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| Early onset or syndromic epilepsy v8.186 | SHROOM4 |
Ida Ertmanska gene: SHROOM4 was added gene: SHROOM4 was added to Early onset or syndromic epilepsy. Sources: Literature Q2_26_promote_green, Q2_26_expert_review tags were added to gene: SHROOM4. Mode of inheritance for gene: SHROOM4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: SHROOM4 were set to 16249884; 25167861; 26740508; 32565546; 32728808; 35663265; 35937050; 36379543; 40905141 Phenotypes for gene: SHROOM4 were set to epilepsy, MONDO:0005027 Review for gene: SHROOM4 was set to GREEN Added comment: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and in one case found in unaffected family members. Other publications: PMID: 32565546 Heide et al., 2020 Patient 44 - fetal case, pregnancy terminated - individual hemizygous for SHROOM4 NM_020717.3c.2050C>T, p.(Arg684*), with complete CC agenesis and other malformations: Blake’s pouch cyst, Turner syndrome: mos 46,X, psu idic(X)(p11.2)[19]/45,X[6]. Method: exome seq. PMID: 32728808 Dong et al., 2021 Individual 31M with a chromosomal insertion affecting SHROOM4, MAGED1, and PFKFB1 - male with moderate dev delay and autism spectrum. Cannot decouple the effect of individual genes being disrupted here. PMID: 35663265 Bian et al., 2022 Chinese epilepsy cohort. Six hemizygous (maternally inherited) missense SHROOM4 variants detected in six cases with idiopathic epilepsy without intellectual disability: c.13C > A, p. Pro5Thr; c.3236A>C, p.Glu1079Ala; c.3581C > T, p.Ser1194Leu; c.4288C > T, p.Arg1430Cys; c.4303G > A, p.Val1435Met; c.4331C > T, p.Pro1444Leu. Seizure onset at 3-16 years (median 5.5yrs). Brain MRI was normal in 6/6 cases. Note: variants p.Ser1194Leu and p.Arg1430Cys have hemizygous individuals reported in gnomAD 4.1.1. PMID: 36209347 Peduto et al., 2022 Report of a 2yo male with SHROOM4 c.4153C>T, p.Arg1385*, which is also present in an unaffected grandfather. The authors question pathogenicity of SHROOM4 LoF variants (missense GoF still seen as potentially disease causing). PMID: 35937050 Lee et al., 2022 Cohort of patients with infantile spasms. Sample IS06 - male; trio WGS detected a SHROOM4 NM_020717: c.269+4A>G hemizygous variant - classified as VUS by authors. PMID: 36379543 Kolvenbach et al., 2023 6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems. Family A: SHROOM4 c.940G>A , p.(Glu314Lys) - 1 affected male and 1 affected heterozygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID. Variant present in 4 het female individuals in gnomAF v4.1.1. Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID. Variant not in gnomAD v4.1.1. Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related). +Functional studies: Embryonic mouse and zebrafish expression studies showed Shroom4 expression in the upper and lower urinary tract, the developing cloaca, the heart and the cerebral CNS. KD studies in zebrafish larvae revealed pronephric cysts, anomalies of the cloaca and the heart, decreased eye-to-head ratio and higher mortality compared with controls. PMID: 40905141 Héron et al., 2025 Patient 62 - female fetal case with complete CC agenesis and a de novo SHROOM4 variant NM_020717.3:c.2050C>T, p.(Arg684*). Pregnancy was terminated. From suppl info. Possibly same case as in PMID: 32565546 ? Same research group. SHROOM4 is not associated with any phenotype in OMIM (accessed 21st Apr 2026). Sources: Literature |
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| Early onset or syndromic epilepsy v2.498 | CPSF3 |
Konstantinos Varvagiannis gene: CPSF3 was added gene: CPSF3 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: CPSF3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CPSF3 were set to 35121750 Phenotypes for gene: CPSF3 were set to Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Microcephaly; Seizures Penetrance for gene: CPSF3 were set to Complete Review for gene: CPSF3 was set to AMBER Added comment: Arnadottir (2022 - PMID: 35121750) describe the phenotype associated with biallelic CPSF3 pathogenic variants. Based on WGS of 56,969 Icelanders and imputing the genotype of another 153,054 chip-genotyped Icelanders, the authors identified missense variants with a deficit of homozygous carriers to what would be expected based on AF. (For variants with MAF>0.4%, for which >=3 hmz carriers would be expected by H-W equilibrium, no identified hmz carriers within this cohort/dataset). A total of 114 such missense variants was identified. 5 of these SNVs, among which a CPSF3 one (NM_016207.3:c.1403G>A / p.Gly468Glu), were however observed in a series of 764 individuals investigated with clinical WGS at the National University Hospital. The CPSF3 variant with a MAF of 0.41% (3 hmz expected but none observed in the population set) was found in homozygosity in 2 closely related individuals, both investigated for FTT, severe DD, ID, microcephaly, seizures but remaining unresolved following WGS with no other candidate variants. Using genealogical information from the db of deCODE genetics, the authors identified 3 couples from the 153k genotyped Icelanders where both partners were htz carriers for this SNV. These 3 couples had 10 offspring, 4 of whom deceased but with the same phenotypic features as above (hypotonia 4/4, ID 4/4, seizures 3/4, microcephaly 2/4). Paraffin embedded samples of 2 of these children and WG & Sanger sequencing confirmed hmz for Gly468Glu in 2 sibs, without other candidate variants. Samples of the 2 other individuals were N/A. Through GeneMatcher 2 