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| Intellectual disability - microarray and sequencing v5.470 | DYNC2H1 | Arina Puzriakova Phenotypes for gene: DYNC2H1 were changed from Short-rib thoracic dysplasia 3 with or without polydactyly, 613091 to Short-rib thoracic dysplasia 3 with or without polydactyly, OMIM:613091 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1628 | PPFIBP1 |
Konstantinos Varvagiannis gene: PPFIBP1 was added gene: PPFIBP1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PPFIBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PPFIBP1 were set to 35830857; 30214071 Phenotypes for gene: PPFIBP1 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of brain morphology; Abnormality of the cerebral white matter; Cerebral calcification; Abnormal cortical gyration; Hypertonia; Spastic tetraplegia; Generalized hypotonia; Small for gestational age; Growth delay; Failure to thrive; Feeding difficulties; abnormal heart morphology; Hearing abnormality; Cryptorchidism; Abnormality of vision Penetrance for gene: PPFIBP1 were set to Complete Review for gene: PPFIBP1 was set to GREEN Added comment: Consider inclusion with green rating in the ID, epilepsy as well as other likely relevant gene panels (microcephaly, white matter disorders, corpus callosum abnormalities, intracerebral calficication disorders, malformations of cortical development, hereditary spastic paraplegia, growth failure in early childhood, etc) based on the summary below. ---- Rosenhahn et al (2022 - PMID: 35830857) describe the phenotype of 16 individuals - belonging to 12 unrelated families - with biallelic PPFIBP1 pathogenic variants. Most (14/16) were born to consanguineous parents. One of these families was previously reported by Shaheen et al (2019 - PMID: 30214071) who first identified PPFIBP1 as a candidate gene for congenital microcephaly. In the current study, Rosenhahn also identified a fetus homozygous for a missense variant and similar features. All individuals presented global DD/ID (16/16 - in 15 cases profound/severe) and epilepsy (16/16 - onset 1d-4y / median 2m - focal seizures in 11/16, epileptic spams in 7/16, generalized onset in 7/16, myoclonic in 6/16 - drug-resistant : 13/16). Almost all (15/16) had microcephaly, commonly congenital (9/16) and progressive (11/16). Other neurological findings included hypertonia (10/16), spastic tetraplegia (6/16), hypotonia (5/16), dystonic movements (3/16) or nystagmus (4/16). Brain abnormalities were identified in all investigated with MRI and included leukoencephalopathy (11/14) mostly periventricular, abnormal cortex morphology (7/14 - polymicrogyria 1, increased cortical thickness 4, pachygyria 3), cortical atrophy, corpus callosum hypoplasia (7/14). Intracranial calcifications were identified in all (9/9) investigated with CT scan. Abnormal growth was reported for several (SGA in 9/16, FTT 8/16, short stature 7/16) often associated with feeding difficulties (7/16). Other features incl. abnormal hearing (4/16), congenital heart defects (7/16), ophthalmologic findings (8/16), undescended testes (3/10). There were no overlapping facial features. The fetus displayed similar features incl. SGA, microcephaly, intracranial calcifications. Investigations incl. exome/genome sequencing (singleton or trio) with Sanger for confirmation/segregation of variants where necessary. Variable previous investigations incl. metabolic screening, TORCH screening, chromosomal studies (CMA) are mentioned in the supplement and were non-diagnostic. Additional candidate variants were identified in few cases although cases with plausible dual diagnoses (e.g. ind14) were not included in the overall phenotypic description. 9 pLoF variants (nonsense, frameshift, 1 splicing) predicted to lead to NMD were identified. There were no functional studies performed. The missense variant c.2177G>T / p.Gly726Val (NM_003622.4) was predicted deleterious by in silico tools while the AA change causing severe steric problems upon modelling. PPFIBP1 encodes PPFIA-binding protein 1 also known as liprin-β1. As the authors discuss: The liprin family of proteins comprises liprins α1 to 4 and liprin β1 and β2 in mammals. Liprin β1 is known to homodimerize and heterodimerize with α-liprins. In fibroblast cultures liprins β1 and α1 colocalize to cell membrane and periphery of focal adhesions. Members of the liprin-α fam. are scaffold proteins playing a role in synapse formation/signaling and axonal transport. A ko model of the PPFIBP1 ortholog in C.elegans displayed abnormal locomotion behavior. In Drosophila, null-allele