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| Intellectual disability - microarray and sequencing v3.1518 | TIAM1 |
Konstantinos Varvagiannis gene: TIAM1 was added gene: TIAM1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: TIAM1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TIAM1 were set to 35240055; 33328293 Phenotypes for gene: TIAM1 were set to Delayed speech and language development; Global developmental delay; Intellectual disability; Seizures; Behavioral abnormality; Abnormality of the endocrine system; Hypothyroidism; Abnormality of nervous system morphology Penetrance for gene: TIAM1 were set to Complete Review for gene: TIAM1 was set to AMBER Added comment: Lu et al (2022 - PMID: 35240055) describe 5 individuals (from 4 families) with biallelic TIAM1 missense variants. The phenotype overall corresponded to a neurodevelopmental disorder with DD (5/5), ID (4/4 individuals of relevant age - 3 families), speech delay (5/5), seizures (5/5 - onset: 2m-13y) and behavioral abnormalities (2/2, sibs with autism and ADHD). Several subjects had endocrine symptoms, namely hypothyroidism (N=3 - 2 families), Addison's disease (1) or hypomagnesemia (1). Non-consistent abnormalities were reported in (3/3) subjects who had a brain MRI. Previous investigations were mentioned for 3 individuals (incl. 2 sibs) and included normal CMA and/or metabolic workup. Singleton or trio exome sequencing (in one family) revealed biallelic missense TIAM1 variants. 6 different missense variants were reported, all ultra-rare or not present in gnomAD (also o/e:0.2, pLI:0.96), with CADD scores in favor of deleterious effect (NM_001353694.2): c.67C>T/p.Arg23Cys*, c.2584C>T/p.Leu862Phe*, c.983G>T/p.Gly328Val*, c.4640C>A/p.Ala1547Glu, c.1144G>C/p.Gly382Arg, c.4016C>T/p.Ala1339Val. TIAM1 encodes a RAC1-specific guanine exchange factor (GEF), regulating RAC1 signaling pathways that in turn affect cell shape, migration, adhesion, growth, survival, and polarity, and influence actin cytoskeletal organization, endocytosis, and membrane trafficking. RAC1 signaling plays important role in control of neuronal morphogenesis and neurite outgrowth (based on the summary by Entrez and authors). TIAM1 is highly expressed in human brain (GTEx). The authors provide evidence that sif, the Drosophila ortholog, is expressed primarily in neurons of the fly CNS (but not in glia). Using different sif LoF mutant flies they demonstrate that loss of sif impairs viability. Surviving flies exhibited climbing defects and seizure-like behaviors, both significantly rescued upon UAS-sif expression. Neuronal specific sif knockdown resulted in similar phenotypes to ubiquitous knockdown, while glial knockdown did not result in climbing defects. The semi-lethal phenotype could be fully rescued by expression of the fly sif cDNA, but only partially by human TIAM1 cDNA reference. Upon expression, 3 patient-variants (R23C, L862F, G328V) had variable rescue abilities similar to or lower (R23C) than TIAM1 Ref. TIAM1 Ref and variants could not rescue the neurological phenotypes though. Higher/ectopic expression of sif or TIAM1 Ref was toxic, which was also observed to a lesser extent for variants. Overall, the evidence provided suggests that the 3 variants tested induce partial LoF. In a recent study cited (PMID: 33328293), Tiam1 KO mice had simplified dendritic arbors, reduced spine density and diminished excitatory transmission in dentate gyrus. The authors comment that this mouse model presented only subtle behavioral abnormalities which they speculate may be secondary to GEF redundancy (eg. Tiam2). There is no TIAM1-associated phenotype in OMIM/G2P/SysID. TIAM1 is included in PanelApp Australia in the ID and epilepsy panels with green rating. Consider inclusion in the current panel with amber rating [As authors discuss: some phenotypic features differed in their small cohort and the contribution of other recessive conditions in 2 consanguineous families cannot be excluded. Also: in fig S1 only status of parents but not of affected/unaffected sibs is specified with the exception of Fam1]. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1237 | SERAC1 | Arina Puzriakova Phenotypes for gene: SERAC1 were changed from 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, 614739; MEGDEL syndrome; 3-MEthylGlutaconic aciduria, Dystonia-Deafness, Hepatopathy, Encephalopathy, Leigh-like syndrome; MEGDHEL syndrome; Intellectual disability to 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, OMIM:614739 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.836 | SERAC1 | Ivone Leong Source: Expert Review Red was removed from gene: SERAC1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1062 | APC2 |
