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| Intellectual disability - microarray and sequencing v5.325 | RBL2 | Sarah Leigh edited their review of gene: RBL2: Added comment: RBL2 variants have been associated with Brunet-Wagner neurodevelopmental syndrome (OMIM:619690) but not with phenotype in Gen2Phen. To date six RBL2 variants have been reported in four unrelated cases of OMIM:619690 (PMIDs: 32105419; 33980986).; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.325 | RBL2 | Sarah Leigh Phenotypes for gene: RBL2 were changed from intellectual diability to Brunet-Wagner neurodevelopmental syndrome, OMIM:619690 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.1 | Arina Puzriakova Panel version 5.0 has been signed off on 2023-03-22 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.1 | Eleanor Williams Panel version 4.0 has been signed off on 2022-11-30 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1648 | CNNM2 | Eleanor Williams Phenotypes for gene: CNNM2 were changed from Hypomagnesemia, seizures, and mental retardation 616418 to Hypomagnesemia, seizures, and mental retardation, OMIM:616418; Hypomagnesemia, seizures, and mental retardation, MONDO:0014631 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1556 | FBXW7 |
Konstantinos Varvagiannis gene: FBXW7 was added gene: FBXW7 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: FBXW7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FBXW7 were set to 33057194; 35395208; 30885698; 26482194; 19963109; 20332316 Phenotypes for gene: FBXW7 were set to Neurodevelopmental abnormality; Global developmental delay; Intellectual disability; Macrocephaly; Microcephaly; Abnormality of brain morphology; Abnormality of the corpus callosum; Abnormality of the cerebellum; Abnormality of the cardiovascular system; Seizures; Strabismus; Abnormality of the palate Penetrance for gene: FBXW7 were set to unknown Review for gene: FBXW7 was set to AMBER Added comment: While Kaplanis et al (2020 - Ref1), identified FBXW7 among 285 genes significantly associated with developmental disorders, a recent study by Stephenson et al (2022 - Ref2) describes the neurodevelopmental phenotype of 35 individuals making this gene relevant to the current panel. There are previous reports of dn/inh germline variants in individuals (likely 7) with tumor predisposition although a neurodevelopmental phenotype was not reported in most cases. There is currently no FBXW7-related phenotype in OMIM. The gene is included in the DD panel of G2P [associated with: FBXW7-related developmental disorder (monoallelic), confidence: definitive, citing the study by Kaplanis et al]. SysID lists FBXW7 among the candidate ID genes (same Ref.). The gene has a green rating for ID in PanelApp Australia (VCGS participating in the recent publication). Consider inclusion with amber/green rating. Also consider inclusion in other panels that may be relevant(macro/microcephaly, seizures, CHD, corpus callosum / cerebellar abnormalities, cleft palate, WT, etc). [1]------------ Kaplanis et al (2020 - PMID: 33057194), by combining exome data from 31,058 parent offspring trios from the DDD study, Radboudumc and GeneDx, identified 285 genes significantly associated with developmental disorders, 28 of which (incl. FBXW7) not previously robustly associated with these disorders. [2]------------ Stephenson et al (2022 - PMID: 35395208) provide clinical information on 35 individuals harboring germline monoallelic FBXW7 variants or chromosomal deletions spanning this gene. The phenotype corresponded to a phenotypically variable NDD characterized by hypotonia (in about 2/3), neurodevelopmental abnormality (34/35 - as discussed later), seizures (8/35), abnormal brain morphology (13/17 - in 7/17 abnormal CC, in 5/17 abn. cerebellum, etc), head circumference (macrocephaly in 10/35, microcephaly in 2/35). Additional features included abnormal palate or uvula morphology (10/35 - cleft palate in 3 from 2 families while 1 individual from a 3rd family had bifid uvula) or abnormal heart morphology (11/35), ophthalmologic features (e.g. strabismus in 5/35) or hearing impairment (2/35). There was no recognizable gestalt (deeply set eyes with upper eyelid fullness in 9/35). As for the DD/ID this ranged from borderline to severe, characterized as mild-moderate in 27/35, severe in 3/35. One individual did not present neurodevelopmental abnormality 1/35. FBXW7 encodes F-box and WD40 domain protein 7 which is part of the SCF E3 ligase complex (SKP1/CUL1/F-box protein) exerting a role of recognition and binding of target proteins for degradation by the ubiquitin proteasome system. In this way FBWX7 participates in regulating a network of proteins involved in cell division, growth, differentiation (as summarized by Roversi et al - Ref2). Most individuals were investigated by trio-WES/WGS (few with singleton WES or CMA only). 28 germline FBXW7 variants were identified incl. missense (N=21), pLoF (predicted or not to undergo NMD) and 2 deletions encompassing but not limited to FBXW7. Additional SNVs/CNVs (e.g. an inh intragenic DPP6 dup in one individual (#9) with deletion, other de novo 4q CNVs (#10), an inh 22q spanning partially an ISCA TS region, a CACNA1A and KMT2D SNV, etc) were reported in few individuals. Most variants arose dn (N=30) with two individuals displaying mosaicism (2/30) and three individuals having inherited the variant from their affected parent. CNVs had occurred dn. 3 missense SNVs were recurrent in unrelated individuals. All variants identified affected all FBXW7 isoforms. As the authors comment missense variants clustered at the C-terminal half of the protein with most (16/21) occurring within the WD40 domain. [The N-terminal part commented in the literature to affect localization]. The crystal structure of FBXW7 and SKP1 complex has been determined with CYCLIN E1/DISC1 as substrates, and in silico modeling revealed that all missense variants aligned with residues required for this interaction, or adjacent ones. All were absent from gnomAD, while missense variants from gnomAD (N=78) were not predicted have significant effect on the binding affinity. Variant studies revealed that most missense variants (6/7 tested - Arg689Gln being the exception) are unlikely to cause protein instability or degradation in vivo. Co-expression of these missense variants with CYCLIN E1 / E2, known FBXW7 substrates revealed that variants were less efficient at degrading the substrate with variants in the WD40 domain having greater impact (in some cases E1 / E2 - specific). Elav-Gal4 mediated neuronal knockdown of the Drosophila ortholog archipelago (ago) using 2 RNAi-s with different efficiency was shown to affect learning or compromise neuronal function (also related to the level of knockdown). The authors summarize results from animal models for the role of this gene in development and the nervous system. KO mice die in utero at E10.5 manifesting abn. of hematopoietic or vascular development and heart-chamber maturation(*). Some htz knock-in for human cancer variants, display perinatal lethality, abn lung, cleft palate (30%)(*),etc. Conditional gut specific deletion results in impaired differentiation of intestinal goblet cells (*)(constipation in 16/35 in cohort). KO limited to CNS and PNS results in defective sucking and morphological brain abnormalities. Haploinsufficiency in the nervous system was associated with impaired differentiation of neural stem cells (possibly through a Notch-mediated mechanism). KO in Schwann cells of the peripheral nervous system resulted in enhanced myelination. Excessive oligodendrocyte cells and hypermyelination (as a result of elevated Notch & mTOR signaling) are observed in homozygous mutant zebrafish or after morpholino-mediated fbxw7 knockdown. Overall, the authors propose haploinsufficiency or loss-of-function as the underlying mechanism. Finally, as the authors comment, FBXW7 is a tumor suppressor among the most commonly mutated genes in human cancer (3.5%). Germline variants have been previously reported in individuals with cancer (Wilms tumor, rhabdoid, etc - most summarized below). However, none of the 35 individuals in this cohort (oldest 44 y.o.) had any history of cancer. Reports of individuals with germline variants causing (monoallelic) disruption of FBXW7 - cases without DD/ID: [3]------------ Mahamdallie et al (2019 - PMID: 30885698) investigated with WES a cohort of 890 individuals with Wilms tumor (799 non-familial disease, 91 from WT pedigrees). In this context they identified 4 individuals having developed WT (ages: 28-76m) with FBXW7 dn or inherited