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.

Genetic Variants Identified from Epilepsy of Unknown Etiology in Chinese Children by Targeted Exome Sequencing

“…The role of CLCN6 in epilepsy has been suggested but not confirmed in two other studies4344. Two SNVs in CLCN6 have been identified in patients with benign partial epilepsies in infancy (BPEI) or benign familial infantile epilepsy (BFIE) but the causal role has not been established4344. Because of these observations, we classified this de novo missense variant of CLCN6 (c.533 A>C) as likely pathogenic but with weak evidence.…”

“…The Glu178Ala variant is located in one of the transmembrane helix that was likely involved in ion transportation. The role of CLCN6 in epilepsy has been suggested but not confirmed in two other studies4344. Two SNVs in CLCN6 have been identified in patients with benign partial epilepsies in infancy (BPEI) or benign familial infantile epilepsy (BFIE) but the causal role has not been established4344.…”

Association study of genetic variation in the autophagy lysosome pathway genes and risk of eight kinds of cancers

“…ATP6V0D2 , one of the V‐ATPase‐related transcripts, contributed to a high risk of breast cancer, pancreatic cancer and RCC. CLCN6 belongs to a family of the voltage‐dependent chloride channel protein taking part in a multitude of basal cellular processes including intracellular vesicles acidification and transepithelial transport . However, no study has reported the associations of these genes with these cancers.…”

Roles of the ClC Chloride Channel CLH-1 in Food-associated Salt Chemotaxis Behavior ofC. elegans

“…Malfunction of ClC genes results in various diseases such as myotonia, leukodystrophy, hyperaldosteronism and epilepsy in humans (Blanz et al, 2007; Charlet-B. et al, 2002; Fernandes-Rosa et al, 2018; Yamamoto et al, 2015). The causal relationship among ClC malfunction, physiological consequences, and disease manifestations are not fully understood in many cases.…”