Identification of potential heterozygous missense mutation of KCNH2 (c.1478A>G; p. Tyr493Cys) and CACNA1H (c.3382C>T; p. Pro1128Ser) in type 2 long QT syndrome

Background: Type 2 long QT syndrome (LQTS) is a sudden cardiac death related genetic disease. We tried to find the potential gene mutation in the type 2 LQTS pedigree.Material and methods: Genomic DNA was extracted from the peripheral blood of proband and her parents. The exomes were sequenced by whole exon sequencing (WES) followed by genetic analysis. Then, functional annotation and PPI analysis was used to study the biological function and potential interaction of identified mutation genes. In addition, structure and properties analysis of mutated proteins was performed. Finally, Sanger sequencing was used to validate the identified mutations.Results: After sequencing and genetic analysis, the heterozygous missense mutation of KCNH2 (c.1478A>G; p. Tyr493Cys) and CACNA1H (c.3382C>T; p. Pro1128Ser) was found in the proband and her father, while was not found in her mother. Structure and properties analysis of mutated KCNH2 and CACNA1H proteins changed after mutation. Both KCNH2 and CACNA1H were involved in the biological process of regulation of membrane potential. Moreover, KCNH2 protein and CACNA1H protein interacted with each other. Sanger validation result was in line with the WES analysis.Conclusion: Our study found novel heterozygous missense mutations in KCNH2 (c.1478A>G; p. Tyr493Cys) and CACNA1H (c.3382C>T; p. Pro1128Ser), which may be helpful in the early diagnosis and therapy of type 2 LQTS.