OBJECTIVE: Heterozygous 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. METHODS: Exome 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. RESULTS: A 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. SIGNIFICANCE: The 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.

A novel homozygous KCNQ3 loss-of-function variant causes non-syndromic intellectual disability and neonatal-onset pharmacodependent epilepsy / Lauritano, Anna; Moutton, S; Longobardi, Elena; Tran Mau-Them, F; Laudati, G; Nappi, Piera; Soldovieri, Mv; Ambrosino, P; Cataldi, M; Jouan, T; Lehalle, D; Maurey, H; Philippe, C; Miceli, F; Vitobello, A; Taglialatela, M.. - In: EPILEPSIA OPEN. - ISSN 2470-9239. - 4:3(2019), pp. 464-475. [10.1002/epi4.12353]

A novel homozygous KCNQ3 loss-of-function variant causes non-syndromic intellectual disability and neonatal-onset pharmacodependent epilepsy

LAURITANO, ANNA;LONGOBARDI, ELENA;Laudati G;NAPPI, PIERA;Cataldi M;Miceli F;Taglialatela M.
2019

Abstract

OBJECTIVE: Heterozygous 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. METHODS: Exome 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. RESULTS: A 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. SIGNIFICANCE: The 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.
2019
A novel homozygous KCNQ3 loss-of-function variant causes non-syndromic intellectual disability and neonatal-onset pharmacodependent epilepsy / Lauritano, Anna; Moutton, S; Longobardi, Elena; Tran Mau-Them, F; Laudati, G; Nappi, Piera; Soldovieri, Mv; Ambrosino, P; Cataldi, M; Jouan, T; Lehalle, D; Maurey, H; Philippe, C; Miceli, F; Vitobello, A; Taglialatela, M.. - In: EPILEPSIA OPEN. - ISSN 2470-9239. - 4:3(2019), pp. 464-475. [10.1002/epi4.12353]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/769200
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