LoF variants (710G>A / p.Trp237* dn - 1972C>T / p.Arg658* - inh:NA, 1017_1021del5, 670C>T - paternal / p.Arg224* inh:NA - RefSeq not provided). One additional individual with a missense variant (1753A>T / p.Ser585Cys - dn) had developed rhabdoid tumor. While the authors mentioned additional features for other subjects in their cohort, among the 5 individuals with FBXW7 variants, only one had hypotonia (ID_0592) and another (ID_7520) had two febrile convulsions. [4]------------ Roversi et al (2015 - PMID: 26482194) described the phenotype of a 34 y.o. female with syndromic presentation (macrocephaly, nephrotic syndrome due to FSGS, Hodgkin's lymphoma, Wilms tumor, ovarian cystadenoma, breast carcinoma) harboring a 157 kb deletion of 4q31.3. Eventual DD/ID was not reported despite detailed clinical description. The deletion spanned almost the entire FBXW7 gene and a pseudogene (hg19 - chr4:153205202-153362047). The authors provided evidence that the del affected the maternal allele as dn event (maternal mosaicism excluded). Expression of FBXW7 in patient-derived EBV lymphoblastoid cell line revealed decreased levels of expression compared to controls. At somatic level, the authors looked for eventual 2nd hit in tumor tissue (which was not the case) while they demonstrated decreased FBXW7 expression in a WT sample compared to normal renal tissue. Previously, variants in other genes candidate for the phenotype were ruled out (Sanger & MLPA for TP53, BRCA1/2, PALB2, WT1, 11p15 MS-MLPA, std karyotype). [5]------------ Kuiper et al (2015 - PMID: 19963109), in a 58 y.o. patient with recurrence of RCC, identified a constitutional translocation [t(3;4)(q21;q31)]. Using long-range PCR they defined the breakpoints at 3q21.3 (128379059 - hg18) between the PLXNA1 and C3orf56 genes while the chr4 breakpoint was located within the second intron of FBXW7 (pos. 153500813 - hg18). There were no additional phenotypes reported. [6]------------ Williams et al (2010 - PMID: 20332316) reported a patient with WT harboring germline variants in WT1 and FBXW7. While the phenotype was sufficiently explained by a germline stopgain WT1 variant with a frameshift WT1 variant (as 2nd hit) confined to the tumor, the authors identified a germline in-frame FBXW7 insertion in the same individual (c.45_46insCCT / p.Thr15_Gly16insPro - RefS : NA) [if correct corresponding to: https://gnomad.broadinstitute.org/variant/4-153332910-C-CAGG - 345/281696 alleles in gnomAD]. Sources: Literature |
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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 v3.704 | SCN8A | Ivone Leong Added comment: Comment on mode of inheritance: MOI was changed back from "Both monoallelic and biallelic" to "Monoallelic", which reflects the original MOI of the signed off panel (version 3.2). The MOI will be changed back to "Both monoallelic and biallelic" after the panel has been reviewed. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.703 | ALKBH8 | Ivone Leong Added comment: Comment on list classification: This gene has been promoted back to Green status to reflect the rating that was on the signed off version of this panel (version 3.2). This gene should be demoted to Amber at the next review. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.483 | PIGP | Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.482 | PUM1 | Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.481 | RALGAPA1 | Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.480 | RARS | Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.479 | RNF113A | Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.478 | RNF13 | Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.477 | GAD1 | Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.476 | CEP55 | Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.475 | CTU2 | Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.474 | ALG9 | Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.473 | EXT2 | Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.472 | PTRHD1 | Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.471 | TRAPPC4 | Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.470 | UGP2 | Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.469 | CXorf56 | Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.468 | KAT8 | Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.467 | SLC5A6 | Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.466 | SNX27 | Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.465 | WNT1 | Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.464 | PIGK | Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.459 | ALG14 | Arina Puzriakova Added comment: Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.314 | LMNB1 |
Konstantinos Varvagiannis gene: LMNB1 was added gene: LMNB1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: LMNB1 were set to 32910914 Phenotypes for gene: LMNB1 were set to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis Penetrance for gene: LMNB1 were set to unknown Mode of pathogenicity for gene: LMNB1 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: LMNB1 was set to GREEN Added comment: Cristofoli et al (2020 - PMID: 32910914) report 7 individuals (from 5 families) harboring mostly de novo LMNB1 variants. The common phenotype consisted of primary microcephaly (7/7 ranging from -4.4 to -10 SD), DD/ID (7/7), relative short stature in most (+0.7 to -4 SD). Additional features included brain MRI abnormalities (abnormal CC in 3, simplified gyral pattern in 3, small structurally normal brain, etc), seizures (4 individuals from 2 families), limb spasticity (1/7), cortical visual impairment (in 3), feeding difficulties (5/7), scoliosis (4/7). Non-overlapping dysmorphic features were reported in some. Variants were identified by WES or custom-designed gene panel and included 3 missense variants, 1 in-frame deletion and a splice variant. The in-frame deletion was inherited from a similarly affected parent in whom the variant occurred as a dn event. The splice SNV(NM_005573.3:c.939+1G>A) occurred in 3 sibs and was present as mosaic variant (15%) in the parent. This variant was predicted to result to extension of exon 5 by 6 amino-acids (samples were unavailable for mRNA studies). LMNB1 encodes a B-type lamin (the other being encoded by LMNB2). A- and B- type lamins are major components of the nuclear lamina. As the authors comment, LMNB1 is expressed in almost all cell types beginning at the earliest stages of development. Lamin-deficient mouse models support an essential role of B-type lamins in organogenesis, neuronal migration, patterning during brain development. Functional studies performed, demonstrated impaired formation of LMNB1 nuclear lamina in LMNB1-null HeLa cells transfected with cDNAs for 3 missense variants. Two variants (Lys33Glu/Arg42Trp) were shown to result in decreased nuclear localization with increased abundance in the cytosolic fraction. In patient derived LCLs these variants led to abnormal nuclear morphology. A missense variant in another domain (Ala152Gly - 1st coil domain) resulted also in lower abundance of lamin B1, irregular lamin A/C nuclear lamina, as well as more condensed nuclei (HeLa cells). LMNB1 duplications or missense mutations increasing LMNB1 expression are associated with a different presentation of AD leuodystrophy. A variant previously associated with leukodystrophy (Arg29Trp) was shown to behave differently (present in the nuclear extract but not in the cytosol, lamin B1 to A/C ratio in nuclear extract was not significantly altered compared to wt as was the case for Arg42Trp, Lys33Glu). Given the pLI score of 0.55 as well as the phenotype of individuals with deletions (not presenting microcephaly) the authors predict that a dominant-negative effect applies (rather than haploinsufficiency). Consider inclusion in the following panels : DD/ID (green), epilepsy (amber - 4 of 7 patients belonging to 2 families), primary microcephaly (green), callosome (amber/green - 3 individuals belonging to 3 families), mendeliome (green), etc. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.206 | GNE | Arina Puzriakova Classified gene: GNE as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.206 | GNE | Arina Puzriakova Added comment: Comment on list classification: Rating Amber in view of the mild ID phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.206 | GNE | Arina Puzriakova Gene: gne has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.205 | GNE | Arina Puzriakova reviewed gene: GNE: Rating: AMBER; Mode of pathogenicity: None; Publications: 32053088, 29923088, 10356312, 11326336, 11486897, 27142465; Phenotypes: Sialuria, 269921; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.87 | CDC42BPB | Sarah Leigh Added comment: Comment on phenotypes: CDC42BPB-related Neurodevelopmental Disorder is assigned by Gen2Phen. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.3 | Rebecca Foulger Panel version has been signed off | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.0 | GNE |