Konstantinos Varvagiannis gene: APC2 was added gene: APC2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: APC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: APC2 were set to 31585108; 25753423; 19759310; 22573669 Phenotypes for gene: APC2 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system Penetrance for gene: APC2 were set to Complete Review for gene: APC2 was set to GREEN gene: APC2 was marked as current diagnostic Added comment: Probably 14 individuals from 9 families (8 consanguineous) with biallelic APC2 LoF variants have been reported. ID and brain abnormalities were features in all, although the presentation was quite different between sibs in the first report (PMID: 25753423 - mild/mod ID, ventriculomegaly and CC anomalies, macrocephaly with variable height, Sotos-like facial features) and 12 subsequently described patients (PMID: 31585108 - severe ID, P>A lissencephaly/CC anomalies/ventriculomegaly/paucity of white matter in (almost) all, gT-C/myoclonic seizures in 8/12 with onset 3m-6y, OFC in the low percentiles). In all cases relevant alternative diagnoses (eg. macrocephaly/overgrowth syndromes - 1st report, mutations in other lissencephaly genes, metabolic disorders - 2nd) were ruled out. APC2 encodes Adenomatous polyposis coli protein 2, expressed in the CNS. All variants reported to date were LoF (stopgain/frameshift/splicing) and were supported by parental-only studies. Mutations in the 1st report as well as 4/8 variants from the 2nd report localized within the last exon (NM_005883.2 / longest of >=3 isoforms), although the 2nd report did not observe obvious genotype-phenotype correlations. Despite a pLI of 1 in gnomAD, Lee et al. comment that heterozygous carriers did not have any noticeable phenotype. They further note that carriers were not examined by brain MRI, though. 27 heterozygous high-confidence variants appear in individuals in gnomAD. Finally as commented on, APC2 is not mutated in colon cancer. Animal models: Apc -/- mice displayed disrupted neuronal migration, with defects of lamination of cerebral cortex and cerebellum supporting the observed brain abnormalities. In addition Apc2-deficient mice also presented impaired learning and memory abilities. Extensive additional studies have shown Apc2 co-localization with microtubules affecting their stabilization, distribution along actin fibers (all supporting a role in cytoskeletal organization) and regulation of Rac1 (a Rho GTPase). Generation of Neuro2a cells demonstrated abnormal localization mainly in cell bodies of mutant hAPC2 proteins (due to frameshift in the last exon / deletion of the C-terminal part) - different from wt (neurites, growth cones, cell bodies). The first patient report also provided evidence for Apc2 being a downstream effector of Nsd1, with Nsd1 knockdown brains displaying impaired migration / laminar positioning of cortical neurons (similar to Apc2-/- model) and rescued by forced expression of Apc2. Relevant articles: PMIDs: 19759310 and 22573669 (Shintani et al. 2009 & 2012) [mouse model] PMID: 25753423 (Almuriekhi et al. 2015) [2 individuals + mouse model] PMID: 31585108 (Lee et al. 2019) [12 individuals from 8 families] ----- In OMIM, the APC2-related phenotype is ?Sotos syndrome 3 (MIM 617169 - AR). G2P does not have any associated phenotype for this gene. In SysID, APC2 belongs to the Current primary ID genes. APC2 is included in gene panels for ID offered by some diagnostic laboratories (eg. Radboudumc, GeneDx). ----- Overall, this gene could be considered for inclusion in the ID panel probably as green (>3 individuals/families/variants, highly specific pattern of lissencephaly in 12/14, mouse model supporting migration defects and impaired learning/memory) rather than amber (differences between the 1st and the other families reported as for the OFC and presence of lissencephaly). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1046 | TIMM50 |
