Abstract
Inherited cardiac conduction disease (CCD) is rare; it is caused by a large number of mutations in genes encoding cardiac ion channels and cytoskeletal proteins. Recently, whole-exome sequencing has been successfully used to identify causal mutations for rare monogenic Mendelian diseases. We used trio-based whole-exome sequencing to study a Chinese family with multiple family members affected by CCD, and identified a heterozygous missense mutation (c.343C>T, p.Leu115Phe) in the desmin (DES) gene as the most likely candidate causal mutation for the development of CCD in this family. The mutation is novel and is predicted to affect the conformation of the coiled-coil rod domain of DES according to structural model prediction. Its pathogenicity in desmin protein aggregation was further confirmed by expressing the mutation, both in a cellular model and a CRISPR/CAS9 knock-in mouse model. In conclusion, our results suggest that whole-exome sequencing is a feasible approach to identify candidate genes underlying inherited conduction diseases.
Highlights
The functional components of the cardiac conduction framework include impulse-generating nodes and the impulse-propagating His-Purkinje system
Using trio-based, whole-exome sequencing techniques, we found a novel point mutation located in DES encoding the muscle-specific, type-III, intermediate filament (IF), desmin
We identified around 115,819 single nucleotide variants (SNVs) and 7007 insertions/deletions (InDels) from three study samples (39,229 to 41,896 variants per subject)
Summary
The functional components of the cardiac conduction framework include impulse-generating nodes and the impulse-propagating His-Purkinje system. Genetic testing techniques, knowledge about the candidate genes, and the size of the pedigrees may hinder efforts to identify relevant genetic defects. This can restrict the analysis to priori-identified candidate genes, and may fail to reveal causal genes in familial CCD if no mutations are found among the known candidate genes. The application of linkage analysis may be jeopardized by the small size of the pedigrees In this regard, generation whole genome or exome sequencing may be helpful in overcoming such limitations [4]. Both cellular and CRISPR/CAS9 knock-in mice modeling further supported its pathogenicity in desmin protein aggregation
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