Family screening outcomes in gene-elusive HCM

Abstract

Hypertrophic cardiomyopathy (HCM) is traditionally viewed as a monogenic disorder; however, a substantial proportion of patients remain gene-elusive despite comprehensive testing. Understanding cascade screening performance in gene-elusive families is essential to guide clinical practice when no molecular explanation is identified. To evaluate family screening outcomes in gene-elusive HCM and identify clinical and demographic factors associated with detection of newly affected relatives. Among 842 probands referred for HCM genetic testing over 10 years, 637 with longitudinal follow-up at our institution were enrolled in the NatHCM registry. Genetic testing followed UK clinical pathways: referrals were made through our institution’s Clinical Genetics service until 2020, after which testing was mainstreamed within cardiology in line with national implementation of the Genomics England Test Directory. We included families where no pathogenic or likely pathogenic variant was identified (gene-elusive HCM, HCMG–). Data collected included demographics, family structure, screening uptake, diagnostic yield, and the presence of documented family history of HCM prior to the proband’s first evaluation. Screening of first-degree relatives followed guideline-recommended clinical assessment, ECG and echocardiography. We analysed 302 families comprising 1,278 at-risk relatives (42.8% women, 48.0% men). Ethnicity was 46.4% Caucasian, 21.5% Asian, 18.2% Black and 13.9% other. Families had a mean of 4.2 eligible first-degree relatives, and screening was recommended in all. A family history of HCM was documented in 7% prior to proband evaluation and 20.9% by end of follow-up. Family size was moderate in most families (4–6 members, 55%). Generational distribution included 46.5% siblings, 6.3% upper-generation, and 45% lower-generation relatives. Screening uptake was similar across sex and generations but varied by ethnicity, highest among Caucasian relatives (75.8%) and lowest among Black relatives (55.3%). Overall, 74 relatives were diagnosed with HCM, corresponding to 9.7% of screened individuals. Two affected members were present in 11.6% of families and ≥3 in 5.9%. Diagnostic yield was not associated with proband phenotype, ethnicity, sex, age or presence of a VUS. Higher screening uptake (63.9% vs 43.4%) and the presence of documented family history of HCM prior to first evaluation were both associated with identifying additional affected relatives. In gene-elusive HCM families, clinical cascade screening identifies new diagnoses in a modest but clinically meaningful proportion of relatives. Screening yield is driven by uptake levels and existing family history, supporting systematic phenotypic screening even when no causative genetic variant is detected.Determinants of Positive Family ScreeningFamilies with and without positive screening