Whole‐exome sequencing identifies a novel mutation of GPD1L (R189X) associated with familial conduction disease and sudden death

摘要

Abstract Cardiac conduction disease (CCD) is a serious disorder and the leading cause of mortality worldwide. It is characterized by arrhythmia, syncope or even sudden cardiac death caused by the dysfunction of cardiac voltage-gated channel. Previous study has demonstrated that mutations in genes encoding voltage-gated channel and related proteins were the crucial genetic lesion of CCD. In this study, we employed whole-exome sequencing to explore the potential causative genes in a Chinese family with ventricular tachycardia and syncope. A novel nonsense mutation (c.565C>T/p.R189X) of glycerol-3-phosphate dehydrogenase-like ( GPD1L ) was identified and co-segregated with the affected family members. GPD1L is a crucial interacting protein of SCN5A, a gene encoded sodium channel α-subunit Na_v1.5 and mainly associated with Brugada syndrome (BrS). The novel mutation (c.565C>T/p.R189X) may result in a premature stop codon at position 189 in exon 4 of the GPD1L gene and lead to functional haploinsufficiency of GPD1L due to mRNA carrying this mutation will be degraded by nonsense-mediated mRNA decay, which has been confirmed by Western blot in HEK293 cells transfected HIS-GPD1L plasmid. The levels of GPD1L decreasing may disturb the function of Na_v1.5 and induce arrhythmia and syncope in the end. In conclusion, our study not only further supported the important role of GPD1L in CCD, but also expanded the spectrum of GPD1L mutations and will contribute to the genetic diagnosis and counselling of families with CCD.