Konstantinos Varvagiannis gene: TIMM50 was added gene: TIMM50 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: TIMM50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TIMM50 were set to 27573165; 30190335; 31058414; Serajee et al. (ASHG conference 2015 - abstract Nr. 2299T) Phenotypes for gene: TIMM50 were set to 3-methylglutaconic aciduria, type IX (MIM 617698) Penetrance for gene: TIMM50 were set to Complete Review for gene: TIMM50 was set to GREEN gene: TIMM50 was marked as current diagnostic Added comment: Biallelic pathogenic TIMM50 variants cause 3-methylglutaconic aciduria, type IX (MIM 617698). At least 9 affected individuals from 5 unrelated (but often consanguineous) families of variable origin have been reported (based on a conference abstract and PMIDs : 27573165, 30190335, 31058414). TIMM50 encodes encodes a subunit of the mitochondrial presequence import machinery called the TIM23 complex. TIMM50 serves as a major receptor in the intermembrane space that binds to proteins on their way to cross the mitochondrial inner membrane (summary by Shahrour et al., 2017 and OMIM). The highly overlapping patient clinical features [seizures, DD and ID - the latter in all age-appropriate individuals (5 from 3 families - refs 2,4)], metabolic investigations (lactate elevations in many, elevated urinary 3MGA in almost all, variable mitochondrial complex deficiencies in some), additional extensive functional evidence of mitochondrial dysfunction or the similar phenotypes in other types of 3-methylglutaconic aciduria all support a role for the gene. [AUH- / CLPB- / DNAJC19- / HTRA2- / OPA3- / SERAC1-related methylglutaconic acidurias are all included as relevant disorders in the ID panel, with the respective genes rated green.] TIMM50 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx). The gene is not associated with any phenotype in G2P As a result this gene could be considered for inclusion/upgrade as green in both ID and epilepsy panels respectively. --------- [1] - Serajee et al. (ASHG conference 2015 - abstract Nr. 2299T) reported on a patient born to consanguineous parents of South Asian ancestry with intractable epilepsy, microcephaly, DD and spastic quadriplegia. Metabolic investigations revealed increased urinary 3MGA. Two similarly affected sisters with demonstrated increase of 3MGA, were deceased following an infection. WES in the affected child, 2 unaffected sibs and the parents suggested a homozygous missense variant as the likely cause of the disorder in the proband (c.1114G>A / p.G372S - Reference not specified though the variant probably corresponds to ENST00000314349.4 and ClinVar's entry VCV000208697.1 - www.ncbi.nlm.nih.gov/clinvar/variation/208697/). [2] - Shahroor et al. (2017, PMID: 27573165) reported on 2 consanguineous families, each with 2 affected individuals. Two sibs from the 1st family (of Bedouin origin) presented with seizures (onset at 3m and 4m respectively), DD and ID with slightly elevated plasma lactate and increased urinary 3MGA upon metabolic investigations. Enzymatic activities of mitochondrial complex I-V were carried out for 1 sib and were normal also after normalization for citrate synthase. Following a SNP array, WES was carried out in affected children and their parents. Both sibs were homozygous for a missense SNV [NM_001001563.1:c.755C>T / p.Thr252Met]. Segregation studies - also in 3 unaffected sibs - supported a role for the variant. Two sibs from the 2nd family (of Muslim origin) presented with seizures (myoclonic jerks at 3m, generalized tonic movements at 2m - respectively) with DD and ID. Urinary 3MGA was elevated for both, with CSF lactate also elevated in one. WES revealed homozygosity for p.Arg217Trp (NM_001001563.1:c.649C>T) and segregation studies in parents and an unaffected sib were again compatible. The authors could not demonstrate pathogenicity of the variants in a yeast based system although - as also commented on in Ref 4 - the human TIMM50 could not rescue the yeast ΔΤim50 growth defect and global conservation between the two proteins is poor. [3] - Reyes et al. (2018, PMID: 30190335) reported on one individual with onset of infantile spasms at the age of 2m with hypsarrythmia upon EEG and psychomotor regression. Leigh-like features were noted upon brain MRI. Lactate was elevated in both plasma and CSF. Urinary 3MGA was normal. WES, Sanger confirmation and segregation studies demonstrated compound htz for 2 variants (NM_001001563:c.335C>A or p.S112* and c.569G>C