Zornitza Stark gene: GNE was added gene: GNE was added to Intellectual disability. Sources: Expert list Mode of inheritance for gene: GNE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: GNE were set to Sialuria, MIM#269921 Review for gene: GNE was set to GREEN gene: GNE was marked as current diagnostic Added comment: Metabolic disorder with varying degrees of ID being a feature. Bi-allelic variants cause Nonaka myopathy, MIM#605820 Sources: Expert list |
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| Intellectual disability - microarray and sequencing v3.0 | CLDN19 | Zornitza Stark reviewed gene: CLDN19: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypomagnesemia 5, renal, with ocular involvement, MIM# 248190; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1143 | AFF3 |
Konstantinos Varvagiannis changed review comment from: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence. The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy]. 9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13. AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development. Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot. Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study]. Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects. Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant. Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3. ---- Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)]. ---- In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM. Some diagnostic laboratories include AFF3 in their ID panel (eg. among the many co-authors' affiliations GeneDx and Victorian Clinical Genetics - which was already listed as source for AFF3 in the current panel). ---- As a result this gene can be considered for upgrade to green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article). [Review modified to add additional reference/case report]; to: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb deletion affecting only AFF3 (LAF4) and removing also this sequence. The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy]. 9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13. AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development. Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot. Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study]. Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects. Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant. Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3. ---- Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)]. ---- In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM. Some diagnostic laboratories include AFF3 in their ID panel (eg. among the many co-authors' affiliations GeneDx and Victorian Clinical Genetics - which was already listed as source for AFF3 in the current panel). ---- As a result this gene can be considered for upgrade to green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article). [Review modified to add additional reference/case report] |
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| Intellectual disability - microarray and sequencing v2.1143 |
Rebecca Foulger List of related panels changed from Coarse facial features including Coffin-Siris-like disorders; ID; Moderate; severe or profound intellectual disability; Schizophrenia plus additional features; Intellectual disability - microarray; fragile X and sequencing to Coarse facial features including Coffin-Siris-like disorders; ID; Moderate; severe or profound intellectual disability; Schizophrenia plus additional features; Intellectual disability - microarray; fragile X and sequencing; R29 Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; Component Of Super Panel; GMS signed-off |
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| Intellectual disability - microarray and sequencing v2.1021 | MED13 |
Konstantinos Varvagiannis changed review comment from: Snijders Blok et al. (2018 - PMID: 29740699) report on 13 individuals with MED13 mutations. Features included DD with speech difficulties (both universal) and motor delay in some. ID was observed in at least 9/13 and in most cases was in the borderline/mild range (moderate ID reported for 1 individual). Other features were ASD (5/13), ADHD, eye/vision abnormalities and in few individuals obstipation or congenital heart anomalies. Some possibly overlapping facial characteristics were also noted. MED13 and MED13L are mutually exclusive components of the CDK8 kinase module that regulates the activity of the Mediator complex. The Mediator transmits signals from various transcription factors to RNA polymerase II (Pol II). Reversible binding of the CDK8 kinase controls Mediator - Pol II interaction (prevents Pol II recruitment) and thus acts as a molecular switch in Pol II - mediated transcription. DD and ID are features of the MED13L- and CDK8- related disorders. 3 stopgain, 2 frameshift, 6 missense variants and 1 in-frame deletion were reported. In 11 cases, the variants had occurred as de novo events, while 1 individual had inherited a nonsense variant from a similarly affected mother (unknown inheritance in her case). Effect of a stopgain variant was studied with similar (total) transcript levels between the affected patient and his parents/controls upon qPCR. Sanger sequencing of cDNA amplicons was suggestive of the presence of an aberrant transcript at ~70% levels relative to the normal transcript. Truncated protein was undetectable by Western Blot in mononuclear blood cells from affected subjects. Total MED13 protein levels were not clearly different when comparing an affected individual with his unaffected parent (?). Missense variants and the inframe deletion clustered either in the N- or the C-terminal domain, with the N-terminal ones all (T326I, T326del, P327S, P327Q / NM_005121.2 - NP_005112.2) affecting positions of a known phosphodegron sequence, important for the protein's ubiquitination and degradation. Another previously studied variant (T326A) had been shown to prevent degradation. As a result, the variants affecting aa 326-327 might lead to altered (increased) levels of MED13. The remaining missense variants affected the C-terminal portion (Q2060L, A2064V). As a result the impact of the different subcategories of variants remains unclear/inconclusive. MED13 is not associated with any phenotype in OMIM. This gene is part of the DD panel of G2P, associated with "MED13 - Neurodevelopment disorder" (dis. confidence : probable / mutation consequence : LoF / GDD, speech/language delay, ID, autistic behavior among the assigned phenotypes). MED13 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc). ID is part of the phenotype of MED13-related disorder, however as the severity in most individuals - when present - was in the borderline/mild range (not relevant for the present panel) and/or the underlying effect of mutations remains unclear, amber rating can probably be considered for this gene. Sources: Radboud University Medical Center, Nijmegen, Literature; to: Snijders Blok et al. (2018 - PMID: 29740699) report on 13 individuals with MED13 mutations. Features included DD with speech difficulties (both universal) and motor delay in some. ID was observed in at least 9/13 and in most cases was in the borderline/mild range (moderate ID reported for 1 individual). Other features were ASD (5/13), ADHD, eye/vision abnormalities and in few individuals obstipation or congenital heart anomalies. Some possibly overlapping facial characteristics were also noted. MED13 and MED13L are mutually exclusive components of the CDK8 kinase module that regulates the activity of the Mediator complex. The Mediator transmits signals from various transcription factors to RNA polymerase II (Pol II). Reversible binding of the CDK8 kinase controls Mediator - Pol II interaction (prevents Pol II recruitment) and thus acts as a molecular switch in Pol II - mediated transcription. DD and ID are features of the MED13L- and CDK8- related disorders. 