Genetic testing for hypertrophic cardiomyopathy (HCM) is an established clinical technique, supported by
30 years of research into its genetic aetiology. 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, while research into new genes and mechanisms remains essential, re-assessment 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 benefitted from new standardised 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. While this review focuses on HCM, many of the
issues discussed are also relevant to other inherited cardiac diseases.