Key result
Whole exome sequencing and segregation analysis identified a recurrent TNNT2 Arg173Trp missense mutation (cumulative LOD score 9.3) that perfectly segregated with the dilated cardiomyopathy phenotype in two large families.
Why the study?
Does whole exome sequencing with segregation analysis identify pathogenic variants in familial dilated cardiomyopathy?
Observational (n=16)
Yes
Does whole exome sequencing with segregation analysis identify pathogenic variants in familial dilated cardiomyopathy?
Whole exome sequencing combined with segregation analysis in distant affected relatives is a viable diagnostic strategy for identifying pathogenic variants in genetically heterogeneous diseases like dilated cardiomyopathy.
Supports TNNT2 Arg173Trp testing in select familial DCM; leaves open prevalence, penetrance, and broader utility.
Dilated cardiomyopathy (DCM) commonly causes heart failure and shows extensive genetic heterogeneity that may be amenable to newly developed next-generation DNA sequencing of the exome. In this study we report the successful use of exome sequencing to identify a pathogenic variant in the TNNT2 gene using segregation analysis in a large DCM family. Exome sequencing was performed on three distant relatives from a large family with a clear DCM phenotype. Missense, nonsense, and splice variants were analyzed for segregation among the three affected family members and confirmed in other relatives by direct sequencing. A c.517T C>T, Arg173Trp TNNT2 variant segregated with all affected family members and was also detected in one additional DCM family in our registry. The inclusion of segregation analysis using distant family members markedly improved the bioinformatics filtering process by removing from consideration variants that were not shared by all affected subjects. Haplotype analysis confirmed that the variant found in both DCM families was located on two distinct haplotypes, supporting the notion of independent mutational events in each family. In conclusion, an exome sequencing strategy that includes segregation analysis using distant affected relatives within a family represents a viable diagnostic strategy in a genetically heterogeneous disease like DCM.
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Campbell et al. (2013) conducted an observational in Familial Dilated Cardiomyopathy (n=16). TNNT2 Arg173Trp variant vs. Unaffected family members was evaluated on Identification and segregation of pathogenic genetic variant with DCM phenotype. Whole exome sequencing and segregation analysis identified a recurrent TNNT2 Arg173Trp missense mutation (cumulative LOD score 9.3) that perfectly segregated with the dilated cardiomyopathy phenotype in two large families.
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