3 stopgain, 2 frameshift, 6 missense variants and 1 in-frame deletion were reported. In 11 cases, the variants had occurred as de novo events, while 1 individual had inherited a nonsense variant from a similarly affected mother (unknown inheritance in her case). Effect of a stopgain variant was studied with similar (total) transcript levels between the affected patient and his parents/controls upon qPCR. Sanger sequencing of cDNA amplicons was suggestive of the presence of an aberrant transcript at ~70% levels relative to the normal transcript. Truncated protein was undetectable by Western Blot in mononuclear blood cells from affected subjects. Total MED13 protein levels were not clearly different when comparing an affected individual with his unaffected parent (?). Missense variants and the inframe deletion clustered either in the N- or the C-terminal domain, with the N-terminal ones all (T326I, T326del, P327S, P327Q / NM_005121.2 - NP_005112.2) affecting positions of a known phosphodegron sequence, important for the protein's ubiquitination and degradation. Another previously studied variant (T326A) had been shown to prevent degradation. As a result, the variants affecting aa 326-327 might lead to altered (increased) levels of MED13. The remaining missense variants affected the C-terminal portion (Q2060L, A2064V). As a result the impact of the different subcategories of variants remains unclear/inconclusive. MED13 is not associated with any phenotype in OMIM. This gene is part of the DD panel of G2P, associated with "MED13 - Neurodevelopment disorder" (dis. confidence : probable / mutation consequence : LoF / GDD, speech/language delay, ID, autistic behavior among the assigned phenotypes). MED13 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc). ID is part of the phenotype of MED13-related disorder. However as the severity in most individuals - when present - was in the borderline/mild range (not relevant for the present panel) and/or the underlying effect of mutations remains unclear, amber rating seems more appropriate. Sources: Radboud University Medical Center, Nijmegen, Literature |
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| Intellectual disability - microarray and sequencing v2.1021 | MED13 |
Konstantinos Varvagiannis gene: MED13 was added gene: MED13 was added to Intellectual disability. Sources: Radboud University Medical Center, Nijmegen,Literature Mode of inheritance for gene: MED13 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MED13 were set to 29740699 Phenotypes for gene: MED13 were set to Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Attention deficit hyperactivity disorder; Abnormality of the eye; Constipation Penetrance for gene: MED13 were set to unknown Review for gene: MED13 was set to AMBER gene: MED13 was marked as current diagnostic Added comment: Snijders Blok et al. (2018 - PMID: 29740699) report on 13 individuals with MED13 mutations. Features included DD with speech difficulties (both universal) and motor delay in some. ID was observed in at least 9/13 and in most cases was in the borderline/mild range (moderate ID reported for 1 individual). Other features were ASD (5/13), ADHD, eye/vision abnormalities and in few individuals obstipation or congenital heart anomalies. Some possibly overlapping facial characteristics were also noted. MED13 and MED13L are mutually exclusive components of the CDK8 kinase module that regulates the activity of the Mediator complex. The Mediator transmits signals from various transcription factors to RNA polymerase II (Pol II). Reversible binding of the CDK8 kinase controls Mediator - Pol II interaction (prevents Pol II recruitment) and thus acts as a molecular switch in Pol II - mediated transcription. DD and ID are features of the MED13L- and CDK8- related disorders. 3 stopgain, 2 frameshift, 6 missense variants and 1 in-frame deletion were reported. In 11 cases, the variants had occurred as de novo events, while 1 individual had inherited a nonsense variant from a similarly affected mother (unknown inheritance in her case). Effect of a stopgain variant was studied with similar (total) transcript levels between the affected patient and his parents/controls upon qPCR. Sanger sequencing of cDNA amplicons was suggestive of the presence of an aberrant transcript at ~70% levels relative to the normal transcript. Truncated protein was undetectable by Western Blot in mononuclear blood cells from affected subjects. Total MED13 protein levels were not clearly different when comparing an affected individual with his unaffected parent (?). Missense variants and the inframe deletion clustered either in the N- or the C-terminal domain, with the N-terminal ones all (T326I, T326del, P327S, P327Q / NM_005121.2 - NP_005112.2) affecting positions of a known phosphodegron sequence, important for the protein's ubiquitination and degradation. Another previously studied variant (T326A) had been shown to prevent degradation. As a result, the variants affecting aa 326-327 might lead to altered (increased) levels of MED13. The remaining missense variants affected the C-terminal portion (Q2060L, A2064V). As a result the impact of the different subcategories of variants remains unclear/inconclusive. MED13 is not associated with any phenotype in OMIM. This gene is part of the DD panel of G2P, associated with "MED13 - Neurodevelopment disorder" (dis. confidence : probable / mutation consequence : LoF / GDD, speech/language delay, ID, autistic behavior among the assigned phenotypes). MED13 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc). ID is part of the phenotype of MED13-related disorder, however as the severity in most individuals - when present - was in the borderline/mild range (not relevant for the present panel) and/or the underlying effect of mutations remains unclear, amber rating can probably be considered for this gene. Sources: Radboud University Medical Center, Nijmegen, Literature |
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| Intellectual disability - microarray and sequencing v2.996 | AFF3 |
Konstantinos Varvagiannis changed review comment from: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence. The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy]. 9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13. AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development. Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot. Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study]. Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects. Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant. Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3. ---- In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM. Some diagnostic laboratories include AFF3 in their ID panel (eg. among the many co-authors' affiliations GeneDx and Victorian Clinical Genetics - which was already listed as source for AFF3 in the current panel). ---- As a result this gene can be considered for upgrade to green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).; to: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence. The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy]. 9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13. AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development. Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot. Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study]. Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects. Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant. Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3. ---- Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)]. ---- In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM. Some diagnostic laboratories include AFF3 in their ID panel (eg. among the many co-authors' affiliations GeneDx and Victorian Clinical Genetics - which was already listed as source for AFF3 in the current panel). ---- As a result this gene can be considered for upgrade to green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article). [Review modified to add additional reference/case report] |
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| Intellectual disability - microarray and sequencing v2.938 | TRPM3 |
