title: A Potential Oligogenic Etiology of Hypertrophic Cardiomyopathy: A Classic Single-Gene Disorder.
abstract: BACKGROUND
  Hypertrophic cardiomyopathy (HCM) is a prototypic single-gene disease caused mainly by mutations in genes encoding sarcomere proteins. Despite the remarkable advances, the causal genes in ≈40% of the HCM cases remain unknown, typically in small families and sporadic cases, wherein cosegregation could not be established.
  
  
  OBJECTIVE
  To test the hypothesis that the missing causal genes in HCM is, in part, because of an oligogenic cause, wherein the pathogenic variants do not cosegregate with the phenotype.
  
  
  RESULTS
  A clinically affected trio with HCM underwent clinical evaluation, electrocardiography, echocardiography, magnetic resonance imaging, and whole exome sequencing. Pathogenic variants in the whole exome sequencing data were identified using established algorithms. Family members were genotyped by Sanger sequencing and cosegregation was analyzed. The siblings had a severe course, whereas the mother had a mild course. Variant analysis showed that the trio shared 145 heterozygous pathogenic variants in 139 genes, including 2 in cardiomyopathy genesTTNandALPK3. The siblings also had the pathogenic variant p.Ala13Thr variant inMYL2, a known gene for HCM. The sibling's father also carried the p.Ala13Thr variant, in whom an unambiguous diagnosis of HCM could not be made because of concomitant severe aortic stenosis. TheTTNvariant segregated with HCM, except in a 7-year-old boy, who had a normal phenotype. TheALPK3variant, shared by the affected trio, did not segregate with the phenotype.
  
  
  CONCLUSIONS
  We posit that a subset of HCM might be oligogenic caused by multiple pathogenic variants that do not perfectly cosegregate with the phenotype.
authors.affiliation: From the Center for Cardiovascular Genetics, Institute of Molecular Medicine and Department of Medicine, University of Texas Health Sciences Center at Houston, and Texas Heart Institute.
authors.forename: Lili
authors.initials: L
authors.lastname: Li
authors.affiliation: From the Center for Cardiovascular Genetics, Institute of Molecular Medicine and Department of Medicine, University of Texas Health Sciences Center at Houston, and Texas Heart Institute.
authors.forename: Matthew Neil
authors.initials: MN
authors.lastname: Bainbridge
authors.affiliation: From the Center for Cardiovascular Genetics, Institute of Molecular Medicine and Department of Medicine, University of Texas Health Sciences Center at Houston, and Texas Heart Institute.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Tan
authors.affiliation: From the Center for Cardiovascular Genetics, Institute of Molecular Medicine and Department of Medicine, University of Texas Health Sciences Center at Houston, and Texas Heart Institute.
authors.forename: James T
authors.initials: JT
authors.lastname: Willerson
authors.affiliation: From the Center for Cardiovascular Genetics, Institute of Molecular Medicine and Department of Medicine, University of Texas Health Sciences Center at Houston, and Texas Heart Institute. Ali.J.Marian@uth.tmc.edu.
authors.forename: Ali J
authors.initials: AJ
authors.lastname: Marian
mesh_terms: D000328:Adult; D024722:Cardiac Myosins / Q000191:economics* / Q000235:genetics; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D064211:Connectin / Q000235:genetics*; D059472:Exome; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D018994:Myosin Light Chains / Q000191:economics* / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D024722:Cardiac Myosins; D064211:Connectin; D009124:Muscle Proteins; D018994:Myosin Light Chains; D011494:Protein Kinases; C000618184:Alpk3 protein, human; C577285:TTN protein, human; C107184:myosin light chain 2
keywords: bioinformatics; cardiomyopathy; echocardiography; exome; genetic testing; siblings