Intellectual disability - microarray and sequencing
Gene: CTR9This gene currently has no phenotype listed in OMIM so checked in PMID:35499524 to make sure the gene name is mentioned. It is so the gene-checked tag added.Created: 16 Oct 2023, 4:58 p.m. | Last Modified: 16 Oct 2023, 4:58 p.m.
Panel Version: 5.311
The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.Created: 11 Oct 2023, 9:34 a.m. | Last Modified: 11 Oct 2023, 9:34 a.m.
Panel Version: 5.286
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Comment on list classification: This gene should be rated GREEN as there are sufficient unrelated cases (at least 10) reported with varying degrees (mild to severe) intellectual disability.Created: 3 Mar 2023, 3:45 p.m. | Last Modified: 3 Mar 2023, 3:45 p.m.
Panel Version: 4.103
As noted by the reviewer, PMID: 35499524 reported 13 unrelated cases identified with heterozygous variants in CTR9 gene (11 different variants) and they presented with overlapping neurodegenerative phenotypes including intellectual disability, hypotonia, joint hyperlaxity, speech delay, coordination problems, tremor, and autism spectrum disorder. Mild dysmorphism and cardiac anomalies were less frequent. The intellect levels were determined only for 11 patients (the rest are too young) and 8 out of these 11 patients were reported with variable degree of intellectual disability, while other three had impairments in other domains or learning difficulties.
PMID:35717577 reported two additional unrelated cases with non-synonymous heterozygous CTR9 variants (p.Glu15Asp and p.Pro25Arg) and they presented with macrocephaly, motor delay, and intellectual disability. In addition, functional studies in zebrafish also showed that knockout/ over-expression of CTR9 variants caused motor defects and enlargement of telencephalon (homologous to the mammalian cerebrum).
This gene has not yet been associated with relevant phenotypes in OMIM. It has been associated with Wilms tumour in Gene2Phenotype (phenotype not relevant to this panel).Created: 3 Mar 2023, 3:30 p.m. | Last Modified: 3 Mar 2023, 3:30 p.m.
Panel Version: 4.96
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Macrocephaly, HP:0000256; Motor delay, HP:0001270; intellectual disability, MONDO:0001071
Publications
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).Created: 5 May 2022, 3:42 p.m. | Last Modified: 5 May 2022, 3:42 p.m.
Panel Version: 3.1562
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Delayed speech and language development; Motor delay; Intellectual disability; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Tag gene-checked tag was added to gene: CTR9.
Tag Q1_23_promote_green was removed from gene: CTR9.
Source NHS GMS was added to CTR9. Source Expert Review Green was added to CTR9. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Gene: ctr9 has been classified as Amber List (Moderate Evidence).
Gene: ctr9 has been classified as Amber List (Moderate Evidence).
Gene: ctr9 has been classified as Amber List (Moderate Evidence).
Tag Q1_23_promote_green tag was added to gene: CTR9.
Gene: ctr9 has been classified as Amber List (Moderate Evidence).
Gene: ctr9 has been classified as Amber List (Moderate Evidence).
Gene: ctr9 has been classified as Amber List (Moderate Evidence).
Gene: ctr9 has been classified as Amber List (Moderate Evidence).
Publications for gene: CTR9 were set to 35499524; 35717577
Publications for gene: CTR9 were set to 35499524; 35717577
Publications for gene: CTR9 were set to 35499524; 35717577
Phenotypes for gene: CTR9 were changed from Macrocephaly, HP:0000256; Motor delay, HP:0001270; intellectual disability, MONDO:0001071; Delayed speech and language development; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system to Macrocephaly, HP:0000256; Motor delay, HP:0001270; intellectual disability, MONDO:0001071; Delayed speech and language development; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system
Phenotypes for gene: CTR9 were changed from Macrocephaly, HP:0000256; Motor delay, HP:0001270; intellectual disability, MONDO:0001071; Delayed speech and language development; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system to Macrocephaly, HP:0000256; Motor delay, HP:0001270; intellectual disability, MONDO:0001071; Delayed speech and language development; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system
Publications for gene: CTR9 were set to 35499524; 35717577
Publications for gene: CTR9 were set to 35499524; 35717577
Publications for gene: CTR9 were set to 35499524; 35717577
Phenotypes for gene: CTR9 were changed from Macrocephaly, HP:0000256; Motor delay, HP:0001270; intellectual disability, MONDO:0001071; Delayed speech and language development; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system to Macrocephaly, HP:0000256; Motor delay, HP:0001270; intellectual disability, MONDO:0001071; Delayed speech and language development; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system
Phenotypes for gene: CTR9 were changed from Delayed speech and language development; Motor delay; Intellectual disability; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system to Macrocephaly, HP:0000256; Motor delay, HP:0001270; intellectual disability, MONDO:0001071; Delayed speech and language development; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system
Publications for gene: CTR9 were set to 35499524; 35717577
Publications for gene: CTR9 were set to 35499524; 35717577
Publications for gene: CTR9 were set to 35499524; 35717577
Publications for gene: CTR9 were set to 35499524; 35717577
Publications for gene: CTR9 were set to 35499524; 35717577
Mode of pathogenicity for gene: CTR9 was changed from None to None
Publications for gene: CTR9 were set to 35499524; 2815719; 25363760; 27479843; 25099282; 29292210
Mode of pathogenicity for gene: CTR9 was changed from None to None
Mode of pathogenicity for gene: CTR9 was changed from None to None
Mode of pathogenicity for gene: CTR9 was changed from None to None
Mode of pathogenicity for gene: CTR9 was changed from None to None
Mode of pathogenicity for gene: CTR9 was changed from None to None
Mode of pathogenicity for gene: CTR9 was changed from None to None
Mode of pathogenicity for gene: CTR9 was changed from None to None
Mode of pathogenicity for gene: CTR9 was changed from None to None
Mode of pathogenicity for gene: CTR9 was changed from None to None
Mode of pathogenicity for gene: CTR9 was changed from None to None
Mode of inheritance for gene: CTR9 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mode of pathogenicity for gene: CTR9 was changed from None to None
Mode of pathogenicity for gene: CTR9 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Mode of inheritance for gene: CTR9 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mode of inheritance for gene: CTR9 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mode of inheritance for gene: CTR9 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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