Preliminary results of whole exome sequencing in a clinical hypertrophic cardiomyopathy cohort in India

Abstract

Abstract Funding Acknowledgements Type of funding sources: None. Background Hypertrophic cardiomyopathy (HCM), characterized by unexplained left ventricular hypertrophy and outcomes ranging from normal life expectancy to heart failure and sudden cardiac death, has a global prevalence of about 1 in 500. Genetic testing helps to improve care of patients with HCM and their family members as children of carriers have a 50% chance of inheriting the disease. However, there is limited availability, awareness and application of genetic testing modalities, particularly whole exome sequencing (WES), in the management of HCM in India. Purpose This study aimed to analyze the results of WES in a clinical HCM cohort in India. Methods Patients with unexplained moderate to severe cardiomyopathy presenting to our centre from 2017 to 2022 and consenting for genetic testing were included in the study. Following a thorough clinical diagnostic process including 3-generational family history, electrocardiogram and echocardiogram in all patients and exercise stress test, Holter monitoring and cardiac magnetic resonance imaging where applicable, pre-test counseling was provided and WES performed using genomic DNA isolated from whole blood samples. A total of 33 affected individuals including 1 affected family member from 32 families were processed for genetic testing. A multidisciplinary team comprising of cardiologist, cardiothoracic surgeon, physician with expertise in cardiogenetics, geneticist and genetic counselor carried out the study in a tertiary cardiac centre. Results Age of the probands (n=32) at the time of the study was 47.8±15.9 years and 24 (75%) were males. There was concomitant hypertension in 11 (34%), type 2 diabetes mellitus in 6 (19%), arrhythmias in 6 (19%) and coronary artery disease in 2 (6%) probands. Obstructive HCM was present in 2 (6%) probands. Disease-causing significant variants (Pathogenic/Likely pathogenic) were detected in 8 (25%, Table), variants of uncertain significance in 17 (53%) and no significant variants were detected in 7 cases. Cascade genetic testing of significant variants among 7 family members of 4 probands showed segregation of the pathogenic variant in 4 asymptomatic carriers. Conclusions The yield of whole exome sequencing in a clinical HCM cohort in India was 25%. Of note the rare variants of uncertain significance in the cardiomyopathy genes makes genetic counseling and disease management challenging. However, large-scale studies in the context of Indian population are expected to bring clarity on the role of these variants in disease manifestation. A multidisciplinary team approach incorporating genetic testing modalities such as whole exome sequencing and cascade screening is the way forward in the comprehensive management of patients with HCM and their families.