title: Whole exome sequencing identifies a troponin T mutation hot spot in familial dilated cardiomyopathy.
abstract: 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.
authors.affiliation: Cardiovascular Institute and Adult Medical Genetics, University of Colorado, Aurora, Colorado, United States of America.
authors.forename: Nzali
authors.initials: N
authors.lastname: Campbell
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Sinagra
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Jones
authors.forename: Dobromir
authors.initials: D
authors.lastname: Slavov
authors.forename: Katherine
authors.initials: K
authors.lastname: Gowan
authors.forename: Marco
authors.initials: M
authors.lastname: Merlo
authors.forename: Elisa
authors.initials: E
authors.lastname: Carniel
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Fain
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Aragona
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Lenarda
authors.forename: Luisa
authors.initials: L
authors.lastname: Mestroni
authors.forename: Matthew R G
authors.initials: MR
authors.lastname: Taylor
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D059472:Exome / Q000235:genetics*; D005260:Female; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D020107:Troponin T / Q000235:genetics*
chemical_list: D020107:Troponin T