Konstantinos Varvagiannis changed review comment from: Dyment et al. (2019 - https://doi.org/10.1038/s41431-019-0462-x) report on 7 unrelated individuals with a recurrent de novo TRPM3 missense variant [NM_020952.4:c.2509G>A - NP_066003.3:p.(Val837Met)] as well as an additional individual with a further de novo missense variant [c.2810C>A or p.(Pro937Gln) - same ref. sequences]. Overlapping features included hypotonia (7/8 - in one case mixed tone abnormality), DD/ID (8/8 - all individuals at appropriate age - degree relevant), EEG-confirmed epilepsy (7/8). Autism-like features were observed in 4 (out of 6 for whom this information was reported). Other features were noted in a minority (or were private to certain) of these individuals. Different clinical types of seizures were reported incl. absence, generalized-toni-clonic, infantile spasms as well as subclinical ones. Onset was in infancy or early childhood. In all individuals the variant was found following trio exome sequencing. The first variant fulfilled ACMG criteria to be classified as pathogenic due to it's de novo occurrence, prevalence in affected individuals (>=6 affected individuals and in the same time) absence from population databases, in silico predictions in favour of pathogenicity (PS2, PS4_Moderate, PM2, PP3). The Pro937Gln variant is however classified as a VUS. The subject harboring this variant had an additional de novo variant in another gene (DDB1) not associated with any phenotype, to date. Several other genetic causes had previously been ruled out for most individuals by other investigations : aCGH was normal in all, FMR1 testing in 6 subjects, genes (PHF6, MECP2, MCT8) or smaller panels for ID (the latter in 3 subjects), mtDNA or testing of nuclear genes for mitochondrial disorders, etc. TRPM3 encodes transient receptor potential (TRP) cation channel, subfamily M, member 3. TRP channels are a superfamily of gated cation channels sensitive to various physical or chemical stimuli (Clapham 2003 - PMID: 14654832 cited) eg. temperature or pain. The gene is highly expressed in the brain in humans and other vertebrates (Grimm et al. 2003 - PMID : 12672799 and GTEx - https://gtexportal.org/home/gene/TRPM3). Animal models : In rat brain, expression is initially restricted to neurons but later - as myelination progresses - shifts to oligodendrocytes (cited : Hoffmann et al. 2010 - PMID: 20163522). Most subjects had normal brain MRI appart from one individual with nonspecific white matter hyperintensities and another with possible mild cerebral volume loss. Trpm3 -/- mice show attenuated nocifensive behavior after heat or dermal injection of pregnenolone sulfate. Heat or pain insensitivity was reported only for 2 individuals. Functional studies were not carried out, although some hypotheses are proposed following in silico modeling of the TRPM3 variants using an available structure for TRPM7. As discussed by Dyment et al., happloinsufficiency appears to be unlikely given the presence of LoF variants in ExAC/gnomAD (pLI of 0), some intragenic copy number variants in DGV. In addition, pathogenicity of deletions spanning only TRPM3 or additional proximal genes was not evident in 2 cases: - In the first case a exon 1-9 deletion was found in 2 brothers with Becker muscular dystrophy due to DMD intragenic duplication and autism/cognitive impairment though the TRPM3 deletion was found also in unaffected family members. The deletion was also found in unaffected relatives. A multiple hit hypothesis was hypothesized for this family. [Pagnamenta et al. 2011 - PMID: 21484199] - Kuniba et al. [2009 - PMID: 19343044] reported a 1.27-Mb deletion spanning TRPM3, KLF9, SMC5 and MAMDC2 in a patient with Kabuki syndrome working diagnosis. Segregation studies were however not possible. At the time, the molecular etiology of Kabuki syndrome (KMT2D/KDM6A) was not known. ----- TRPM3 is not associated with any phenotype in OMIM or G2P. This gene is included in panels for ID offered by some diagnostic laboratories (eg. GeneDx participating in the above study). ----- As a result, TRPM3 seems to fulfill criteria for inclusion in the ID/epilepsy panels probably as green (# of individuals, degree of ID relevant, EEG-confirmed epilepsy) or amber (if further functional evidence would be required). [Please consider eligibility for inclusion in other possibly relevant panels eg. autism, etc]. Sources: Literature; to: Dyment et al. (2019 - https://doi.org/10.1038/s41431-019-0462-x) report on 7 unrelated individuals with a recurrent de novo TRPM3 missense variant [NM_020952.4:c.2509G>A - NP_066003.3:p.(Val837Met)] as well as an additional individual with a further de novo missense variant [c.2810C>A or p.(Pro937Gln) - same ref. sequences]. Overlapping features included hypotonia (7/8 - in one case mixed tone abnormality), DD/ID (8/8 - all individuals at appropriate age - degree relevant), EEG-confirmed epilepsy (7/8). Autism-like features were observed in 4 (out of 6 for whom this information was reported). Other features were noted in a minority (or were private to certain) of these individuals. Different clinical types of seizures were reported incl. absence, generalized-toni-clonic, infantile spasms as well as subclinical ones. Onset was in infancy or early childhood. In all individuals the variant was found following trio exome sequencing. The first variant fulfilled ACMG criteria to be classified as pathogenic due to it's de novo occurrence, prevalence in affected individuals (>=6 affected individuals and in the same time) absence from population databases, in silico predictions in favour of pathogenicity (PS2, PS4_Moderate, PM2, PP3). The Pro937Gln variant is however also present once in gnomAD (1/251370 alleles or AF:3.98e-6) and is classified as VUS according to the ACMG criteria. The subject harboring this variant had an additional de novo variant in another gene (DDB1) not associated with any phenotype, to date. Several other genetic causes had previously been ruled out for most individuals by other investigations : aCGH was normal in all, FMR1 testing in 6 subjects, genes (PHF6, MECP2, MCT8) or smaller panels for ID (the latter in 3 subjects), mtDNA or testing of nuclear genes for mitochondrial disorders, etc. TRPM3 encodes transient receptor potential (TRP) cation channel, subfamily M, member 3. TRP channels are a superfamily of gated cation channels sensitive to various physical or chemical stimuli (Clapham 2003 - PMID: 14654832 cited) eg. temperature or pain. The gene is highly expressed in the brain in humans and other vertebrates (Grimm et al. 2003 - PMID : 12672799 and GTEx - https://gtexportal.org/home/gene/TRPM3). Animal models : In rat brain, expression is initially restricted to neurons but later - as myelination progresses - shifts to oligodendrocytes (cited : Hoffmann et al. 2010 - PMID: 20163522). Most subjects had normal brain MRI appart from one individual with nonspecific white matter hyperintensities and another with possible mild cerebral volume loss. Trpm3 -/- mice show attenuated nocifensive behavior after heat or dermal injection of pregnenolone sulfate. Heat or pain insensitivity was reported only for 2 individuals. Functional studies were not carried out, although some hypotheses are proposed following in silico modeling of the TRPM3 variants using an available structure for TRPM7. As discussed by Dyment et al., happloinsufficiency appears to be unlikely given the presence of LoF variants in ExAC/gnomAD (pLI of 0), some intragenic copy number variants in DGV. In addition, pathogenicity of deletions spanning only TRPM3 or additional proximal genes was not evident in 2 cases: - In the first case a exon 1-9 deletion was found in 2 brothers with Becker muscular dystrophy due to DMD intragenic duplication and autism/cognitive impairment though the TRPM3 deletion was found also in unaffected family members. The deletion was also found in unaffected relatives. A multiple hit hypothesis was hypothesized for this family. [Pagnamenta et al. 2011 - PMID: 21484199] - Kuniba et al. [2009 - PMID: 19343044] reported a 1.27-Mb deletion spanning TRPM3, KLF9, SMC5 and MAMDC2 in a patient with Kabuki syndrome working diagnosis. Segregation studies were however not possible. At the time, the molecular etiology of Kabuki syndrome (KMT2D/KDM6A) was not known. ----- TRPM3 is not associated with any phenotype in OMIM or G2P. This gene is included in panels for ID offered by some diagnostic laboratories (eg. GeneDx participating in the above study). ----- As a result, TRPM3 seems to fulfill criteria for inclusion in the ID/epilepsy panels probably as green (# of individuals, degree of ID relevant, EEG-confirmed epilepsy) or amber (if further functional evidence would be required). [Please consider eligibility for inclusion in other possibly relevant panels eg. autism, etc]. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.938 | TRPM3 |
