Dataset Information

Single nucleotide variations in CLCN6 identified in patients with benign partial epilepsies in infancy and/or febrile seizures.

ABSTRACT: Nucleotide alterations in the gene encoding proline-rich transmembrane protein 2 (PRRT2) have been identified in most patients with benign partial epilepsies in infancy (BPEI)/benign familial infantile epilepsy (BFIE). However, not all patients harbor these PRRT2 mutations, indicating the involvement of genes other than PRRT2. In this study, we performed whole exome sequencing analysis for a large family affected with PRRT2-unrelated BPEI. We identified a non-synonymous single nucleotide variation (SNV) in the voltage-sensitive chloride channel 6 gene (CLCN6). A cohort study of 48 BPEI patients without PRRT2 mutations revealed a different CLCN6 SNV in a patient, his sibling and his father who had a history of febrile seizures (FS) but not BPEI. Another study of 48 patients with FS identified an additional SNV in CLCN6. Chloride channels (CLCs) are involved in a multitude of physiologic processes and some members of the CLC family have been linked to inherited diseases. However, a phenotypic correlation has not been confirmed for CLCN6. Although we could not detect significant biological effects linked to the identified CLCN6 SNVs, further studies should investigate potential CLCN6 variants that may underlie the genetic susceptibility to convulsive disorders.

SUBMITTER: Yamamoto T

PROVIDER: S-EPMC4368117 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Single nucleotide variations in CLCN6 identified in patients with benign partial epilepsies in infancy and/or febrile seizures.

Yamamoto Toshiyuki T Shimojima Keiko K Sangu Noriko N Komoike Yuta Y Ishii Atsushi A Abe Shinpei S Yamashita Shintaro S Imai Katsumi K Kubota Tetsuo T Fukasawa Tatsuya T Okanishi Tohru T Enoki Hideo H Tanabe Takuya T Saito Akira A Furukawa Toru T Shimizu Toshiaki T Milligan Carol J CJ Petrou Steven S Heron Sarah E SE Dibbens Leanne M LM Hirose Shinichi S Okumura Akihisa A

PloS one 20150320 3

Nucleotide alterations in the gene encoding proline-rich transmembrane protein 2 (PRRT2) have been identified in most patients with benign partial epilepsies in infancy (BPEI)/benign familial infantile epilepsy (BFIE). However, not all patients harbor these PRRT2 mutations, indicating the involvement of genes other than PRRT2. In this study, we performed whole exome sequencing analysis for a large family affected with PRRT2-unrelated BPEI. We identified a non-synonymous single nucleotide variati ...[more]

PMID: 25794116

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Project description:ObjectiveADGRV1 gene encodes adhesion G protein-coupled receptor-V1 that is involved in synaptic function. ADGRV1 mutations are associated with audio-visual disorders. Although previous experimental studies suggested that ADGRV1 variants were associated with epilepsy, clinical evidence is limited and the phenotype spectrum is to be defined.MethodsTrio-based targeting sequencing was performed in a cohort of 101 cases with febrile seizure (FS) and epilepsy with antecedent FS. Protein modeling was used to assess the damaging effects of variants. The genotype-phenotype correlations of the ADGRV1 variants in epilepsy and audio-visual disorders were analyzed.ResultsADGRV1 variants were identified in nine unrelated cases (8.91%), including two heterozygous frameshift variants, six heterozygous missense variants, and a pair of compound heterozygous variants. These variants presented a statistically higher frequency in this cohort than that in control populations. Most missense variants were located at CalX-β motifs and changed the hydrogen bonds. These variants were inherited from the asymptomatic parents, indicating an incomplete penetrance. We also identified SCN1A variants in 25 unrelated cases (24.75%) and SCN9A variants in 3 unrelated cases (2.97%) in this cohort. Contrary to SCN1A variant-associated epilepsy that revealed seizure was aggravated by sodium channel blockers, ADGRV1 variants were associated with mild epilepsy with favorable responses to antiepileptic drugs. The patients denied problems with audio-visual-vestibular abilities in daily life. However, audio-visual tests revealed auditory and visual impairment in the patient with compound heterozygous variants, auditory or vestibular impairment in the patients with heterozygous frameshift, or hydrogen-bond changed missense variants but no abnormalities in the patients with missense variants without hydrogen-bond changes. Previously reported ADGRV1 variants that were associated with audio-visual disorders were mostly biallelic/destructive variants, which were significantly more frequent in the severe phenotype of audio-visual disorders (Usher syndrome 2) than in other mild phenotypes. In contrast, the variants identified in epilepsy were monoallelic, missense mainly located at CalX-β, or affected isoforms VLGR1b/1c.SignificanceADGRV1 is potentially associated with FS-related epilepsy as a susceptibility gene. The genotype, submolecular implication, isoforms, and damaging severity of the variants explained the phenotypical variations. ADGRV1 variant-associated FS/epilepsy presented favorable responses to antiepileptic drugs, implying a clinical significance.

Dataset Information

Single nucleotide variations in CLCN6 identified in patients with benign partial epilepsies in infancy and/or febrile seizures.

Publications

Single nucleotide variations in CLCN6 identified in patients with benign partial epilepsies in infancy and/or febrile seizures.

Similar Datasets

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