Preliminary results of whole exome sequencing in a clinical hypertrophic cardiomyopathy cohort in India. (25th January 2023)

• Record Type: Journal Article
• Authors: Chockalingam, P; Thenral, S G; Ramprasad, V; Anantharaman, R
• Is Part Of: European heart journal. Volume 44(2023)Supplement 1
• Publication Date: 2023-01-25
• Subjects: Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehac779.068
• Languages: English
• ISSNs: 0195-668X

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.