PortalPublikationenDoubly heterozygous LMNA and TTN mutations revealed by exome...

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

Standard

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy. / Roncarati, Roberta; Viviani Anselmi, Chiara; Krawitz, Peter; Lattanzi, Giovanna; von Kodolitsch, Yskert; Perrot, Andreas; di Pasquale, Elisa; Papa, Laura; Portararo, Paola; Columbaro, Marta; Forni, Alberto; Faggian, Giuseppe; Condorelli, Gianluigi; Robinson, Peter N.

in: EUR J HUM GENET, Jahrgang 21, Nr. 10, 10.2013, S. 1105-1111.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Roncarati, R, Viviani Anselmi, C, Krawitz, P, Lattanzi, G, von Kodolitsch, Y, Perrot, A, di Pasquale, E, Papa, L, Portararo, P, Columbaro, M, Forni, A, Faggian, G, Condorelli, G & Robinson, PN 2013, 'Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy', EUR J HUM GENET, Jg. 21, Nr. 10, S. 1105-1111. https://doi.org/10.1038/ejhg.2013.16

APA

Roncarati, R., Viviani Anselmi, C., Krawitz, P., Lattanzi, G., von Kodolitsch, Y., Perrot, A., di Pasquale, E., Papa, L., Portararo, P., Columbaro, M., Forni, A., Faggian, G., Condorelli, G., & Robinson, P. N. (2013). Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy. EUR J HUM GENET, 21(10), 1105-1111. https://doi.org/10.1038/ejhg.2013.16

Vancouver

Roncarati R, Viviani Anselmi C, Krawitz P, Lattanzi G, von Kodolitsch Y, Perrot A et al. Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy. EUR J HUM GENET. 2013 Okt;21(10):1105-1111. https://doi.org/10.1038/ejhg.2013.16

Bibtex

@article{e62a6bc236634958aeee95a911445bef,
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. ",
keywords = "Adolescent, Adult, Aged, Cardiomyopathy, Dilated/diagnosis, Child, Connectin/genetics, Exome, Female, Heterozygote, Humans, Lamin Type A/genetics, Male, Middle Aged, Mutation, Pedigree, Sarcomeres/pathology, Sequence Analysis, DNA/methods",
author = "Roberta Roncarati and {Viviani Anselmi}, Chiara and Peter Krawitz and Giovanna Lattanzi and {von Kodolitsch}, Yskert and Andreas Perrot and {di Pasquale}, Elisa and Laura Papa and Paola Portararo and Marta Columbaro and Alberto Forni and Giuseppe Faggian and Gianluigi Condorelli and Robinson, {Peter N}",
year = "2013",
month = oct,
doi = "10.1038/ejhg.2013.16",
language = "English",
volume = "21",
pages = "1105--1111",
journal = "EUR J HUM GENET",
issn = "1018-4813",
publisher = "NATURE PUBLISHING GROUP",
number = "10",

}

RIS

TY - JOUR

T1 - Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

AU - Roncarati, Roberta

AU - Viviani Anselmi, Chiara

AU - Krawitz, Peter

AU - Lattanzi, Giovanna

AU - von Kodolitsch, Yskert

AU - Perrot, Andreas

AU - di Pasquale, Elisa

AU - Papa, Laura

AU - Portararo, Paola

AU - Columbaro, Marta

AU - Forni, Alberto

AU - Faggian, Giuseppe

AU - Condorelli, Gianluigi

AU - Robinson, Peter N

PY - 2013/10

Y1 - 2013/10

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Cardiomyopathy, Dilated/diagnosis

KW - Child

KW - Connectin/genetics

KW - Exome

KW - Female

KW - Heterozygote

KW - Humans

KW - Lamin Type A/genetics

KW - Male

KW - Middle Aged

KW - Mutation

KW - Pedigree

KW - Sarcomeres/pathology

KW - Sequence Analysis, DNA/methods

U2 - 10.1038/ejhg.2013.16

DO - 10.1038/ejhg.2013.16

M3 - SCORING: Journal article

C2 - 23463027

VL - 21

SP - 1105

EP - 1111

JO - EUR J HUM GENET

JF - EUR J HUM GENET

SN - 1018-4813

IS - 10

ER -