Prevalence of variants detected by whole-exome sequencing in hypertrophic cardiomyopathy.

A proportion of patients with hypertrophic cardiomyopathy (HCM) have a diagnosis of cardiac amyloidosis. Hereditary transthyretin amyloid cardiomyopathy (ATTRv-CM) is caused by mutations in the gene. Our aim was to study the prevalence of potentially amyloidogenic variants in a whole-exome sequencing (WES) study of a large HCM cohort. 770 consecutive HCM probands underwent WES and clinical characterisation. Patients with rare or known pathogenic variants in underwent 99mTechnetium labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy and were retrospectively re-assessed for clinical features of amyloidosis. Two patients had rare variants of unknown significance and four had the known pathogenic V122I () variant (one homozygous and also heterozygous for a likely pathogenic variant and another double heterozygous for a likely pathogenic variant). Four out of 6 patients with variants underwent DPD scintigraphy; the only positive study was in the patient with the homozygous V122I () variant. Pathogenic variants are rare in carefully assessed HCM patients and may occur in double heterozygosity with pathogenic sarcomere variants. The lack of evidence for an amyloidosis phenotype in all but one variant carrier illustrates the importance of complete clinical evaluation of HCM patients that harbour pathogenic variants.