or p.G190A). Functional studies demonstrated among others decrease in all components of the TIM23 complex and decreased mitochondrial membrane potential. Patient fibroblasts grown in glucose had lower levels of all complex II and IV subunits and one complex I subunit (due to the impairment in import system) with decreased mitochondrial respiration and increase in ROS production. Growth in galactose - shifting energy production toward OxPhos - caused massive cell death. The phenotype was rescued/substantially improved following complementation of patient fibroblasts with wt TIMM50. [4] - Tort et al. (2019, PMID: 31058414) reported on a boy with seizures and ID (diagnosis of West syndrome), Leigh-like MRI anomalies, cardiomyopathy with elevated plasma and CSF lactate and persistent urinary elevation of 3MGA. The proband was found to be compound heterozygous for 2 TIMM50 variants [NM_001001563.5:c.341 G>A (p.Arg114Gln) in trans with c.805 G>A (p.Gly269Ser)] following WES and Sanger confirmation/segregation studies. In patient fibroblasts TIMM50 protein levels were severely reduced upon WB although mRNA levels were similar to control. Muscle biopsy revealed decreased activity of the complexes I-IV, when normalized to the citrate synthase activity. Accumulation of lipidic material in muscle fibers was shown to be associated with mitochondria upon EM. Expression and sublocalization of mitochondria-targeted proteins were not found to be affected in patient fibroblasts. In extracts from muscle biopsy reduced protein levels of SDHA, COX4L and MTCO1 were demonstrated, in line with the disruptions in the activities of the MRC. Mitochondrial morphology and network were shown to be altered in patient fibroblasts. Patient fibroblasts showed marked reduction of max respiratory capacity. Similar reduction was noted in CRISPR/Cas9 generated TIMM50-ko HEK293T cells, but rescued upon transient transfection with a plasmid encoding for wt TIMM50. (Functional studies better summarized in the respective articles). Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.1021 | PAK1 |
Konstantinos Varvagiannis changed review comment from: Horn et al. (2019 - doi.org/10.1093/brain/awz264) report on 4 additional individuals with de novo missense PAK1 pathogenic variants. ID, seizures and macrocephaly and walking difficulties were observed in all (4/4). ASD was reported in 3 (but was not among the features in the study by Harms et al). PAK1 encodes p21 protein-activated kinase 1. The protein has 2 major domains, an autoregulatory and a protein kinase domain. Homodimerization masks the active site of the kinase, leading to autoinhibition (inactive form). PAK1 is activated by dissociation into monomers upon binding of the GTP-bound forms of the Rho GTPases CDC42 and RAC1. TRIO and HACE1 are indirect regulators of PAK1, via RAC1. PAK1 in turn, activates LIMK1 which plays a critical role in dendritic spine morphogenesis and brain function. CDC42, RAC1, TRIO, HACE1 are all associated with neurodevelopmental disorders. Activation of RAC-PAK1-LIMK1 pathway has been demonstrated for Fragile-X syndrome (sharing ID, macrocephaly and seizures). Mutations in PAK3, another member of the group I PAK subfamily with similar activation mechanism to PAK1 (by CDC42 / RAC1), cause Mental retardation, X-linked 30/47 (MIM 300558) (Green rating in the current panel). 4 additional missense variants - further to the 2 previously described ones - were found, all as de novo events: c.397T>C (p.Ser133Pro) / c.361C>T p.(Pro121Ser) / c.328T>A p.(Ser110Thr) / c.1409T>G (p.Leu470Arg) [For the specific variants, cDNA and aa change are the same for both NM_001128620.1 and NM_002576]. The 3 former variants located within the autoinhibitory domain while the latter in the protein kinase domain though - again - close to the autoinhibitory one (in tertiary structure). A gain of function effect by reduced ability of autoinhibition (leading to autophosphorylation) and activation of PAK1 is the suggested mechanism. Gain of function is also supported by the fact that Pak1-/- do not exhibit neurodevelopmental anomalies / abnormal head size. PAK1 is not particularly intolerant to LoF variants as suggested by its pLI of 0.67. The corresponding phenotype in OMIM is Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158). The gene is part of the DD panel of G2P, associated with "Neurodevelopmental