Bigger isn’t always better: an exploration into hypertrophic cardiomyopathy genetic testing

The inherited cardiac condition team

As part of my DPhil I have been fortunate to work closely with a team of experts that diagnose and manage individuals, and families, affected by inherited cardiac conditions.

Hypertrophic cardiomyopathy

The most common inherited cardiac condition is hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy, colloquially shorted to HCM, is an inherited condition (usually autosomal dominant) that affects ~1 in 500 individuals, and is well recognised as a cause of sudden death within young adults. The use of genetics has helped to advance care for families affected by this disease, but for the majority of individuals diagnosed with HCM, a genetic diagnosis is never provided, which prevents the screening of their first degree relatives.

Is less more for HCM genetic testing?

Consequently, an increasingly large selection of genes are being scoured for genetic variants that may explain the cause of hypertrophic cardiomyopathy. Whilst intuitively this may seem reasonable, in the hope that a causal variant is detected, such practices are of limited value and rather than providing definitive answers often generate a list of variants of uncertain significance.

A case-control study using whole genome sequencing data

To further investigate whether there is any value in searching for variants within an expanded list genes associated with hypertrophic cardiomyopathy a case-control study was designed, using genome sequencing data generated by the NIHR’s BioResource for Rare Disease. This included 240 individuals diagnosed with HCM, who did not have a genetic diagnosis despite previous screening using a conventional gene panel, and 6,229 controls. 51 genes that had been previously proposed for HCM testing were interrogated using a combination of burden testing and manually variant interpretation.


Our results provided no support for the screening of a broad set of HCM-associated genes, with over 99% of variants found being classified as a variant of uncertain significance (VUS).

The manuscript can be found within Genetics in Medicine.

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