Distinct familial profile in gene elusive hypertrophic cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) has traditionally been viewed as a monogenic disorder. Increasing evidence indicates that gene-elusive HCM represents a distinct subgroup with differing clinical characteristics. Understanding its familial expression and natural history is essential to inform personalised management strategies. To characterise the phenotype and clinical outcomes of affected relatives in gene-elusive HCM and compare them with probands. Among 842 patients referred for HCM genetic testing over a 10-year period, 637 with clinical follow-up were enrolled in a natural history registry. Families in which probands had negative genetic testing (HCMG–) were included. Of 1,278 at-risk relatives, 74 (9.7%) were diagnosed with HCM through screening; 28 had complete follow-up. These were compared with 294 probands. Affected relatives were younger at diagnosis than probands (48.4 ± 16.1 vs 54.1 ± 12.6 years; p = 0.032), with similar follow-up (6.6 ± 5.1 vs 6.4 ± 3.8 years; p = 0.88). Relatives demonstrated a milder structural phenotype: isolated basal septal hypertrophy was more common (42.3% vs 5.1%) and apical hypertrophy less frequent (11.5% vs 31.0%; p < 0.001). Maximal wall thickness (14.0 ± 2.4 vs 16.6 ± 3.3 mm; p < 0.001) and left atrial diameter (38.1 ± 4.8 vs 41.9 ± 6.1 mm; p = 0.003) were lower. Seventy-five percent had borderline wall thickness (13–15 mm). Cardiovascular risk factors were highly prevalent: 50% of relatives were hypertensive at diagnosis, and 93% had ≥1 risk factor by final follow-up. Relatives were less symptomatic (46.4% vs 78.2%; p < 0.001), had fewer patients in NYHA class ≥ II, and showed a lower prevalence of LV outflow tract obstruction (3.7% vs 26.2%; p = 0.03). Arrhythmias were less common: atrial fibrillation/flutter occurred in 15.4% of relatives vs 29.5% of probands. Only three cardiovascular events occurred in relatives (fast atrial fibrillation, stroke, acute pericarditis). Sudden cardiac death (SCD) risk was low in both groups but lowest in relatives: only one had an estimated SCD risk ≥4%, compared with 9.8% of probands. All symptomatic ventricular arrhythmias occurred in probands. Relatives with gene-elusive HCM identified through family screening exhibit a predominantly mild structural phenotype, lower arrhythmic burden, and few adverse outcomes compared with probands. The high prevalence of cardiovascular risk factors among relatives suggests a significant contribution to disease expression in this subgroup.Affected Relatives vs ProbandsCV Risk at Diagnosis: Affected Relatives