Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy

Nadine Norton, Duanxiang Li, Evadnie Rampersaud, Ana Morales, Eden R Martin, Stephan L Zuchner, Shengru Guo, Michael Gonzalez, Dale J. Hedges, Peggy D. Robertson, Niklas Krumm, Deborah A. Nickerson, Ray E. Hershberger

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Background-Familial dilated cardiomyopathy (DCM) is a genetically heterogeneous disease with >30 known genes. TTN truncating variants were recently implicated in a candidate gene study to cause 25% of familial and 18% of sporadic DCM cases. Methods and Results-We used an unbiased genome-wide approach using both linkage analysis and variant filtering across the exome sequences of 48 individuals affected with DCM from 17 families to identify genetic cause. Linkage analysis ranked the TTN region as falling under the second highest genome-wide multipoint linkage peak, multipoint logarithm of odds, 1.59. We identified 6 TTN truncating variants carried by individuals affected with DCM in 7 of 17 DCM families (logarithm of odds, 2.99); 2 of these 7 families also had novel missense variants that segregated with disease. Two additional novel truncating TTN variants did not segregate with DCM. Nucleotide diversity at the TTN locus, including missense variants, was comparable with 5 other known DCM genes. The average number of missense variants in the exome sequences from the DCM cases or the ≈5400 cases from the Exome Sequencing Project was ≈23 per individual. The average number of TTN truncating variants in the Exome Sequencing Project was 0.014 per individual. We also identified a region (chr9q21.11-q22.31) with no known DCM genes with a maximum heterogeneity logarithm of odds score of 1.74. Conclusions-These data suggest that TTN truncating variants contribute to DCM cause. However, the lack of segregation of all identified TTN truncating variants illustrates the challenge of determining variant pathogenicity even with full exome sequencing.

Original languageEnglish
Pages (from-to)144-153
Number of pages10
JournalCirculation: Cardiovascular Genetics
Volume6
Issue number2
DOIs
StatePublished - Apr 1 2013

Fingerprint

Exome
Dilated Cardiomyopathy
Genome
Genes
Virulence
Nucleotides

Keywords

  • Dilated cardiomyopathy
  • Exome
  • Genetics
  • Genome-wide analysis
  • Human

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics

Cite this

Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy. / Norton, Nadine; Li, Duanxiang; Rampersaud, Evadnie; Morales, Ana; Martin, Eden R; Zuchner, Stephan L; Guo, Shengru; Gonzalez, Michael; Hedges, Dale J.; Robertson, Peggy D.; Krumm, Niklas; Nickerson, Deborah A.; Hershberger, Ray E.

In: Circulation: Cardiovascular Genetics, Vol. 6, No. 2, 01.04.2013, p. 144-153.

Research output: Contribution to journalArticle

Norton, N, Li, D, Rampersaud, E, Morales, A, Martin, ER, Zuchner, SL, Guo, S, Gonzalez, M, Hedges, DJ, Robertson, PD, Krumm, N, Nickerson, DA & Hershberger, RE 2013, 'Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy', Circulation: Cardiovascular Genetics, vol. 6, no. 2, pp. 144-153. https://doi.org/10.1161/CIRCGENETICS.111.000062
Norton, Nadine ; Li, Duanxiang ; Rampersaud, Evadnie ; Morales, Ana ; Martin, Eden R ; Zuchner, Stephan L ; Guo, Shengru ; Gonzalez, Michael ; Hedges, Dale J. ; Robertson, Peggy D. ; Krumm, Niklas ; Nickerson, Deborah A. ; Hershberger, Ray E. / Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy. In: Circulation: Cardiovascular Genetics. 2013 ; Vol. 6, No. 2. pp. 144-153.
@article{79233fb8c3534e09bacd0b4cc89f1873,
title = "Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy",
abstract = "Background-Familial dilated cardiomyopathy (DCM) is a genetically heterogeneous disease with >30 known genes. TTN truncating variants were recently implicated in a candidate gene study to cause 25{\%} of familial and 18{\%} of sporadic DCM cases. Methods and Results-We used an unbiased genome-wide approach using both linkage analysis and variant filtering across the exome sequences of 48 individuals affected with DCM from 17 families to identify genetic cause. Linkage analysis ranked the TTN region as falling under the second highest genome-wide multipoint linkage peak, multipoint logarithm of odds, 1.59. We identified 6 TTN truncating variants carried by individuals affected with DCM in 7 of 17 DCM families (logarithm of odds, 2.99); 2 of these 7 families also had novel missense variants that segregated with disease. Two additional novel truncating TTN variants did not segregate with DCM. Nucleotide diversity at the TTN locus, including missense variants, was comparable with 5 other known DCM genes. The average number of missense variants in the exome sequences from the DCM cases or the ≈5400 cases from the Exome Sequencing Project was ≈23 per individual. The average number of TTN truncating variants in the Exome Sequencing Project was 0.014 per individual. We also identified a region (chr9q21.11-q22.31) with no known DCM genes with a maximum heterogeneity logarithm of odds score of 1.74. Conclusions-These data suggest that TTN truncating variants contribute to DCM cause. However, the lack of segregation of all identified TTN truncating variants illustrates the challenge of determining variant pathogenicity even with full exome sequencing.",
keywords = "Dilated cardiomyopathy, Exome, Genetics, Genome-wide analysis, Human",
author = "Nadine Norton and Duanxiang Li and Evadnie Rampersaud and Ana Morales and Martin, {Eden R} and Zuchner, {Stephan L} and Shengru Guo and Michael Gonzalez and Hedges, {Dale J.} and Robertson, {Peggy D.} and Niklas Krumm and Nickerson, {Deborah A.} and Hershberger, {Ray E.}",
year = "2013",
month = "4",
day = "1",
doi = "10.1161/CIRCGENETICS.111.000062",
language = "English",
volume = "6",
pages = "144--153",
journal = "Circulation. Genomic and precision medicine",
issn = "1942-325X",
publisher = "Lippincott Williams and Wilkins Ltd.",
number = "2",

