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.
authors: Cardiovascular Division, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
authors: Nadine
authors: N
authors: Norton
authors: Duanxiang
authors: D
authors: Li
authors: Evadnie
authors: E
authors: Rampersaud
authors: Ana
authors: A
authors: Morales
authors: Eden R
authors: ER
authors: Martin
authors: Stephan
authors: S
authors: Zuchner
authors: Shengru
authors: S
authors: Guo
authors: Michael
authors: M
authors: Gonzalez
authors: Dale J
authors: DJ
authors: Hedges
authors: Peggy D
authors: PD
authors: Robertson
authors: Niklas
authors: N
authors: Krumm
authors: Deborah A
authors: DA
authors: Nickerson
authors: Ray E
authors: RE
authors: Hershberger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002899:Chromosomes, Human, Pair 9; D064211:Connectin; D059472:Exome / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D056426:Genetic Loci; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense; D016017:Odds Ratio; D010375:Pedigree; D011494:Protein Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D064211:Connectin; D009124:Muscle Proteins; C577285:TTN protein, human; D011494:Protein Kinases