mutants resulted in altered axon outgrowth and synapse formation of R7 photoreceptors and reduced neuromuscular junction size (Refs provided in article). Using a PPFIBP1/hlb-1 ko C.elegans model the authors demonstrated defects in spontaneous and light-induced behavior. Sensitivity of the worms to an acetylcholinesterase inhibitor (aldicarb) was suggestive of a presynaptic defect. ---- There is currently no PPFIBP1 - associated phenotype in OMIM / G2P. SysNDD lists PPFIBP1 among the ID genes (limited evidence based on the 3 sibs reported by Shaheen et al, 2019 - PMID: 30214071). In PanelApp Australia the gene is listed with green rating for ID, epilepsy, microcephaly based on the medRxiv pre-print. Sources: Literature |
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| Intellectual disability - microarray and sequencing 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 |
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| Intellectual disability - microarray and sequencing v3.500 | PRKAR1B |
Konstantinos Varvagiannis gene: PRKAR1B was added gene: PRKAR1B was added to Intellectual disability. 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 |
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| Intellectual disability - microarray and sequencing v3.500 | CEP120 | Ivone Leong Phenotypes for gene: CEP120 were changed from Joubert syndrome 31 (MIM 617761); Short-rib thoracic dysplasia 13 with or without polydactyly (MIM 616300) to Joubert syndrome 31 (617761); Short-rib thoracic dysplasia 13 with or without polydactyly (616300) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.170 | CEP120 |
Konstantinos Varvagiannis gene: CEP120 was added gene: CEP120 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CEP120 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CEP120 were set to 27208211 Phenotypes for gene: CEP120 were set to Joubert syndrome 31 (MIM 617761); Short-rib thoracic dysplasia 13 with or without polydactyly (MIM 616300) Penetrance for gene: CEP120 were set to Complete Review for gene: CEP120 was set to GREEN Added comment: Pathogenic CEP120 variants have been reported in recessive ciliopathies, namely Short-rib thoracic dysplasia 13 with or without polydactyly (MIM 616300) and Joubert syndrome 31 (MIM 617761). The former is associated with a severe/lethal outcome (4 unrelated infants described by Shaheen et al 2015 - PMID: 25361962, 2 fetuses reported by Roosing et al 2016 - PMID: 27208211). Roosing et al however, also provided details on 4 unrelated subjects with Joubert syndrome diagnosis. All presented with a neurologic phenotype of hypotonia, DD, cognitive impairment and exhibited a molar tooth sign. As a result, this gene can be considered for inclusion in the ID panel with green rating (>3 individuals/variants, consistent ciliopathy phenotype). Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.3 | NEK1 | Zornitza Stark reviewed gene: NEK1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Short-rib thoracic dysplasia 6 with or without polydactyly, MIM# 263520; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.3 | WDR19 | Zornitza Stark reviewed gene: WDR19: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Short-rib thoracic dysplasia 5 with or without polydactyly, OMIM #614376, Nephronophthisis 13, OMIM #614377, Senior-Loken syndrome 8, OMIM#616307; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.0 | DYNC2H1 | Zornitza Stark reviewed gene: DYNC2H1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Short-rib thoracic dysplasia 3 with or without polydactyly, MIM#613091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.503 | CIC | Louise Daugherty Classified gene: CIC as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.503 | CIC | Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.503 | CIC | Louise Daugherty Gene: cic has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.494 | CIC | Louise Daugherty Classified gene: CIC as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.494 | CIC | Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.494 | CIC | Louise Daugherty Gene: cic has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.480 | CIC | Louise Daugherty Classified gene: CIC as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.480 | CIC | Louise Daugherty Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.480 | CIC | Louise Daugherty Gene: cic has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.468 | CIC | Louise Daugherty Source Victorian Clinical Genetics Services was added to CIC. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||