Dataset Information

Late-onset cluster seizures and intellectual disability associated with a novel truncation variant in SMC1A.

ABSTRACT: SMC1A variants are known to cause Cornelia de Lange Syndrome (CdLS) which encompasses a clinical spectrum of intellectual disability, dysmorphic features (long or thick eyebrows, a hypomorphic philtrum and small nose) and, in some cases, epilepsy. More recently, SMC1A truncating variants have been described as the cause of a neurodevelopmental disorder with early-childhood onset drug-resistant epilepsy with seizures that occur in clusters, similar to that seen in PCDH19-related epilepsy, but without the classical features of CdLS. Here, we report the case of a 28-year-old woman with a de novo heterozygous truncating variant in SMC1A who unusually presented with seizures at the late age of 12 years and had normal development into adulthood.

SUBMITTER: Elwan M

PROVIDER: S-EPMC9194849 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Late-onset cluster seizures and intellectual disability associated with a novel truncation variant in SMC1A.

Elwan Menatalla M Fowkes Ross R Lewis-Smith David D Winder Amy A Baker Mark R MR Thomas Rhys H RH

Epilepsy & behavior reports 20220602

SMC1A variants are known to cause Cornelia de Lange Syndrome (CdLS) which encompasses a clinical spectrum of intellectual disability, dysmorphic features (long or thick eyebrows, a hypomorphic philtrum and small nose) and, in some cases, epilepsy. More recently, SMC1A truncating variants have been described as the cause of a neurodevelopmental disorder with early-childhood onset drug-resistant epilepsy with seizures that occur in clusters, similar to that seen in PCDH19-rela ...[more]

PMID: 35712061

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Project description:ObjectiveHeterozygous variants in KCNQ2 or, more rarely, KCNQ3 genes are responsible for early-onset developmental/epileptic disorders characterized by heterogeneous clinical presentation and course, genetic transmission, and prognosis. While familial forms mostly include benign epilepsies with seizures starting in the neonatal or early-infantile period, de novo variants in KCNQ2 or KCNQ3 have been described in sporadic cases of early-onset encephalopathy (EOEE) with pharmacoresistant seizures, various age-related pathological EEG patterns, and moderate/severe developmental impairment. All pathogenic variants in KCNQ2 or KCNQ3 occur in heterozygosity. The aim of this work was to report the clinical, molecular, and functional properties of a new KCNQ3 variant found in homozygous configuration in a 9-year-old girl with pharmacodependent neonatal-onset epilepsy and non-syndromic intellectual disability.MethodsExome sequencing was used for genetic investigation. KCNQ3 transcript and subunit expression in fibroblasts was analyzed with quantitative real-time PCR and Western blotting or immunofluorescence, respectively. Whole-cell patch-clamp electrophysiology was used for functional characterization of mutant subunits.ResultsA novel single-base duplication in exon 12 of KCNQ3 (NM_004519.3:c.1599dup) was found in homozygous configuration in the proband born to consanguineous healthy parents; this frameshift variant introduced a premature termination codon (PTC), thus deleting a large part of the C-terminal region. Mutant KCNQ3 transcript and protein abundance was markedly reduced in primary fibroblasts from the proband, consistent with nonsense-mediated mRNA decay. The variant fully abolished the ability of KCNQ3 subunits to assemble into functional homomeric or heteromeric channels with KCNQ2 subunits.SignificanceThe present results indicate that a homozygous KCNQ3 loss-of-function variant is responsible for a severe phenotype characterized by neonatal-onset pharmacodependent seizures, with developmental delay and intellectual disability. They also reveal difference in genetic and pathogenetic mechanisms between KCNQ2- and KCNQ3-related epilepsies, a crucial observation for patients affected with EOEE and/or developmental disabilities.

Dataset Information

Late-onset cluster seizures and intellectual disability associated with a novel truncation variant in SMC1A.

Publications

Late-onset cluster seizures and intellectual disability associated with a novel truncation variant in <i>SMC1A</i>.

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