title: Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives.
abstract: The American Heart Association (AHA) recommends family screening for hypertrophic cardiomyopathy (HCM). We assessed the outcome of family screening combining clinical evaluation and screening for sarcomere gene mutations in a cohort of 90 Danish HCM patients and their close relatives, in all 451 persons. Index patients were screened for mutations in all coding regions of 10 sarcomere genes (MYH7, MYL3, MYBPC3, TNNI3, TNNT2, TPM1, ACTC, CSRP3, TCAP, and TNNC1) and five exons of TTN. Relatives were screened for presence of minor or major diagnostic criteria for HCM and tracking of DNA variants was performed. In total, 297 adult relatives (>18 years) (51.2%) fulfilled one or more criteria for HCM. A total of 38 HCM-causing mutations were detected in 32 index patients. Six patients carried two disease-associated mutations. Twenty-two mutations have only been identified in the present cohort. The genetic diagnostic yield was almost twice as high in familial HCM (53%) vs. HCM of sporadic or unclear inheritance (19%). The yield was highest in families with an additional history of HCM-related clinical events. In relatives, 29.9% of mutation carriers did not fulfil any clinical diagnostic criterion, and in 37.5% of relatives without a mutation, one or more criteria was fulfilled. A total of 60% of family members had no mutation and could be reassured and further follow-up ceased. Genetic diagnosis may be established in approximately 40% of families with the highest yield in familial HCM with clinical events. Mutation-screening was superior to clinical investigation in identification of individuals not at increased risk, where follow-up is redundant, but should be offered in all families with relatives at risk for developing HCM.
authors.affiliation: Department of Clinical Biochemistry, Statens Serum Institute, Copenhagen, Denmark. psa@ssi.dk
authors.forename: Paal Skytt
authors.initials: PS
authors.lastname: Andersen
authors.forename: Ole
authors.initials: O
authors.lastname: Havndrup
authors.forename: Lotte
authors.initials: L
authors.lastname: Hougs
authors.forename: Karina M
authors.initials: KM
authors.lastname: Sørensen
authors.forename: Morten
authors.initials: M
authors.lastname: Jensen
authors.forename: Lars Allan
authors.initials: LA
authors.lastname: Larsen
authors.forename: Paula
authors.initials: P
authors.lastname: Hedley
authors.forename: Alex Rojas Bie
authors.initials: AR
authors.lastname: Thomsen
authors.forename: Johanna
authors.initials: J
authors.lastname: Moolman-Smook
authors.forename: Michael
authors.initials: M
authors.lastname: Christiansen
authors.forename: Henning
authors.initials: H
authors.lastname: Bundgaard
mesh_terms: D000199:Actins / Q000235:genetics; D000328:Adult; D000368:Aged; D024722:Cardiac Myosins / Q000235:genetics; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D064211:Connectin; D004252:DNA Mutational Analysis; D003718:Denmark; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D060588:LIM Domain Proteins; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics; D018994:Myosin Light Chains / Q000235:genetics; D012518:Sarcomeres / Q000378:metabolism* / Q000473:pathology; D014335:Tropomyosin / Q000235:genetics; D019209:Troponin C / Q000235:genetics; D019210:Troponin I / Q000235:genetics; D020107:Troponin T / Q000235:genetics; D055815:Young Adult; D000099163:Myosin Binding Protein C
chemical_list: D000199:Actins; D024722:Cardiac Myosins; D002352:Carrier Proteins; D064211:Connectin; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D018995:Myosin Heavy Chains; D018994:Myosin Light Chains; D014335:Tropomyosin; D019209:Troponin C; D019210:Troponin I; D020107:Troponin T; D000099163:Myosin Binding Protein C; C526913:ACTC1 protein, human; C501641:MYH7 protein, human; C577292:TCAP protein, human; C490775:TPM1 protein, human; C090114:cysteine and glycine-rich protein 3