Disorder" (monoallelic, activating / disease confidence : probable). PAK1 is included in the gene panel for ID offered by Radboudumc.; to: Based on a further recent study, PAK1 can probably be upgraded to green in both ID and epilepsy gene panels: Horn et al. (2019 - doi.org/10.1093/brain/awz264) report on 4 additional individuals with de novo missense PAK1 pathogenic variants. ID, seizures and macrocephaly and walking difficulties were observed in all (4/4). ASD was reported in 3 (but was not among the features in the study by Harms et al). PAK1 encodes p21 protein-activated kinase 1. The protein has 2 major domains, an autoregulatory and a protein kinase domain. Homodimerization masks the active site of the kinase, leading to autoinhibition (inactive form). PAK1 is activated by dissociation into monomers upon binding of the GTP-bound forms of the Rho GTPases CDC42 and RAC1. TRIO and HACE1 are indirect regulators of PAK1, via RAC1. PAK1 in turn, activates LIMK1 which plays a critical role in dendritic spine morphogenesis and brain function. CDC42, RAC1, TRIO, HACE1 are all associated with neurodevelopmental disorders. Activation of RAC-PAK1-LIMK1 pathway has been demonstrated for Fragile-X syndrome (sharing ID, macrocephaly and seizures). Mutations in PAK3, another member of the group I PAK subfamily with similar activation mechanism to PAK1 (by CDC42 / RAC1), cause Mental retardation, X-linked 30/47 (MIM 300558) (Green rating in the current panel). 4 additional missense variants - further to the 2 previously described ones - were found, all as de novo events: c.397T>C (p.Ser133Pro) / c.361C>T p.(Pro121Ser) / c.328T>A p.(Ser110Thr) / c.1409T>G (p.Leu470Arg) [For the specific variants, cDNA and aa change are the same for both NM_001128620.1 and NM_002576]. The 3 former variants located within the autoinhibitory domain while the latter in the protein kinase domain though - again - close to the autoinhibitory one (in tertiary structure). A gain of function effect by reduced ability of autoinhibition (leading to autophosphorylation) and activation of PAK1 is the suggested mechanism. Gain of function is also supported by the fact that Pak1-/- do not exhibit neurodevelopmental anomalies / abnormal head size. PAK1 is not particularly intolerant to LoF variants as suggested by its pLI of 0.67. The corresponding phenotype in OMIM is Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158). The gene is part of the DD panel of G2P, associated with "Neurodevelopmental Disorder" (monoallelic, activating / disease confidence : probable). PAK1 is included in the gene panel for ID offered by Radboudumc. (Previous review below) |
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| Intellectual disability - microarray and sequencing v2.1021 | PAK1 |
Konstantinos Varvagiannis edited their review of gene: PAK1: Added comment: Horn et al. (2019 - doi.org/10.1093/brain/awz264) report on 4 additional individuals with de novo missense PAK1 pathogenic variants. ID, seizures and macrocephaly and walking difficulties were observed in all (4/4). ASD was reported in 3 (but was not among the features in the study by Harms et al). PAK1 encodes p21 protein-activated kinase 1. The protein has 2 major domains, an autoregulatory and a protein kinase domain. Homodimerization masks the active site of the kinase, leading to autoinhibition (inactive form). PAK1 is activated by dissociation into monomers upon binding of the GTP-bound forms of the Rho GTPases CDC42 and RAC1. TRIO and HACE1 are indirect regulators of PAK1, via RAC1. PAK1 in turn, activates LIMK1 which plays a critical role in dendritic spine morphogenesis and brain function. CDC42, RAC1, TRIO, HACE1 are all associated with neurodevelopmental disorders. Activation of RAC-PAK1-LIMK1 pathway has been demonstrated for Fragile-X syndrome (sharing ID, macrocephaly and seizures). Mutations in PAK3, another member of the group I PAK subfamily with similar activation mechanism to PAK1 (by CDC42 / RAC1), cause Mental retardation, X-linked 30/47 (MIM 300558) (Green rating in the current panel). 4 additional missense variants - further to the 2 previously described ones - were found, all as de novo events: c.397T>C (p.Ser133Pro) / c.361C>T p.(Pro121Ser) / c.328T>A p.