Family screening in hypertrophic cardiomyopathy - clinical and genetic yield at baseline

Abstract

Abstract Background Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder, often with monogenic inheritance and accordingly, familial aggregation of HCM is common. International guidelines recommend family screening of relatives of patients with HCM to allow pre-symptomatic identification and early interventions. The clinical and genetic yield of implemented screening programs have been scarcely described and might improve by adjustments. We hypothesized that screening can be improved. Purpose To assess the yield of clinical and genetic family screening in HCM at first screening visit. Methods The study was a retrospective study of clinical and genetic cascade screening of adult relatives (age ≥18 years) of HCM probands, screened for familial occurrence of HCM from 2006 to 2022 at a regional assembly of clinics for inherited cardiac diseases (population 2.6 million). We collected demographic, clinical, symptomatic, and genetic characteristics from electronic health records, and a national pedigree database. Diagnostic work-up included a 12-lead ECG, and echocardiography. Relatives of probands carrying a likely pathogenic (LP) or pathogenic (P) variant were also offered cascade genetic testing. Patients and relatives were diagnosed according to the 2014 ESC guidelines. Results We included 603 adult relatives (55% female, mean age 44±15 years) (table 1). At baseline, 118 relatives (20%) fulfilled diagnostic criteria for HCM, and 135 (22%) were carriers of LP/P variants; 78 (13%) of these did not fulfill diagnostic criteria for HCM. Thus, the combined clinical and genetic yield of baseline screening was 33%. A total of 108 (18%) clinically unaffected relatives did not carry the family’s LP/P variant and were discharged from follow-up. This indicates that 50% of the relatives at baseline could be categorized as affected, genetically predisposed or clinically and genetically not at risk. Relatives fulfilling criteria for HCM at baseline were older (51 vs. 42 years, p<0.001), more likely to report cardiopulmonary symptoms (46% vs 16%, p<0.001), be male (59% vs 41%, p<0.001), and have abnormal ECG features (40% vs. 12%, p<0.001), compared to relatives not fulfilling criteria for HCM at baseline. On echocardiography, relatives fulfilling criteria for HCM had a mean maximal wall thickness of 17±4 mm and 14% had left ventricular outflow tract obstruction (gradient at rest/Valsalva≥30 mmHg). Conclusion At baseline screening, one in three relatives of HCM patients were diagnosed with HCM or found to be genetically predisposed to the disease. One in five clinically unaffected relatives not carrying the proband’s disease-causing variant could be discharged from screening. Considering the pattern of inheritance in HCM, the theoretical risk of developing HCM in the remaining 50% of the relatives is low. The non-diagnostic findings may be useful for identification of the remaining truly at-risk relatives.Table 1:Baseline characteristics