Konstantinos Varvagiannis gene: TRPM3 was added gene: TRPM3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: TRPM3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TRPM3 were set to doi.org/10.1038/s41431-019-0462-x Phenotypes for gene: TRPM3 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior Penetrance for gene: TRPM3 were set to unknown Mode of pathogenicity for gene: TRPM3 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: TRPM3 was set to GREEN gene: TRPM3 was marked as current diagnostic Added comment: Dyment et al. (2019 - https://doi.org/10.1038/s41431-019-0462-x) report on 7 unrelated individuals with a recurrent de novo TRPM3 missense variant [NM_020952.4:c.2509G>A - NP_066003.3:p.(Val837Met)] as well as an additional individual with a further de novo missense variant [c.2810C>A or p.(Pro937Gln) - same ref. sequences]. Overlapping features included hypotonia (7/8 - in one case mixed tone abnormality), DD/ID (8/8 - all individuals at appropriate age - degree relevant), EEG-confirmed epilepsy (7/8). Autism-like features were observed in 4 (out of 6 for whom this information was reported). Other features were noted in a minority (or were private to certain) of these individuals. Different clinical types of seizures were reported incl. absence, generalized-toni-clonic, infantile spasms as well as subclinical ones. Onset was in infancy or early childhood. In all individuals the variant was found following trio exome sequencing. The first variant fulfilled ACMG criteria to be classified as pathogenic due to it's de novo occurrence, prevalence in affected individuals (>=6 affected individuals and in the same time) absence from population databases, in silico predictions in favour of pathogenicity (PS2, PS4_Moderate, PM2, PP3). The Pro937Gln variant is however classified as a VUS. The subject harboring this variant had an additional de novo variant in another gene (DDB1) not associated with any phenotype, to date. Several other genetic causes had previously been ruled out for most individuals by other investigations : aCGH was normal in all, FMR1 testing in 6 subjects, genes (PHF6, MECP2, MCT8) or smaller panels for ID (the latter in 3 subjects), mtDNA or testing of nuclear genes for mitochondrial disorders, etc. TRPM3 encodes transient receptor potential (TRP) cation channel, subfamily M, member 3. TRP channels are a superfamily of gated cation channels sensitive to various physical or chemical stimuli (Clapham 2003 - PMID: 14654832 cited) eg. temperature or pain. The gene is highly expressed in the brain in humans and other vertebrates (Grimm et al. 2003 - PMID : 12672799 and GTEx - https://gtexportal.org/home/gene/TRPM3). Animal models : In rat brain, expression is initially restricted to neurons but later - as myelination progresses - shifts to oligodendrocytes (cited : Hoffmann et al. 2010 - PMID: 20163522). Most subjects had normal brain MRI appart from one individual with nonspecific white matter hyperintensities and another with possible mild cerebral volume loss. Trpm3 -/- mice show attenuated nocifensive behavior after heat or dermal injection of pregnenolone sulfate. Heat or pain insensitivity was reported only for 2 individuals. Functional studies were not carried out, although some hypotheses are proposed following in silico modeling of the TRPM3 variants using an available structure for TRPM7. As discussed by Dyment et al., happloinsufficiency appears to be unlikely given the presence of LoF variants in ExAC/gnomAD (pLI of 0), some intragenic copy number variants in DGV. In addition, pathogenicity of deletions spanning only TRPM3 or additional proximal genes was not evident in 2 cases: - In the first case a exon 1-9 deletion was found in 2 brothers with Becker muscular dystrophy due to DMD intragenic duplication and autism/cognitive impairment though the TRPM3 deletion was found also in unaffected family members. The deletion was also found in unaffected relatives. A multiple hit hypothesis was hypothesized for this family. [Pagnamenta et al. 2011 - PMID: 21484199] - Kuniba et al. [2009 - PMID: 19343044] reported a 1.27-Mb deletion spanning TRPM3, KLF9, SMC5 and MAMDC2 in a patient with Kabuki syndrome working diagnosis. Segregation studies were however not possible. At the time, the molecular etiology of Kabuki syndrome (KMT2D/KDM6A) was not known. ----- TRPM3 is not associated with any phenotype in OMIM or G2P. This gene is included in panels for ID offered by some diagnostic laboratories (eg. GeneDx participating in the above study). ----- As a result, TRPM3 seems to fulfill criteria for inclusion in the ID/epilepsy panels probably as green (# of individuals, degree of ID relevant, EEG-confirmed epilepsy) or amber (if further functional evidence would be required). [Please consider eligibility for inclusion in other possibly relevant panels eg. autism, etc]. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.595 | STAG2 |
Konstantinos Varvagiannis gene: STAG2 was added gene: STAG2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: STAG2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: STAG2 were set to 29263825; 28296084; 30158690; 30447054; 19449417; 26443594; 25677961; 23637084; 25450604 Phenotypes for gene: STAG2 were set to Global developmental delay; Intellectual disability; Abnormality of head or neck; Microcephaly; Growth delay; Hearing impairment; Abnormal heart morphology Penetrance for gene: STAG2 were set to unknown Review for gene: STAG2 was set to GREEN gene: STAG2 was marked as current diagnostic Added comment: Several affected individuals (from at least 8 unrelated) families have been reported in the literature. The phenotype consists - among others - of DD/ID. STAG2 is located on long arm of chromosome X (Xq25). Based on these reports, both males and females can be affected. Soardi et al. (2017 - PMID: 29263825) report an affected male belonging to a large pedigree with 4 other similarly affected males. The disorder in this pedigree followed a typical X-linked inheritance pattern. All affected males were hemizygous for a missense variant (NM_001042749.1:c.980G>A or p.Ser327Asn). Common phenotype consisted of moderate ID, short stature, sensory hearing loss and some similar facial features. Unaffected males did not harbor the variant. Heterozygous females were not affected. Co-segragation of the variant with the affected status under an X-linked model, appeared unlikely to have occurred by chance (probability of 1/131,072 - logarithm of odds score of 5.12). Mullegama et al. (2017 - PMID: 28296084) report on an 8-year-old girl harboring a de novo nonsense variant in STAG2 (NM_001042749.1:c.205C>T or p.Arg69Ter). This individual presented - among others with - DD, microcephaly, growth delay, digit anomalies, particular facial features, and anomalies of other systems (eg. hearing loss, cardiac defect, etc). The authors summarize the features of 2 subjects from the DDD study as available in DECIPHER, without additional details. [Variants of these individuals NM_001042749.1:c.1913_1922del10 or p.(A638Vfs*10) / NM_001042749.1:c.1811G>A p.(R604Q)]. Yuan et al. (2018 - PMID: 30158690) report on 4 females with de novo LoF STAG2 variants as well as 1 male subject with a de novo missense one. DD (5/5) and ID (4/4) were features in all individuals for whom this information was available. One additional female had an intragenic STAG2 deletion, although this subject was not reported to have DD or ID (table S6 : microcephaly, seizures and facial phenotype). It is not known whether the deletion was inherited or had occurred as a de novo event. All variants from this study have been submitted in ClinVar (phenotype : STAG2-related disorder). Mullegama et al. (2018 - PMID: 30447054) report on a 4-year-old male with DD, microcephaly, growth delay, digit anomalies due to a de novo missense STAG2 variant (c.3027A>T or p.Lys1009Asn). As discussed by the authors at the time of the study 33 males with Xq25 duplications and ID had been reported (PMIDs cited: 19449417, 26443594, 25677961, 23637084, 25450604). Discussed in these articles : STAG2 (or STAG1) is one of the 4 core proteins of the cohesin complex, the other 3 being SMC1A, SMC3 and RAD21. Mutations in genes encoding these proteins or their interactors (eg. NIBPL, HDAC8, ESCO2, etc) have been associated cohesinopathies, a group of multisystem developmental disorders (eg. Cornelia de Lange syndrome, Roberts/SC phocomelia, etc). It has been commented that the phenotype of STAG2-related disorder presents overlap with other cohesinopathies (eg. DD, microcephaly and growth retardation, craniofacial features, anomalies of the digits, etc). Decreased proportion of nuclei with premature sister chromatid separation compared to controls was found on one occasion (suggestive of tighter sister chromatid cohesion) [Mullegama-A]. Sister chromatid cohesion was not affected in another report [Soardi et al.]