A rare splice-site variant in TNNT2: the need for ancestral diversity in genomic reference data sets

Inherited cardiomyopathies, including hypertrophic (HCM), dilated (DCM), and restrictive (RCM) cardiomyopathies affect ∼1 in 200–500 in the population. Genetic testing is standard practice and typically identifies causal variants in approximately half of cases. Cardiac troponin T (TNNT2) is an integral protein in the cardiac sarcomere and is definitively associated with HCM and DCM.

The underrepresentation of diverse ancestries in genomic data sets complicates variant interpretation, especially for non-European populations, where genetic testing has a lower diagnostic yield.1 Among rare monogenic diseases, allele frequency in population reference databases contributes to understanding whether a variant is potentially pathogenic. While global efforts like gnomAD v4.0 have improved ancestral diversity, individuals with Oceanian ancestry, i.e. a geographical region on the Pacific Ocean comprising Australasia, Melanesia, Micronesia, and Polynesia, remain underrepresented.

We report a variant, TNNT2; NM_001001430.3: c.571-1G>A (rs483352835), in two unrelated probands with Oceanian ancestry and cardiac phenotypes, seen at a specialized genetic heart disease clinic in Sydney, Australia, who consented to research-based whole-genome sequencing (RPA Hospital Sydney Local Health District Human Research Ethics Committee X15-0089).