1 and Ctr9 appear to mediate involvement of Paf1C in induction of mitophagy (several Refs provided). In silico modeling: a group of N-terminal variants likely destabilize structure, another group possibly perturbs CTR9-PAF1 interactions and a 3rd class influences interactions with other subunits. p.Glu15Lys did not appear to influence protein stability. Functional studies: H3K4/H3K36 methylation analysis, mitochondrial quality assessment and RNA-seq studies in fibroblasts did not provide conclusive evidence for downstream consequences of the variants (albeit a brain-specific effect - as demonstrated for other disorders – cannot be excluded). Animal models: In zebrafish, the Paf1C complex has been shown to play a role in cardiac specification and heart morphogenesis with ctr9 mutants showing severe defects in morphogenesis of primitive heart tube (cited PMID: 21338598). This supports a role of the CTR9 variants in the cardiac abnormalities observed in 4 individuals. Although Paf1C zebrafish homologues are required for Notch-regulated transcription (cited PMID: 17721442), there was no supporting evidence from RNA-seq analyses performed by the authors. In Drosophila, Ctr9 has a key role at multiple stages of nervous system development in Drosophila (cited PMID: 27520958). In rat, Ctr9 is expressed in dopaminergic neurons, with its expression not restricted to the nucleus, regulating dopamine transporter activity (cited PMID: 26048990). As commented, de novo CTR9 variants have been identified in indivdiduals with developmental disorders in larger cohorts, though without phenotypic details (DDD study - PMID:2815719, De Rubeis et al, 2014 - PMID: 25363760, Lelieveld et al PMID: 27479843) [ https://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=CTR9 ] Two previous studies (Hanks et al, 2014 - PMID: 25099282, Martins et al 2018, PMID: 29292210) have identified individuals with pLoF variants [in almost all cases leading to skipping of ex9 e.g. NM_014633.4:c.958-9A>G or (RefSeq not provided) c.1194+2T>C, c.1194+3A>C, the single exception being c.106C>T/p.Q36*] in individuals and families with Wilms tumor after exclusion of other genetic causes. Analyses of tumor samples revealed in several of these cases either LOH (most commonly) or truncating variants as second hits. These individuals did not display neurodevelopmental phenotypes (despite detailed clinical information provided in the 2 studies). CTR9 is included in the gene panels for WT and Tumor predisposition - childhood onset with green rating. [In addition few individuals with hyperparathyroidism jaw tumor syndrome due to heterozygous variants in CDC73 - another subunit of the PAF1 complex - have been reported with WT]. Given these reports, commenting on the embryonic lethality of Ctr9 homozygous ko mice (MGI) and the observation of only missense variants in their cohort Meuwissen, Verstraeten, Ranza et al presume that a dominant-negative effect may apply for the variants they report. Consider inclusion in the current panel with amber (variant effect/underlying mechanism unknown) or green rating (>3 individuals/families/variants, multiple reports, some supporting evidence from animal models). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.510 | CACNA1E |
Konstantinos Varvagiannis gene: CACNA1E was added gene: CACNA1E was added to Intellectual disability. Sources: Expert Review,Literature Mode of inheritance for gene: CACNA1E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CACNA1E were set to 29942082 Phenotypes for gene: CACNA1E were set to Global developmental delay; Intellectual disability; Seizures; Dystonia; Congenital contracture; Macrocephaly Penetrance for gene: CACNA1E were set to Incomplete Mode of pathogenicity for gene: CACNA1E was set to Other Review for gene: CACNA1E was set to GREEN Added comment: Helbig et al. (https://doi.org/10.1016/j.ajhg.2018.09.006) report on 30 individuals with pathogenic variants in CACNA1E. The phenotype was consistent with a developmental and epileptic encephalopathy, with hypotonia, early-onset and refractory seizures, severe to profound developmental delay and intellectual disability. Additional relatively common features included hyperkinetic movement disorder (severe dystonia which was observed in 40%, other dyskinesias in another 20%), congenital joint contractures of variable degree and joint involvement (approx. 40% of individuals) and macrocephaly (approx. 40%). There were no common facial dysmorphic features observed. Of note, epilepsy was not a feature in 4 cases (age 1 to 4 years) so few of these individuals may be investigated for their developmental delay/intellectual disability or other features. Missense variants: All the 30 subjects described harbored a missense variant in CACNA1E which in all cases where parental studies were possible (29/30) occurred as a de novo event. There were 4 recurrent variants, explaining the phenotype in 20 patients in total while the rest of the individuals had private mutations. Functional studies were performed and suggested a gain-of-function effect for these variants (increased calcium inward currents). Loss-of-function (LoF) variants: Apart from the main cohort of patients, the authors note the presence of 3 individuals with such variants incl.: - one individual with a nonsense variant present in the mosaic state (6/22 reads) in peripheral blood. - one individual with a frameshift variant inherited from his unaffected parent. - one individual with a nonsense variant for whom parental studies were not possible. The authors comment that these indivdiduals presented with milder phenotype compared to those with missense variants. More information on these subjects is provided in the supplement as the article focuses on missense SNVs. As the authors also note, several LoF variants exist in gnomAD, although the gene appears to be LoF intolerant (pLI=1). Penetrance: Seems to be complete for missense SNVs and possibly incomplete for LoF ones. --- A previous study by Heyne et al. (PMID: 29942082) implicated de novo variants (DNVs) in CACNA1E with neurodevelopmental disorders for the first time. This study however does not provide clinical details on the phenotype of the affected individuals, while it seems to present overlap as to the individuals reported (eg. includes subjects from the DDD study and others). --- Details as to a few - possibly further - de novo coding variants reported to date can be found at the denovo-db: http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=CACNA1E --- As a result this gene can be considered for inclusion in this panel as green. Sources: Expert Review, Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | IVD | BRIDGE consortium edited their review of IVD | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | IVD | BRIDGE consortium edited their review of IVD | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | IVD | BRIDGE consortium reviewed IVD | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||