. Western blot demonstrated significant reduction of STAG2 levels for a nonsense variant [Mullegama-A]. Levels were not perturbed for a missense variant [Soardi et al.]. Upon immunofluorescence STAG2 presented normal (nuclear) localization for a missense variant for which this was studied [Soardi et al.]. Perturbation of the cell cycle profile (higher percentage of G2/M cells) was demonstrated for patient fibroblasts compared to controls on one occasion where this was studied. [Soardi et al.]. Microarray expression studies in patient fibroblasts demonstrated altered transcription (upregulation) of genes implicated in cell division, mitosis and DNA replication upon comparison with normal fibroblasts [Soardi et al.]. The effect of a missense variant on STAG2 binding to other cohesin subunits (SCC1, SMC1 and SMC3) and regulators was studied. Binding was found to be reduced in vivo (in HeLa cells) for SCC1 (its direct binding partner) as well as SMC1, SMC3 (possibly indirectly). Reduced STAG2 binding to cohesin regulators was also shown in vivo. However, in vitro studies were not suggestive of impaired binding of STAG2 to SCC1 (a finding difficult to explain) [Soardi et al.]. STAG2 appears to be intolerant to LoF variants (pLI of 1 in ExAC). Z-Score for missense variants is 5.11. Mullegama et al. (B) comment that Xq25 duplications in males may be associated with milder phenotypes compared to intragenic variants. They further hypothesize that males are able to survive less damaging variants while females are able to survive more deleterious (eg. LoF) ones though with more severe phenotypes (similarity to the MECP2 model is discussed). ---------- STAG2 is not associated with any phenotype in OMIM. In G2P this gene is associated with STAG2-related developmental delay with microcephaly and congenital anomalies (disease confidence : confirmed / Both DD and ID among the phenotypes assigned to this entry). ---------- STAG2 is included in gene panels for ID offered by some diagnostic laboratories. ---------- 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 v2.588 | ZNF462 |
Konstantinos Varvagiannis gene: ZNF462 was added gene: ZNF462 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: ZNF462 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ZNF462 were set to 28513610; 29427787; 14564155; 12825074 Phenotypes for gene: ZNF462 were set to Ptosis; Prominent metopic ridge; Craniosynostosis; Global developmental delay; Intellectual disability; Autistic behavior Penetrance for gene: ZNF462 were set to unknown Review for gene: ZNF462 was set to AMBER gene: ZNF462 was marked as current diagnostic Added comment: Weiss et al. (PMID: 28513610) report on 8 individuals (from 6 unrelated families) with heterozygous pathogenic variants affecting ZNF462. Frequent features included ptosis metopic ridging, craniosynostosis, dysgenesis of corpus callosum. DD (with or without ASD) was a feature in 4 (4/8), one of whom was reported to present mild ID. 4 LoF mutations as well as 2 9q31.2 deletions spanning also other genes are reported [NM_021224.4]: Fam. 1 - c.3787C>T p.(Arg1263*) (familial) - Normal development in all 3 family members Fam. 2 - c.2979_2980delinsA p.(Val994Trpfs*147) (de novo) - DD Fam. 3 - c.4263delA p.(Glu1422Serfs*6) (de novo) - DD Fam. 4 - Chr9:g.(108940763-110561397)del (hg19) (de novo) - Normal development Fam. 5- Chr9:g(108464368-110362345)del (hg19) (de novo) - DD with mild ID Fam. 6 - c.5145delC p.(Tyr1716Thrfs*28) (de novo) - DD There were no expression/functional studies performed although haploinsufficiency can be presumed based on these variants (ZNF462 has a pLI of 1 in ExAC). ----------- Cosemans et al. (PMID: 29427787) report on an individual investigated - among others - for mild ID and ASD. This individual harbored a de novo (complex) translocation disrupting ZNF462 and KLF12. As this subject presented similar features to those reported by Weiss et al. (eg. craniofacial anomalies, abn. development, ASD) and given that KLF12 is not associated with any disorder, the phenotype of this individual was thought to be secondary to disruption of ZNF462. Details on this patient - before delineation of the translocation breakpoints - were provided previously by Fryns and Hendrickx ( PMID:9297446). ----------- Cited by the previous article, a further case of ZNF462 disruption due to translocation was previously published in the literature (same individual - Talisetti et al. PMID: 14564155 / Ramocki et al. PMID: 12825074). Profound ID was among the features of this individual although the translocation disrupted also a further ID gene (ASXL2). ----------- In ClinVar 8 variants have been submitted as pathogenic/likely pathogenic although a phenotype is provided only for 3 variants published by Weiss et al.(submitting lab participating in PMID: 28513610 / SCV000494060.1 corresp. to Fam.1 / SCV000494061.1 - Fam.2 / SCV000494062.1 - Fam. 3). ----------- Several individuals with de novo coding variants in ZNF462 have been reported in the context of larger cohorts (some with ID as a principal feature). http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=ZNF462 ----------- In Decipher apart from the DDD study participants DDD4K.03663 and DDD4K.03792 (appearing in the denovo-db) with LoF and abnormality of the nervous system, several further individuals have been submitted. 2 of these subjects, harbored a de novo LoF (submitted as pathogenic) and had ID as a feature. ---------- ZNF462 is included in the DD panel of G2P, associated with Craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay [Disease confidence: probable / Global DD (but not ID) among the phenotypes assigned to this entry]. This gene is not associated with any phenotype in OMIM. ---------- ZNF462 is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc). ---------- As a result this gene can be considered for inclusion in the ID panel probably as amber (or green if the current evidence is thought to be sufficient). Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.588 | TBC1D20 |
Konstantinos Varvagiannis gene: TBC1D20 was added gene: TBC1D20 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: TBC1D20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TBC1D20 were set to 24239381; 26063829 Phenotypes for gene: TBC1D20 were set to Warburg Micro syndrome 4 (MIM 615663) Penetrance for gene: TBC1D20 were set to Complete Review for gene: TBC1D20 was set to GREEN gene: TBC1D20 was marked as current diagnostic Added comment: Biallelic pathogenic variants in TBC1D20 cause Warburg Micro syndrome 4 (MIM 615663). --------- Liegel et al. (PMID: 24239381) report on 7 individuals from 5 unrelated families. ID was a universal feature along with opthalmological, endocrine and other neurological features of the disorder. Seizures were noted in 4 individuals from 2 families. Table S4 of this article provides clinical details on each subject. All affected individuals were homozygous for LoF variants, private to each family. 3 nonsense variants, 1 frameshift one as well as an intragenic deletion (exons 2-8) were identified. These subjects belonged to a cohort of 77 individuals with suspected Warburg Micro syndrome (WMS) or disorders of the same spectrum (eg. Martsof syndrome). Screening for TBC1D20 mutations in these individuals was performed after identification of a homozygous LoF Tbc1d20 mutation in blind sterile mice, presenting a phenotype somewhat similar to WMS (congenital cataracts and testicular anomalies). Alternative causes of WM (eg. pathogenic variants in RAB3GAP1, RAB3GAP2 and RAB18) had previously been excluded in this cohort. The authors demonstrated aberrant lipid droplet formation in embryonic fibroblasts from blind sterile mice as well as in fibroblasts from individuals with a diagnosis of WMS due to mutations in either of TBC1D20, RAB18 and RAB3GAP1. --------- TBC1D20 is included in the DD panel of G2P, associated with Warburg micro syndrome 4 (Disease confidence: probable / ID among the phenotypes assigned to this entry). This gene is included in gene panels for ID offered by different diagnostic laboratories (incl. Radboudumc). --------- As a result, TBC1D20 can be considered for inclusion in the ID panel as green (or amber). Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.588 | CTNNA2 |
