title: Exome Sequencing Identifies Pathogenic and Modifier Mutations in a Child With Sporadic Dilated Cardiomyopathy.
abstract: BACKGROUND
  Idiopathic dilated cardiomyopathy (DCM) is typically diagnosed in adulthood, yet familial cases exhibit variable age-dependent penetrance and a subset of patients develop sporadic DCM in childhood. We sought to discover the molecular basis of sporadic DCM in an 11-year-old female with severe heart failure necessitating cardiac transplantation.
  
  
  RESULTS
  Parental echocardiograms excluded asymptomatic DCM. Whole exome sequencing was performed on the family trio and filtered for rare, deleterious, recessive, and de novo variants. Of the 8 candidate genes identified, only 2 had a role in cardiac physiology. A de novo missense mutation in TNNT2 was identified, previously reported and functionally validated in familial DCM with markedly variable penetrance. Additionally, recessive compound heterozygous truncating mutations were identified in XIRP2, a member of the ancient Xin gene family, which governs intercalated disc (ICD) maturation. Histomorphological analysis of explanted heart tissue revealed misregistration, mislocalization, and shortening of ICDs, findings similar to Xirp2(-/-) mice.
  
  
  CONCLUSIONS
  The synergistic effects of TNNT2 and XIRP2 mutations, resulting in perturbed sarcomeric force generation and transmission, respectively, would account for an early-onset heart failure phenotype. Whereas the importance of Xin proteins in cardiac development has been well established in animal models, this study implicates XIRP2 as a novel modifier gene in the pathogenesis of DCM.
authors.affiliation: Mayo Graduate School, Molecular Pharmacology and Experimental Therapeutics Track, Mayo Clinic, Rochester, MN (P.A.L.) Cardiovascular Genetics Research Laboratory, Mayo Clinic, Rochester, MN (P.A.L., T.M.O.).
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Long
authors.affiliation: Department of Pathology, University of Arizona Medical Center, Tucson, AZ (B.T.L.).
authors.forename: Brandon T
authors.initials: BT
authors.lastname: Larsen
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN (J.M.E.).
authors.forename: Jared M
authors.initials: JM
authors.lastname: Evans
authors.affiliation: Cardiovascular Genetics Research Laboratory, Mayo Clinic, Rochester, MN (P.A.L., T.M.O.) Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN (T.M.O.) Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN (T.M.O.).
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Olson
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D006352:Heart Ventricles / Q000473:pathology / Q000648:ultrastructure; D006579:Heterozygote; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D046529:Microscopy, Electron, Transmission; D020125:Mutation, Missense / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D017422:Sequence Analysis, DNA; D020107:Troponin T / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D009687:Nuclear Proteins; C545568:TNNT2 protein, human; D020107:Troponin T; C500306:XIRP2 protein, human
keywords: dilated cardiomyopathy; genetics; heart failure; pediatrics; whole exome sequencing