Abstract
BackgroundInherited cardiac conduction diseases (CCD) are rare but are caused by mutations in a myriad of genes. Recently, whole-exome sequencing has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases.ObjectiveTo investigate the genetic background of a family affected by inherited CCD.Methods and ResultsWe used whole-exome sequencing to study a Chinese family with multiple family members affected by CCD. Using the pedigree information, we proposed a heterozygous missense mutation (c.G695T, Gly232Val) in the lamin A/C (LMNA) gene as a candidate mutation for susceptibility to CCD in this family. The mutation is novel and is expected to affect the conformation of the coiled-coil rod domain of LMNA according to a structural model prediction. Its pathogenicity in lamina instability was further verified by expressing the mutation in a cellular model.ConclusionsOur results suggest that whole-exome sequencing is a feasible approach to identifying the candidate genes underlying inherited conduction diseases.
Highlights
The functional components of the cardiac conduction system can be broadly divided into the impulse-generating nodes and the impulse-propagating His-Purkinje system
We used whole-exome sequencing to evaluate a family with autosomal dominant conduction diseases (CCD) and identified a heterozygous missense mutation (NM_005572, c.G695T, G232V) in the lamin A/C (LMNA) gene as the most likely candidate mutation
The ANNOVAR program predicted that this mutation would be damaging, and the HHpred software predicted that it would affect the conformation of the LMNA coiled-coil rod domain
Summary
The functional components of the cardiac conduction system can be broadly divided into the impulse-generating nodes and the impulse-propagating His-Purkinje system. The familial clustering of idiopathic CCD has led to the discovery of a large number of mutations identified in genes encoding ion channels (VoltageGated Sodium Channel Subunit Alpha (SCN5A), Hyperpolarization Activated Cyclic Nucleotide-Gated Potassium Channel 4 (HCN4), Potassium Inwardly-Rectifying Channel Subfamily J Member 2 (KCNJ2)), cardiac transcription factors (Homeobox protein Nkx-2.5 (NKX2-5), T-box transcription factor (TBX5)), gap junctions (Connexin 40 (Cx40)), energy metabolism regulators (5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2)) and structural proteins (lamin A/C (LMNA)) that cause progressive conduction system disease in the absence of structural heart disease [1,2]. Inherited cardiac conduction diseases (CCD) are rare but are caused by mutations in a myriad of genes. Whole-exome sequencing has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases. We proposed a heterozygous missense mutation (c.G695T, Gly232Val) in the lamin A/C (LMNA) gene as a candidate mutation for susceptibility to CCD in this family. Conclusions: Our results suggest that whole-exome sequencing is a feasible approach to identifying the candidate genes underlying inherited conduction diseases
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