Konstantinos Varvagiannis gene: CTNNA2 was added gene: CTNNA2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CTNNA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CTNNA2 were set to 30013181 Phenotypes for gene: CTNNA2 were set to Cortical dysplasia, complex, with other brain malformations 9 (MIM 618174) Penetrance for gene: CTNNA2 were set to Complete Review for gene: CTNNA2 was set to AMBER Added comment: Biallelic loss-of-function mutations in CTNNA2 cause cortical dysplasia, complex, with other brain malformations 9 (MIM 618174). ------- Schaffer et al. (PMID: 30013181) report on 7 individuals from 3 unrelated consanguineous families. All individuals presented with profoundly impaired motor and cognitive development (severe ID in 6/7 for whom this information was available, all 6 from 2 families - a further individual from the 3rd family was non-ambulatory with absent speech at the age of 28 months), with acquired microcephaly and intractable seizures (7/7 - onset: 6m-3y - atonic/myoclonic/infantile spasms). Pachygyria without posterior-anterior gradient or focal dysplasias was common to all. CTNNA2 encodes αN-catenin. It is expressed in human fetal brain, mainly in regions expressing migration markers DCX and TUJ1. Reduced migration was shown for iPSC-derived neural progenitor cells from an affected individual, compared to controls. The protein contains a putative actin-binding domain (ABD) at its C terminus. Several lines of evidence are provided that this domain is critical for the process of neuronal migration. ------- CTNNA2 is included in the DD panel of G2P associated with disordered cortical neuronal migration (Disease confidence: probable / ID and seizures among the phenotypes assigned to this entry). This gene is not commonly included in gene panels for intellectual disability. ------- As a result CTNNA2 could be considered for inclusion in this panel as amber or possibly green. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.588 | TSEN15 |
Konstantinos Varvagiannis gene: TSEN15 was added gene: TSEN15 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: TSEN15 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TSEN15 were set to 27392077; 25558065 Phenotypes for gene: TSEN15 were set to Pontocerebellar hypoplasia, type 2F (MIM 617026) Penetrance for gene: TSEN15 were set to Complete Review for gene: TSEN15 was set to GREEN gene: TSEN15 was marked as current diagnostic Added comment: Biallelic pathogenic variants in TSEN15 cause Pontocerebellar hypoplasia, type 2F (MIM 617026). Four individuals with molecular confirmation of the diagnosis, from 3 unrelated consanguineous families have been reported by Breuss et al. (PMID: 27392077). One of these individuals was previously included in a study of neurogenetic disorders in consanguineous families (Alazami et al. - PMID: 25558065). A similarly affected sib (possibly not tested) was reported for one patient. DD with variable degrees of ID (mild to severe), progressive microcephaly were common to all. Seizures were noted in 2 individuals. MRI images (for the feature of pontocerebellar hypoplasia - PCH) were only available for 2 families. Affected subjects were homozygous for missense variants private to each family, namely: - NM_052965.3:c.226T>G (p.Trp76Gly) - NM_052965.3:c.346C>T (p.His116Tyr) - NM_052965.3:c.455A>G (p.Tyr152Cys) Trp76Gly and Tyr152Cys resulted in reduced protein abundance while His116Tyr did not have an effect on TSEN15 expression levels. TSEN15 is part of the tRNA splicing endonuclease complex, the 3 other components of which (TSEN2, TSEN34, TSEN54) have already been associated with PCH. The complex interacts with an RNA kinase encoded by CLP1. All 3 variants resulted in altered stoichiometry (/relative abundance) of the 3 other subunits of the complex as well as the relative levels of CLP1. Almost complete loss of in vitro tRNA cleavage activity was the case for purified complexes from all 3 mutants. ------ TSEN15 is included in the DD panel of G2P associated with Pontocerebellar Hypoplasia and Progressive Microcephaly (Disease confidence: probable). ID is among the assigned phenotypes. This gene is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc). ------ As a result, TSEN15 could be considered for inclusion in this panel as green (or amber). Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.579 | RPIA |
Konstantinos Varvagiannis gene: RPIA was added gene: RPIA was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: RPIA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RPIA were set to 14988808; 20499043; 28801340; 30088433 Phenotypes for gene: RPIA were set to Ribose 5-phosphate isomerase deficiency, MIM 608611. Penetrance for gene: RPIA were set to unknown Review for gene: RPIA was set to GREEN gene: RPIA was marked as current diagnostic Added comment: Biallelic pathogenic variants in RPIA cause Ribose 5-phosphate isomerase deficiency, MIM 608611. PMID: 14988808 is the first report on the disorder with molecular (incl. genetic) confirmation of the diagnosis. A patient initially investigated for early developmental delay, leukoencephalopathy, seizures with onset at 4 years, with subsequent neurologic regression and peripheral neuropathy at the age of 7, was suspected to have a disorder of the pentose phosphate pathway on the basis of highly elevated polyols on brain MRS and body fluid analysis. Reduced ribose 5-phosphate isomerase activity was shown in fibroblasts. Genetic testing demonstrated the presence of a missense (NM_144563.2:c.404C>T / NP_653164.2:p.Ala135Val - previously referred to as A61V) as well as a frameshift variant (NM_144563.2:c.762delG / NP_653164.2:p.Asn255Ilefs). Additional extensive supportive functional studies were published a few years later (PMID: 20499043). [This patient was initially described in PMID: 10589548]. PMID: 28801340 is a report on a second patient. This individual presented with delayed early development (independent walking and speech achieved at 2 and 5 years respectively), seizures and regression at the age of 7 with MRI white matter abnormalities. Review of magnetic resonance spectroscopy (MRS) was suggestive of elevated polyols (arabitol and ribitol). In line with this, genetic testing revealed a homozygous missense variant in RPIA (NM_144563.2:c.592T>C or p.Phe198Leu). Urine analysis confirmed elevated excretion of polyols, thus confirming the diagnosis. PMID: 30088433 reports on a boy with neonatal onset leukoencephalopathy and developmental delay having undergone early metabolic testing and aCGH (the latter at the age of 16 months). Persistance of his delay motivated exome sequencing at the age of approx. 4.5 years which demonstrated 2 RPIA variants (NM_144563.2:c.253G>A or p.Ala85Thr and NM_144563.2:c.347-1G>A). Measurement of ribitol and arabitol in urine demonstrated significant elevations (>20x) consistent with this diagnosis. RPIA is included in gene panels for intellectual disability offered by various diagnostic laboratories. As a result this gene can be considered for inclusion in this panel as green (or amber). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.535 | ATP1A1 |
Konstantinos Varvagiannis gene: ATP1A1 was added gene: ATP1A1 was added to Intellectual disability. Sources: Expert Review,Literature Mode of inheritance for gene: ATP1A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ATP1A1 were set to 30388404 Phenotypes for gene: ATP1A1 were set to Hypomagnesemia; Seizures; Intellectual disability Penetrance for gene: ATP1A1 were set to unknown Review for gene: ATP1A1 was set to GREEN Added comment: PMID: 30388404 reports on 3 subjects from 3 families with de novo pathogenic variants in ATP1A1. All 3 presented with similar phenotype consisting of hypomagnesemia, early onset refractory seizures as well as intellectual disability. Alternative causes of hypomagnesemia with seizures (eg. due to TRPM6 mutations) were excluded while the phenotype of the 3 patients differed from similar disorder in that hypomagnesemia as well as seizures were not responsive to magnesium supplementation. Three different missense variants are reported (L302R, G303R, M859R) all as de novo occurences and after confirmation of paternity. Functional studies were suggestive of loss of the ATPase function, abnormal cation permeabilities as well as reduced level of expression (the latter was significant for at least for 2 of the 3 variants). Mutations in ATP1A1 have also been reported in patients with Charcot-Marie-Tooth type 2 (CMT2DD - MIM: 618036) although the variants reported to date map seem to cluster within the helical linker region (residues 592 to 608). The young age of the patients with epilepsy and intellectual disability did not allow conclusions on eventual peripheral neuropathy in these individuals. As a result this gene can be considered for inclusion in this panel as green (or amber). Sources: Expert Review, Literature |
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