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

Friday,2013-11-08 15:59 America/Los_Angeles — poolea2
TitleExome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy.
Publication TypeJournal Article
Year of Publication2013
AuthorsNorton, N, Li, D, Rampersaud, E, Morales, A, Martin, ER, Zuchner, S, Guo, S, Gonzalez, M, Hedges, DJ, Robertson, PD, Krumm, N, Nickerson, DA, Hershberger, RE
Corporate/Institutional AuthorsNational Heart, Lung, and Blood Institute GO Exome Sequencing Project and the Exome Sequencing Project Family Studies Project Team
JournalCirc Cardiovasc Genet
Volume6
Issue2
Pagination144-53
Date Published2013 Apr
ISSN1942-3268
KeywordsAdolescent, Adult, Aged, Cardiomyopathy, Dilated, Chromosomes, Human, Pair 9, Connectin, Exome, Female, Genetic Heterogeneity, Genetic Linkage, Genetic Loci, Genome, Human, Humans, Male, Middle Aged, Muscle Proteins, Mutation, Missense, Odds Ratio, Pedigree, Protein Kinases, Sequence Analysis, DNA, Young Adult
Abstract<p>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.</p>
DOI10.1161/CIRCGENETICS.111.000062
Alternate JournalCirc Cardiovasc Genet
PubMed ID23418287
PubMed Central IDPMC3815606
Grant ListN01-HC-25195 / HC / NHLBI NIH HHS / United States
HL-077916 / HL / NHLBI NIH HHS / United States
N01HC-55021 / HC / NHLBI NIH HHS / United States
RC2 HL-066583 / HL / NHLBI NIH HHS / United States
RC2 HL102923 / HL / NHLBI NIH HHS / United States
UC2 HL102926 / HL / NHLBI NIH HHS / United States
42117 / / PHS HHS / United States
UC2 HL103010 / HL / NHLBI NIH HHS / United States
42115 / / PHS HHS / United States
F32 HL-083714 / HL / NHLBI NIH HHS / United States
HL-103010 / HL / NHLBI NIH HHS / United States
N01WH22110 / WH / WHI NIH HHS / United States
N01-HC48049 / HC / NHLBI NIH HHS / United States
U01HL-089897 / HL / NHLBI NIH HHS / United States
N01-HC48050 / HC / NHLBI NIH HHS / United States
N01 HC-95171 / HC / NHLBI NIH HHS / United States
N01 HC-55015 / HC / NHLBI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
R02HL-095396 / HL / NHLBI NIH HHS / United States
R01 HL094976 / HL / NHLBI NIH HHS / United States
42110 / / PHS HHS / United States
RC2 HL-101779 / HL / NHLBI NIH HHS / United States
N01HC-85079 / HC / NHLBI NIH HHS / United States
42121 / / PHS HHS / United States
42131 / / PHS HHS / United States
U01 HL-089856 / HL / NHLBI NIH HHS / United States
HL094976 / HL / NHLBI NIH HHS / United States
N01-HC48048 / HC / NHLBI NIH HHS / United States
RR-024156 / RR / NCRR NIH HHS / United States
42109 / / PHS HHS / United States
P50 HL-084946 / HL / NHLBI NIH HHS / United States
32118 / / PHS HHS / United States
AG-15928 / AG / NIA NIH HHS / United States
R01 NS17950 / NS / NINDS NIH HHS / United States
32115 / / PHS HHS / United States
32109 / / PHS HHS / United States
AG033193 / AG / NIA NIH HHS / United States
AG-20098 / AG / NIA NIH HHS / United States
42123 / / PHS HHS / United States
M01 RR-07122 / RR / NCRR NIH HHS / United States
42126 / / PHS HHS / United States
42112 / / PHS HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
42130 / / PHS HHS / United States
K23 AR-52742 / AR / NIAMS NIH HHS / United States
24152 / / PHS HHS / United States
32119 / / PHS HHS / United States
N01-HC95159 / HC / NHLBI NIH HHS / United States
AG08122 / AG / NIA NIH HHS / United States
AG-027058 / AG / NIA NIH HHS / United States
HL-102924 / HL / NHLBI NIH HHS / United States
N01 HC-55020 / HC / NHLBI NIH HHS / United States
32108 / / PHS HHS / United States
HL58626 / HL / NHLBI NIH HHS / United States
42116 / / PHS HHS / United States
HR-46002 / HR / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
N01-HC-35129 / HC / NHLBI NIH HHS / United States
N01 HC-55222 / HC / NHLBI NIH HHS / United States
42132 / / PHS HHS / United States
N01HC-55017 / HC / NHLBI NIH HHS / United States
N01-HC48047 / HC / NHLBI NIH HHS / United States
N01-HC-95169 / HC / NHLBI NIH HHS / United States
HL-102926 / HL / NHLBI NIH HHS / United States
42122 / / PHS HHS / United States
42111 / / PHS HHS / United States
R01 NS042733 / NS / NINDS NIH HHS / United States
090532 / / Wellcome Trust / United Kingdom
N01-HC-75150 / HC / NHLBI NIH HHS / United States
N01 HC-15103 / HC / NHLBI NIH HHS / United States
42113 / / PHS HHS / United States
UL1 RR-025014 / RR / NCRR NIH HHS / United States
42124 / / PHS HHS / United States
32106 / / PHS HHS / United States
RC2 HL-101651 / HL / NHLBI NIH HHS / United States
UC2 HL102923 / HL / NHLBI NIH HHS / United States
N01 HC-55018 / HC / NHLBI NIH HHS / United States
N01HC-95172 / HC / NHLBI NIH HHS / United States
UC2 HL102924 / HL / NHLBI NIH HHS / United States
R01 HL058626 / HL / NHLBI NIH HHS / United States
HL-102925 / HL / NHLBI NIH HHS / United States
HL-69197 / HL / NHLBI NIH HHS / United States
32102 / / PHS HHS / United States
R01 HL-068890 / HL / NHLBI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
N01-HC-45133 / HC / NHLBI NIH HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
32105 / / PHS HHS / United States
42118 / / PHS HHS / United States
42129 / / PHS HHS / United States
32113 / / PHS HHS / United States
32122 / / PHS HHS / United States
HL-76285 / HL / NHLBI NIH HHS / United States
N01HC-55016 / HC / NHLBI NIH HHS / United States
N01-HC-85239 / HC / NHLBI NIH HHS / United States
42107 / / PHS HHS / United States
32100 / / PHS HHS / United States
AG-023629 / AG / NIA NIH HHS / United States
32111 / / PHS HHS / United States
42114 / / PHS HHS / United States
44221 / / PHS HHS / United States
5R00 HG004316 / HG / NHGRI NIH HHS / United States
HL102923 / HL / NHLBI NIH HHS / United States
32101 / / PHS HHS / United States
HG-004738 / HG / NHGRI NIH HHS / United States
42125 / / PHS HHS / United States
42108 / / PHS HHS / United States
32112 / / PHS HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States
UC2 HL102925 / HL / NHLBI NIH HHS / United States
N01 HC-95170 / HC / NHLBI NIH HHS / United States
N01-HC95095 / HC / NHLBI NIH HHS / United States
42120 / / PHS HHS / United States
42119 / / PHS HHS / United States
R01 NS039987 / NS / NINDS NIH HHS / United States
N01 HC-55019 / HC / NHLBI NIH HHS / United States

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