Abstract
Genetic cardiomyopathies (CM) are disorders that affect morphology and function of cardiac muscle. Significant number of genes have been implicated in causing the phenotype. It is one of the leading genetic causes of death in young. We performed a study to understand the genetic variants in primary cardiomyopathies in an Indian cohort. Study comprised of 22 probands (13 with family history) representing hypertrophic (n = 10), dilated (n = 7), restrictive (n = 2) and arrhythmogenic ventricular(n = 3) cardiomyopathies. Genomic DNA was target captured with a panel of 46 genes and libraries sequenced on Illumina platform. Analysis identified, reported pathogenic as well as novel pathogenic (n = 6) variants in 16 probands. Of the 10 HCM patients, candidate variants were identified in nine of them involving sarcomere genes (62%, MYBPC3, MYH6, MYH7, MYL3, TTN), Z-disc (10%, ACTN2, LDB3, NEXN,), desmosome (10%, DSG2, DSP, PKP2) cytoskeletal (4%, DTNA) and ion channel (10% RYR2). In four DCM patients, variants were identified in genes NEXN, LMNA and TTN. Three arrhythmogenic right ventricular cardiomyopathy (ARVD) patients carried mutations in desmosome genes. Rare TTN variants were identified in multiple patients. Targeted capture and sequencing resulted in identification of candidate variants in about 70% of the samples which will help in management of disease in affected individual as well as in screening and early diagnosis in asymptomatic family members. Amongst the analysed cases, 22% were inconclusive without any significant variant identified. Study illustrates the utility of next-generation multi-gene panel as a cost-effective genetic testing to screen all forms of primary cardiomyopathies.
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Data availability
Data for this project has been submitted to SRA.
Submission ID: SUB13511810.
Bio-Project ID: PRJNA981695.
Novel variants submitted to ClinVar submission ID.
SUB13566647: SCV003934993—SCV003934997
SUB13566662: SCV003934999
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Acknowledgements
The authors thank the Christian Medical College Vellore for clinical evaluation, samples, isolation of DNA and support in interpretation of the data, the DSIR certified R&D unit of Genotypic technology for supporting sequencing and analysis of the data, Dr. Raja Mugasimangalam, Founder and CEO, Genotypic Technology for support and the Illumina, Inc. for the TruSight cardiomyopathy panel (Illumina Cat No: TG-141-1004) to perform targeted next-generation sequencing on the Indian primary cardiomyopathy probands.
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Mrs. Saroja M. K. has contributed to wet lab experiments, data analysis, compilation of information and manuscript preparation. Dr. Gautham Arunachal has contributed in the genetic workup, sample sourcing, data analysis and interpretation of variants. Mr. Kumar Gautam Singh has contributed to custom annotations of the variants. Dr. Sumita Danda has contributed in phenotyping, analysis, interpretation and review of the manuscript. Dr. Sudha Rao has contributed in analysis, interpretation and manuscript editing. Dr. Viji Samuel and Dr. Paul George have contributed in clinical workup and phenotyping.
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The study protocol was approved by the Institutional Review Board of the Christian Medical College (CMC), Vellore-(IRB min. No. 10532 [OBSERVE] dated 15.02.2017).
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Krishnaswamy, S.M., Arunachal, G., Singh, K.G. et al. Investigation of mutation spectrum amongst patients with familial primary cardiomyopathy using targeted NGS in Indian population. J Appl Genetics (2024). https://doi.org/10.1007/s13353-024-00855-2
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DOI: https://doi.org/10.1007/s13353-024-00855-2