title: Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy.
abstract: OBJECTIVE
  A predictable relation between genotype and disease expression is needed in order to use genetic testing for clinical decision-making in hypertrophic cardiomyopathy (HCM). The primary aims of this study were to examine the phenotypes associated with sarcomere protein (SP) gene mutations and test the hypothesis that variation in non-sarcomere genes modifies the phenotype.
  
  
  METHODS
  Unrelated and consecutive patients were clinically evaluated and prospectively followed in a specialist clinic. High-throughput sequencing was used to analyse 41 genes implicated in inherited cardiac conditions. Variants in SP and non-SP genes were tested for associations with phenotype and survival.
  
  
  RESULTS
  874 patients (49.6±15.4 years, 67.8% men) were studied; likely disease-causing SP gene variants were detected in 383 (43.8%). Patients with SP variants were characterised by younger age and higher prevalence of family history of HCM, family history of sudden cardiac death, asymmetric septal hypertrophy, greater maximum LV wall thickness (all p values<0.0005) and an increased incidence of cardiovascular death (p=0.012). Similar associations were observed for individual SP genes. Patients with ANK2 variants had greater maximum wall thickness (p=0.0005). Associations at a lower level of significance were demonstrated with variation in other non-SP genes.
  
  
  CONCLUSIONS
  Patients with HCM caused by rare SP variants differ with respect to age at presentation, family history of the disease, morphology and survival from patients without SP variants. Novel associations for SP genes are reported and, for the first time, we demonstrate possible influence of variation in non-SP genes associated with other forms of cardiomyopathy and arrhythmia syndromes on the clinical phenotype of HCM.
authors.affiliation: UCL Institute of Cardiovascular Science, London, UK.
authors.forename: Luis R
authors.initials: LR
authors.lastname: Lopes
authors.affiliation: UCL Institute of Cardiovascular Science, London, UK.
authors.forename: Petros
authors.initials: P
authors.lastname: Syrris
authors.affiliation: UCL Institute of Cardiovascular Science, London, UK.
authors.forename: Oliver P
authors.initials: OP
authors.lastname: Guttmann
authors.affiliation: UCL Institute of Cardiovascular Science, London, UK The London Chest Hospital, London, UK.
authors.forename: Constantinos
authors.initials: C
authors.lastname: O'Mahony
authors.affiliation: UCL Institute of Cardiovascular Science, London, UK National Heart Centre, Singapore, Singapore.
authors.forename: Hak Chiaw
authors.initials: HC
authors.lastname: Tang
authors.affiliation: UCL Institute of Cardiovascular Science, London, UK.
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Dalageorgou
authors.affiliation: UCL Institute of Cardiovascular Science, London, UK.
authors.forename: Sharon
authors.initials: S
authors.lastname: Jenkins
authors.affiliation: UCL Genomics, Department of Molecular Haematology and Cancer Biology, UCL Institute of Child Health, London, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Hubank
authors.affiliation: Instituto de Investigación Biomédica de la Universidad de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC)-Universidad de A Coruña, A Coruña, Spain.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Monserrat
authors.affiliation: UCL Institute of Cardiovascular Science, London, UK.
authors.forename: William J
authors.initials: WJ
authors.lastname: McKenna
authors.affiliation: UCL Genetics Institute, London, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: UCL Institute of Cardiovascular Science, London, UK.
authors.forename: Perry M
authors.identifier: http://orcid.org/0000-0003-3383-3984
authors.initials: PM
authors.lastname: Elliott
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods*; D016757:Death, Sudden, Cardiac / Q000209:etiology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053208:Kaplan-Meier Estimate; D008131:London; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult
chemical_list: D009124:Muscle Proteins
keywords: GENETICS