additional first-cousin patients from Mexico were identified, being hmz for another CPSF3 variant (c.1061T>C/p.Ile354Thr) and having overlapping phenotype of abnormal muscle tone, ID, seizures and microcephaly. There were no other variants in WES analysis. mRNA studies in WBCs from Gly468Glu htz carriers did not reveal reduced levels and W.Blot of lymphocytes from a hmz individual confirmed expression, overall suggesting that the variant does not affect the protein levels but presumably the function. CPSF3 encodes cleavage and polyadenylation specificity factor 3, a 684 aa protein, subunit of the cleavage and polyadenylation specificity factor compex. As discussed, cleavage and polyadenylation of the 3' of pre-mRNAs is necessary before transport out of the nucleus with CPSF playing a crucial role in the process of cleavage. CPSF3 ko mice exhibit embryonic lethality, while in yeast mutations in key residues of the CPSF3 homolog are lethal. In gnomAD, CPSF3 has a pLI of 0, z-score of 3.61 with no homozygotes for pLoF variants in 141k individuals (or ~57k WGS Icelanders). The 2 missense variants concern highly conserved residues (GERP ~5.8). Both are hypothesized to affect the ability of the protein to bind other factors involved in pre-mRNA cleavage. Overall the authors speculate that not only complete loss of CPSF3 would result in drastic phenotypic effects - as in the murine model - but also variants altering its enzymatic function. There is currently no CPSF3-related phenotype in OMIM, G2P, SysID, The gene is included with green rating in the ID, epilepsy and microcephaly panels in PanelApp Australia. Consider inclusion probably with amber rating (Highly consistent phenotype, biological function, evidence from animal models. 2 identified variants, authors state that follow-up functional studies are needed). Also consider inclusion in other possibly relevant panels. Sources: Literature |
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| Early onset or syndromic epilepsy v1.191 | MAF | Rebecca Foulger Source Wessex and West Midlands GLH was added to MAF. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.190 | MAF | Rebecca Foulger Source NHS GMS was added to MAF. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.189 | MAF | Rebecca Foulger reviewed gene: MAF: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.188 | MAF | Tracy Lester reviewed gene: MAF: Rating: GREEN; Mode of pathogenicity: ; Publications: 25865493; Phenotypes: Ayme-Gripp syndrome, 601088, Cataract 21, multiple types, 610202; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.167 | PIGB |
Konstantinos Varvagiannis gene: PIGB was added gene: PIGB was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: PIGB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGB were set to 31256876 Phenotypes for gene: PIGB were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot Penetrance for gene: PIGB were set to Complete Review for gene: PIGB was set to GREEN Added comment: Murakami et al. (2019 - PMID: 31256876) provide detailed information on 14 individuals from 10 families (4 of which consanguineous) with biallelic pathogenic PIGB variants. Overlapping features included DD/ID (13/13), epilepsy (14/14), deafness (7/14), ophthalmological or brain anomalies, hand and feet anomalies as well as presence of dysmorphic features. ID was common, in those individuals with appropriate age. Some had a previous diagnosis of DOORS syndrome (deafness/onychodystrophy/osteodystrophy,retardation, seizures) and few showed 2-oxoglutatic aciduria which can also be seen in DOORS s. PIGB encodes phosphatidylinositol glycan anchor biosynthesis class B protein. Overall the phenotype was similar to other inherited glycosylphosphatidylinositol (GPI) deficiencies (IGDs). As happens to be the case in some other GPI deficiencies alkaline phosphatase was also elevated in those tested (8/9). 8 missense, 1 stopgain as well as an intronic SNV are reported. All variants were either absent or ultra-rare and with no homozygotes in gnomAD. Affected individuals from 4 families, harbored an intronic SNV in the homozygous state. For this variant - with MAF of 0.0001592 or 6.51x10-5 in ExAC and gnomAD - activation of an aberrant splice acceptor site was shown [NM_004855.4:c.847-10A>G or p.Gln282_Trp283insArgCysGln]. Flow cytometric analysis of blood cells or fibroblasts showed decreased levels for various GPI-AP (GPI-anchored protein) markers in affected individuals. These levels were rescued upon transduction with a PIGB-encoding-Lx304 lentiviral vector of fibroblasts from one affected individual, suggesting that the PIGB defect was responsible. The effect of the variants was evaluated using PIGB-deficient CHO cells, transfected with wt or mutant PIGB cDNAs. FACS analysis and immunoblotting demonstrated that variants were able to restore only slightly/partially - if at all - the surface presence of GPI-APs in the case of variants while the levels of mutant protein were reduced. PIGB is not associated with any phenotype in OMIM/G2P. This gene is not commonly included in gene panels for ID offered by diagnostic laboratories. As a result, this gene can be considered for inclusion in the ID and epilepsy panels probably as green (or amber). Sources: Literature |
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| Early onset or syndromic epilepsy | MAF | Sarah Leigh classified MAF as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy | MAF | Sarah Leigh Added gene to panel | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||