}

TY - JOUR

T1 - Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy

AU - Norton, Nadine

AU - Li, Duanxiang

AU - Rampersaud, Evadnie

AU - Morales, Ana

AU - Martin, Eden R

AU - Zuchner, Stephan L

AU - Guo, Shengru

AU - Gonzalez, Michael

AU - Hedges, Dale J.

AU - Robertson, Peggy D.

AU - Krumm, Niklas

AU - Nickerson, Deborah A.

AU - Hershberger, Ray E.

PY - 2013/4/1

Y1 - 2013/4/1

N2 - Background-Familial dilated cardiomyopathy (DCM) is a genetically heterogeneous disease with >30 known genes. TTN truncating variants were recently implicated in a candidate gene study to cause 25% of familial and 18% of sporadic DCM cases. Methods and Results-We used an unbiased genome-wide approach using both linkage analysis and variant filtering across the exome sequences of 48 individuals affected with DCM from 17 families to identify genetic cause. Linkage analysis ranked the TTN region as falling under the second highest genome-wide multipoint linkage peak, multipoint logarithm of odds, 1.59. We identified 6 TTN truncating variants carried by individuals affected with DCM in 7 of 17 DCM families (logarithm of odds, 2.99); 2 of these 7 families also had novel missense variants that segregated with disease. Two additional novel truncating TTN variants did not segregate with DCM. Nucleotide diversity at the TTN locus, including missense variants, was comparable with 5 other known DCM genes. The average number of missense variants in the exome sequences from the DCM cases or the ≈5400 cases from the Exome Sequencing Project was ≈23 per individual. The average number of TTN truncating variants in the Exome Sequencing Project was 0.014 per individual. We also identified a region (chr9q21.11-q22.31) with no known DCM genes with a maximum heterogeneity logarithm of odds score of 1.74. Conclusions-These data suggest that TTN truncating variants contribute to DCM cause. However, the lack of segregation of all identified TTN truncating variants illustrates the challenge of determining variant pathogenicity even with full exome sequencing.

AB - Background-Familial dilated cardiomyopathy (DCM) is a genetically heterogeneous disease with >30 known genes. TTN truncating variants were recently implicated in a candidate gene study to cause 25% of familial and 18% of sporadic DCM cases. Methods and Results-We used an unbiased genome-wide approach using both linkage analysis and variant filtering across the exome sequences of 48 individuals affected with DCM from 17 families to identify genetic cause. Linkage analysis ranked the TTN region as falling under the second highest genome-wide multipoint linkage peak, multipoint logarithm of odds, 1.59. We identified 6 TTN truncating variants carried by individuals affected with DCM in 7 of 17 DCM families (logarithm of odds, 2.99); 2 of these 7 families also had novel missense variants that segregated with disease. Two additional novel truncating TTN variants did not segregate with DCM. Nucleotide diversity at the TTN locus, including missense variants, was comparable with 5 other known DCM genes. The average number of missense variants in the exome sequences from the DCM cases or the ≈5400 cases from the Exome Sequencing Project was ≈23 per individual. The average number of TTN truncating variants in the Exome Sequencing Project was 0.014 per individual. We also identified a region (chr9q21.11-q22.31) with no known DCM genes with a maximum heterogeneity logarithm of odds score of 1.74. Conclusions-These data suggest that TTN truncating variants contribute to DCM cause. However, the lack of segregation of all identified TTN truncating variants illustrates the challenge of determining variant pathogenicity even with full exome sequencing.

KW - Dilated cardiomyopathy

KW - Exome

KW - Genetics

KW - Genome-wide analysis

KW - Human

UR - http://www.scopus.com/inward/record.url?scp=84876276624&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876276624&partnerID=8YFLogxK

U2 - 10.1161/CIRCGENETICS.111.000062

DO - 10.1161/CIRCGENETICS.111.000062

M3 - Article

C2 - 23418287

AN - SCOPUS:84876276624

VL - 6

SP - 144

EP - 153

JO - Circulation. Genomic and precision medicine

JF - Circulation. Genomic and precision medicine

SN - 1942-325X

IS - 2

ER -