Genetic testing for hypertrophic cardiomyopathy (HCM) is an established clinical technique, supported by 30 years of research into its genetic etiology. Although pathogenic variants are often detected in patients and used to identify at-risk relatives, the effectiveness of genetic testing has been hampered by ambiguous genetic associations (yielding uncertain and potentially false-positive results), difficulties in classifying variants, and uncertainty about genotype-negative patients. Recent case-control studies on rare variation, improved data sharing, and meta-analysis of case cohorts contributed to new insights into the genetic basis of HCM. In particular, although research into new genes and mechanisms remains essential, reassessment of Mendelian genetic associations in HCM argues that current clinical genetic testing should be limited to a small number of validated disease genes that yield informative and interpretable results. Accurate and consistent variant interpretation has benefited from new standardized variant interpretation guidelines and innovative approaches to improve classification. Most cases lacking a pathogenic variant are now believed to indicate non-Mendelian HCM, with more benign prognosis and minimal risk to relatives. Here, we discuss recent advances in the genetics of HCM and their application to clinical genetic testing together with practical issues regarding implementation. Although this review focuses on HCM, many of the issues discussed are also relevant to other inherited cardiac diseases.
Keywords: genetic association; genetic testing; hypertrophic cardiomyopathy.