title: Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy.
abstract: Familial dilated cardiomyopathy (DCM) is a heterogeneous disease; although 30 disease genes have been discovered, they explain only no more than half of all cases; in addition, the causes of intra-familial variability in DCM have remained largely unknown. In this study, we exploited the use of whole-exome sequencing (WES) to investigate the causes of clinical variability in an extended family with 14 affected subjects, four of whom showed particular severe manifestations of cardiomyopathy requiring heart transplantation in early adulthood. This analysis, followed by confirmative conventional sequencing, identified the mutation p.K219T in the lamin A/C gene in all 14 affected patients. An additional variant in the gene for titin, p.L4855F, was identified in the severely affected patients. The age for heart transplantation was substantially less for LMNA:p.K219T/TTN:p.L4855F double heterozygotes than that for LMNA:p.K219T single heterozygotes. Myocardial specimens of doubly heterozygote individuals showed increased nuclear length, sarcomeric disorganization, and myonuclear clustering compared with samples from single heterozygotes. In conclusion, our results show that WES can be used for the identification of causal and modifier variants in families with variable manifestations of DCM. In addition, they not only indicate that LMNA and TTN mutational status may be useful in this family for risk stratification in individuals at risk for DCM but also suggest titin as a modifier for DCM.
authors: 1] Biomedical and Genetic Research Institute (IRGB), Milan Unit, National Research Council of Italy, Milan, Italy [2] Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.
authors: Roberta
authors: R
authors: Roncarati
authors: Chiara
authors: C
authors: Viviani Anselmi
authors: Peter
authors: P
authors: Krawitz
authors: Giovanna
authors: G
authors: Lattanzi
authors: Yskert
authors: Y
authors: von Kodolitsch
authors: Andreas
authors: A
authors: Perrot
authors: Elisa
authors: E
authors: di Pasquale
authors: Laura
authors: L
authors: Papa
authors: Paola
authors: P
authors: Portararo
authors: Marta
authors: M
authors: Columbaro
authors: Alberto
authors: A
authors: Forni
authors: Giuseppe
authors: G
authors: Faggian
authors: Gianluigi
authors: G
authors: Condorelli
authors: Peter N
authors: PN
authors: Robinson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D002648:Child; D064211:Connectin / Q000235:genetics*; D059472:Exome; D005260:Female; D006579:Heterozygote; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D012518:Sarcomeres / Q000473:pathology; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: D064211:Connectin; C494847:LMNA protein, human; D034904:Lamin Type A; C577285:TTN protein, human