(Ser110Thr) / c.1409T>G (p.Leu470Arg) [For the specific variants, cDNA and aa change are the same for both NM_001128620.1 and NM_002576]. The 3 former variants located within the autoinhibitory domain while the latter in the protein kinase domain though - again - close to the autoinhibitory one (in tertiary structure). A gain of function effect by reduced ability of autoinhibition (leading to autophosphorylation) and activation of PAK1 is the suggested mechanism. Gain of function is also supported by the fact that Pak1-/- do not exhibit neurodevelopmental anomalies / abnormal head size. PAK1 is not particularly intolerant to LoF variants as suggested by its pLI of 0.67. The corresponding phenotype in OMIM is Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM 618158). The gene is part of the DD panel of G2P, associated with "Neurodevelopmental Disorder" (monoallelic, activating / disease confidence : probable). PAK1 is included in the gene panel for ID offered by Radboudumc.; Changed rating: GREEN; Changed publications: 30290153, doi.org/10.1093/brain/awz264; Set current diagnostic: yes |
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| Intellectual disability - microarray and sequencing v2.611 | CYFIP2 |
Konstantinos Varvagiannis gene: CYFIP2 was added gene: CYFIP2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CYFIP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CYFIP2 were set to 29534297; 29667327; 30664714; 25432536; 27524794; 12818175; 20537992 Phenotypes for gene: CYFIP2 were set to Epileptic encephalopathy, early infantile 65, 618008 Penetrance for gene: CYFIP2 were set to unknown Review for gene: CYFIP2 was set to GREEN gene: CYFIP2 was marked as current diagnostic Added comment: Heterozygous pathogenic variants in CYFIP2 cause Epileptic encephalopathy, early infantile, 65 (MIM 618008) -------------- [Apologies for any eventual mistakes esp.as for the functional evidence]: Nakashima et al. (2018 - PMID: 29534297) report on 4 unrelated individuals with early-onset epileptic encephalopathy due to de novo missense CYFIP2 variants. The phenotype consisted of early-onset intractable seizures (diagnosis of West syndrome in 2, Ohtahara syndrome in further individuals) with hypotonia (3/4), DD/ID (4/4) and microcephaly (3/4). All variants affected Arg87 residue (NM_001037333.2:c.259C>T or p.Arg87Cys in 2 individuals, the 2 other subjects harbored Arg87Leu and Arg87Pro respectively). CYFIP2 encodes the cytoplasmic FMRP interacting protein 2. CYFIP2 (similar to CYFIP1) is a component of the WAVE regulatory complex (WRC) which has been shown to play a role in actin remodeling, axon elongation, dendritic morphogenesis and synaptic plasticity (several PMIDs cited). In the inactive state of the WRC complex, CYFIP2 binds to the VCA domain of WAVE. GTP-bound Rac1 (GTPase) leads to release of the VCA domain from CYFIP2 which allows binding of this domain to the Arp2/3 complex (active WRC state) and in turn stimulates actin polymerization and lamellipodia formation. Using lymphoblastoid cell lines from affected individuals and healthy controls and CYFIP2 expression was evaluated by Western Blot and was found to be similar between the 2 groups. Additional studies suggested weaker binding of the WAVE1 VCA domain to mutant CYFIP2 compared to WT CYFIP2 (upon transfection of HEK293T cells). This could possibly favor activation of WRC (/the WAVE signalling pathway). As a result a gain-of-function effect on the WAVE signalling pathway is suggested as a possible mechanism. Using B16F1 mouse melanoma cells lamellipodia formation (process in which CYFIP2 has previously been implicated) was not shown to be impaired in the case of mutant CYFIP2. However aberrant accumulation of F-actin (and co-localization with mutant CYFIP2) was observed in the present study. Only large 5q deletions spanning CYFIP2 (and several other genes) have been described to date. Cyfip2 heterozygous knockout in mice results in abnormal behavior and memory loss. WAVE activity was enhanced (despite reduced WAVE protein production). Homozygous Cyfip2 loss is lethal (PMIDs cited by the authors: 25432536, 27524794). Impaired axonal growth, guidance and branching is noted in Drosophila mutants (CYFIP1/2 ortholog) (PMID cited: 12818175). The authors comment that Cyfip2 (nev) mutant zebrafish show a similar phenotype to mutant flies (PMID cited: 20537992). -------------- Peng et al. (2018 - PMID: 29667327) in a study of 56 Chinese families with West Syndrome (epileptic/infantile spasms, hypsarrhytmia and ID) identified 1 individual with the Arg87Cys CYFIP2 variant as a de novo occurrence. -------------- Zweier et al. (2019 - DDD study among the co-authors - PMID: 30664714) report on 12 unrelated subjects with heterozygous pathogenic de novo CYFIP2 variants. The common phenotype consisted of tone abnormalities (12/12), DD/ID (12/12) and seizures (12/12 though a single individual had experienced a single episode of febrile seizure). Absolute or relative microcephaly and/or additional features were also noted in several individuals. 