biostudies-literatureHastings RBritish Heart FoundationMedical Research CouncilNational Institute for Health Research (NIHR)Wellcome Trust426-435https://www.ebi.ac.uk/biostudies/studies/S-EPMC5068189biostudies-literatureUnknown9(5)<h4>Background</h4>High throughput next-generation sequencing techniques have made whole genome sequencing accessible in clinical practice; however, the abundance of variation in the human genomes makes the identification of a disease-causing mutation on a background of benign rare variants challenging.<h4>Methods and results</h4>Here we combine whole genome sequencing with linkage analysis in a 3-generation family affected by cardiomyopathy with features of autosomal dominant left ventricular noncompaction cardiomyopathy. A missense mutation in the giant protein titin is the only plausible disease-causing variant that segregates with disease among the 7 surviving affected individuals, with interrogation of the entire genome excluding other potential causes. This A178D missense mutation, aCirculation. Cardiovascular geneticsCombination of Whole Genome Sequencing, Linkage, and Functional Studies Implicates a Missense Mutation in Titin as a Cause of Autosomal Dominant Cardiomyopathy With Features of Left Ventricular Noncompaction.PMC5068189MR/J010456/1RG/12/16/29939RE/13/1/30181MR/K015664/1NIHR-HCS-D13-04-006RG/15/8/31480FS/12/40/29712201543/Z/16/Z090532/Z/09/ZCH/08/001/25300PG/15/113/31944090532Arnold LKonarev PVGhisleni ATaylor JCde Villiers CPKnight SJGautel MHastings ROrmondroyd LWilmanns MSalatino SBlair EPagnamenta AWatkins HLise SGehmlich KHooper CThomson KLEhler EChatziefthimiou SDfalseCombination of Whole Genome Sequencing, Linkage, and Functional Studies Implicates a Missense Mutation in Titin as a Cause of Autosomal Dominant Cardiomyopathy With Features of Left Ventricular Noncompaction.<h4>Background</h4>High throughput next-generation sequencing techniques have made whole genome sequencing accessible in clinical practice; however, the abundance of variation in the human genomes makes the identification of a disease-causing mutation on a background of benign rare variants challenging.<h4>Methods and results</h4>Here we combine whole genome sequencing with linkage analysis in a 3-generation family affected by cardiomyopathy with features of autosomal dominant left ventricular noncompaction cardiomyopathy. A missense mutation in the giant protein titin is the only plausible disease-causing variant that segregates with disease among the 7 surviving affected individuals, with interrogation of the entire genome excluding other potential causes. This A178D missense mutation, a2016-01-01T00:00:00Z2016 Oct2026-06-11T06:28:45.449Z2019-03-27T02:26:57ZS-EPMC50681892762533710.1161/CIRCGENETICS.116.001431