Imperial College London

Dr Nicky Whiffin

Faculty of MedicineNational Heart & Lung Institute








Hammersmith HospitalHammersmith Campus






BibTex format

author = {Ingles, J and Goldstein, J and Thaxton, C and Caleshu, C and Corty, EW and Crowley, SB and Dougherty, K and Harrison, SM and McGlaughon, J and Milko, LV and Morales, A and Seifert, BA and Strande, N and Thomson, K and Peter, van Tintelen J and Wallace, K and Walsh, R and Wells, Q and Whiffin, N and Witkowski, L and Semsarian, C and Ware, JS and Hershberger, RE and Funke, B},
doi = {10.1161/CIRCGEN.119.002460},
journal = {Circulation: Cardiovascular Genetics},
title = {Evaluating the clinical validity of hypertrophic cardiomyopathy genes},
url = {},
volume = {12},
year = {2019}

RIS format (EndNote, RefMan)

AB - Background:Genetic testing for families with hypertrophic cardiomyopathy (HCM) provides a significant opportunity to improve care. Recent trends to increase gene panel sizes often mean variants in genes with questionable association are reported to patients. Classification of HCM genes and variants is critical, as misclassification can lead to genetic misdiagnosis. We show the validity of previously reported HCM genes using an established method for evaluating gene-disease associations.Methods:A systematic approach was used to assess the validity of reported gene-disease associations, including associations with isolated HCM and syndromes including left ventricular hypertrophy. Genes were categorized as having definitive, strong, moderate, limited, or no evidence of disease causation. We also reviewed current variant classifications for HCM in ClinVar, a publicly available variant resource.Results:Fifty-seven genes were selected for curation based on their frequent inclusion in HCM testing and prior association reports. Of 33 HCM genes, only 8 (24%) were categorized as definitive (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3); 3 had moderate evidence (CSRP3, TNNC1, and JPH2; 33%); and 22 (66%) had limited (n=16) or no evidence (n=6). There were 12 of 24 syndromic genes definitively associated with isolated left ventricular hypertrophy. Of 4191 HCM variants in ClinVar, 31% were in genes with limited or no evidence of disease association.Conclusions:The majority of genes previously reported as causative of HCM and commonly included in diagnostic tests have limited or no evidence of disease association. Systematically curated HCM genes are essential to guide appropriate reporting of variants and ensure the best possible outcomes for HCM families.
AU - Ingles,J
AU - Goldstein,J
AU - Thaxton,C
AU - Caleshu,C
AU - Corty,EW
AU - Crowley,SB
AU - Dougherty,K
AU - Harrison,SM
AU - McGlaughon,J
AU - Milko,LV
AU - Morales,A
AU - Seifert,BA
AU - Strande,N
AU - Thomson,K
AU - Peter,van Tintelen J
AU - Wallace,K
AU - Walsh,R
AU - Wells,Q
AU - Whiffin,N
AU - Witkowski,L
AU - Semsarian,C
AU - Ware,JS
AU - Hershberger,RE
AU - Funke,B
DO - 10.1161/CIRCGEN.119.002460
PY - 2019///
SN - 1942-325X
TI - Evaluating the clinical validity of hypertrophic cardiomyopathy genes
T2 - Circulation: Cardiovascular Genetics
UR -
UR -
VL - 12
ER -