7 missense variants (4 occurrences of the Arg87Cys variant) as well as splice variant (shown to lead to exon skipping) are reported, as de novo events in these individuals. The splice variant was expected to escape NMD producing a truncating protein. Although the variants are distantly located in the primary structure, spatial clustering (in the tertiary structure) is suggested by in silico modelling (all in proximity at the CYFIP2-WAVE1 interface). CYFIP2 appears to be intolerant to both missense and LoF variants (Z-score of 6.15 and pLI of 1 respectively in ExAC). The authors comment that haploinsufficiency as a mechanism is rather unlikely given the absence of small CNVs or variants predicted to lead to NMD. Again, a gain-of-function effect of these variants on WAVE activation (partial-loss-of function in terms of WRC stabilization and/or conformation of the VCA region in the inactive state) is proposed. -------------- CYFIP2 is not associated with any phenotype in G2P. The gene is included in gene panels for intellectual disability offered by some diagnostic laboratories (eg. participants in these studies). -------------- As a result this gene could be considered for inclusion in this panel as green. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.509 | RAC3 |
Konstantinos Varvagiannis gene: RAC3 was added gene: RAC3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: RAC3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RAC3 were set to 30293988; 29276006 Phenotypes for gene: RAC3 were set to Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability Penetrance for gene: RAC3 were set to unknown Mode of pathogenicity for gene: RAC3 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: RAC3 was set to GREEN Added comment: PMID: 30293988 reports on 5 individuals (from 4 different families) with de novo missense variants in RAC3. All individuals demonstrated structural anomalies on brain MRI (notably agenesis/dysgenesis of the corpus callosum, variable degrees of polymicrogyria and ventricular anomalies) as well as shared non-specific neurological features including abnormal muscular tone, global developmental delay and severe to profound intellectual disability. Feeding difficulties were observed in 4/5 patients. All variants reported are missense and are presumed to result in constitutive protein activation, as suggested by previous observations either in RAC3 [eg. the p.(Gln61Leu) mutation] or the highly homologous RAC1 and RAC2. According to the authors this is further supported by the fact that Rac3 -/- mice do not show a severe phenotype while missense variants are underrepresented in the ExAC database (z=1.97) as opposed to loss-of-function variants (pLI=0.04 / probability of loss-of-function intolerance). Of the 3 SNVs reported, 2 variants were in adjacent amino-acid positions [p.(Gln61Leu) and p.(Glu62Lys)]. The latter variant was found in 2 half-sibs born to different fathers, due to suspected maternal gonadal mosaicism (variant absent in all sequencing reads in the maternal DNA sample). The specific variant was also found in a further affected individual from an unrelated family. Finally, as the authors point out a further individual with de novo RAC3 missense variant [p.(Ala59Gly)] was reported previously in an individual with thin corpus callosum and global developmental delay, although the phenotype was felt to be more reminiscent of Robinow syndrome (PMID: 29276006). As a result, this gene can be considered for inclusion in the ID panel as green (or amber). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.468 | RAC1 | Louise Daugherty Source Victorian Clinical Genetics Services was added to RAC1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | RAC1 | Ellen McDonagh Added gene to panel | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||