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| Early onset or syndromic epilepsy v1.351 | APC2 |
Konstantinos Varvagiannis gene: APC2 was added gene: APC2 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: APC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: APC2 were set to 31585108; 25753423; 19759310; 22573669 Phenotypes for gene: APC2 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system Penetrance for gene: APC2 were set to Complete Review for gene: APC2 was set to AMBER Added comment: This gene was reviewed for the ID panel (details below). It could be also be considered for inclusion in the epilepsy panel as amber/green. [Seizures in 8/14 individuals (generalized tonic-clonic/myoclonic, onset 3m - 6yrs) although some individuals were too young when last examined (eg. 8m) and sibs in one family (F7) were discordant for this feature at the ages of 4y7m (+) and 6y (-). Lissencephaly is often associated with seizures which have occasionally been observed in Apc2-deficient mice (PMID cited: 22573669)]. ----- Probably 14 individuals from 9 families (8 consanguineous) with biallelic APC2 LoF variants have been reported. ID and brain abnormalities were features in all, although the presentation was quite different between sibs in the first report (PMID: 25753423 - mild/mod ID, ventriculomegaly and CC anomalies, macrocephaly with variable height, Sotos-like facial features) and 12 subsequently described patients (PMID: 31585108 - severe ID, P>A lissencephaly/CC anomalies/ventriculomegaly/paucity of white matter in (almost) all, gT-C/myoclonic seizures in 8/12 with onset 3m-6y, OFC in the low percentiles). In all cases relevant alternative diagnoses (eg. macrocephaly/overgrowth syndromes - 1st report, mutations in other lissencephaly genes, metabolic disorders - 2nd) were ruled out. APC2 encodes Adenomatous polyposis coli protein 2, expressed in the CNS. All variants reported to date were LoF (stopgain/frameshift/splicing) and were supported by parental-only studies. Mutations in the 1st report as well as 4/8 variants from the 2nd report localized within the last exon (NM_005883.2 / longest of >=3 isoforms), although the 2nd report did not observe obvious genotype-phenotype correlations. Despite a pLI of 1 in gnomAD, Lee et al. comment that heterozygous carriers did not have any noticeable phenotype. They further note that carriers were not examined by brain MRI, though. 27 heterozygous high-confidence variants appear in individuals in gnomAD. Finally as commented on, APC2 is not mutated in colon cancer. Animal models: Apc -/- mice displayed disrupted neuronal migration, with defects of lamination of cerebral cortex and cerebellum supporting the observed brain abnormalities. In addition Apc2-deficient mice also presented impaired learning and memory abilities. Extensive additional studies have shown Apc2 co-localization with microtubules affecting their stabilization, distribution along actin fibers (all supporting a role in cytoskeletal organization) and regulation of Rac1 (a Rho GTPase). Generation of Neuro2a cells demonstrated abnormal localization mainly in cell bodies of mutant hAPC2 proteins (due to frameshift in the last exon / deletion of the C-terminal part) - different from wt (neurites, growth cones, cell bodies). The first patient report also provided evidence for Apc2 being a downstream effector of Nsd1, with Nsd1 knockdown brains displaying impaired migration / laminar positioning of cortical neurons (similar to Apc2-/- model) and rescued by forced expression of Apc2. In OMIM, the APC2-related phenotype is ?Sotos syndrome 3 (MIM 617169 - AR). G2P does not have any associated phenotype for this gene. Relevant articles: PMIDs: 19759310 and 22573669 (Shintani et al. 2009 & 2012) [mouse model] PMID: 25753423 (Almuriekhi et al. 2015) [2 individuals + mouse model] PMID: 31585108 (Lee et al. 2019) [12 individuals from 8 families] Sources: Literature |
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| Early onset or syndromic epilepsy v1.191 | NSD1 | Rebecca Foulger Source Wessex and West Midlands GLH was added to NSD1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.190 | NSD1 | Rebecca Foulger Source NHS GMS was added to NSD1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.189 | NSD1 | Rebecca Foulger reviewed gene: NSD1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.188 | NSD1 | Tracy Lester reviewed gene: NSD1: Rating: GREEN; Mode of pathogenicity: ; Publications: 23592277; Phenotypes: Leukemia, acute myeloid, 601626, Sotos syndrome 1, 117550; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.1253 | NSD1 | Ivone Leong Marked gene: NSD1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.1253 | NSD1 | Ivone Leong Gene: nsd1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.1243 | NSD1 | Ivone Leong Classified gene: NSD1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.1243 | NSD1 | Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. NSD1 is confirmed to be associated with Sotos syndrome on OMIM and Gene2Phenotype, and both databases have listed seizures as a phenotype. GeneReviews stated that ~25% of Sotos syndrome patients have seizures. A large multicentre gene-phenotype association study showed that there are multiple cases (>3) of Sotos syndrome patients who have seizures. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.1243 | NSD1 | Ivone Leong Gene: nsd1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.1242 | NSD1 | Ivone Leong Publications for gene: NSD1 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.1232 | NSD1 | Ivone Leong Mode of inheritance for gene: NSD1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.1225 | NSD1 | Ivone Leong Phenotypes for gene: NSD1 were changed from to Sotos syndrome 1, 117550 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy | NSD1 | Zornitza Stark reviewed gene: NSD1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy | NSD1 | Sarah Leigh Added gene to panel | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||