Comparison of The Carrier Frequency of Pathogenic Variants of DMD Gene in an Indian Cohort

Article type: Research Article

Authors: Nagabushana, Divya^{a; 1} | Polavarapu, Kiran^{a; b; c; d; 1} | Bardhan, Mainak^a | Arunachal, Gautham^e | Gunasekaran, Swetha^e | Preethish-Kumar, Veeramani^a | Anjanappa, Ram Murthy^a | Thomas, PriyaTreesa^f | Sadasivan, Arun^f | Vengalil, Seena^a | Nashi, Saraswati^a | Chawla, Tanushree^a | Warrier, Manjusha^f | Keerthipriya, Muddasu^a | Raju, Sanita^a | Mohan, Dhaarini^a | Nalini, Atchayaram^{a; *}

Affiliations: [a] Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India | [b] Children's Hospital of Eastern Ontario Research Institute, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada | [c] Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada | [d] Brain and Mind Research Institute, University of Ottawa, ON, Canada | [e] Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bengaluru, India | [f] Department of Psychiatric Social Work, National Institute of Mental Health and Neurosciences, Bengaluru, India

Correspondence: [*] Correspondence to: Dr. A. Nalini; Professor of Neurology, Neuromuscular specialist, Department of Neurology, Neuroscience Faculty Center, National Institute of Mental Health and Neurosciences, Bengaluru – 560029. India. Tel.: +91 80 26995139; Fax: +91 80 26564830; E-mail: atchayaramnalini@yahoo.co.in.

Note: [1] Equal contribution.

Abstract: Background:Duchenne muscular dystrophy (DMD) is an X-linked disorder caused due to large deletions, duplications,and small pathogenic variants. This article compares the carrier frequency of different pathogenic variants in the DMD gene for the first time in an Indian cohort. Methods:Ninety-one mothers of genetically confirmed DMD probands are included in this study. Pathogenic variants in the DMD gene in probands were detected by multiplex ligation-dependent probe amplification (MLPA) or next-generation sequencing (NGS). Maternal blood samples were evaluated either by MLPA or Sanger sequencing. The demographic and clinical details for screening of muscle weakness and cardiomyopathy were collected from the confirmed carriers. Results:Out of 91 probands, large deletions and duplications were identified in 46 and 6 respectively, while 39 had small variants. Among the small variants, substitutions predicted to cause nonsense mutations were the most common (61.5%), followed by frameshift causing small insertion/deletions (25.6%) and splice affecting intronic variants (12.8%). Notably, 19 novel small variants predicted to be disease-causing were identified. Of the 91 mothers, 53 (58.7%) were confirmed to be carriers. Exonic deletions had a significantly lower carrier frequency of 47.8% as compared to small variants (64.1%). The mean age of the carriers at evaluation was 30 years. Among the carriers, two were symptomatic with onset in the 4th decade, manifesting with progressive proximal muscle weakness and dilated cardiomyopathy. Conclusion:Carrier frequency of small pathogenic variants differs significantly from large deletions. Small pathogenic variants are more commonly inherited, whereas large deletions arise de novo.

Keywords: Duchenne muscular dystrophy, carrier, large deletions, large duplications, small pathogenic variants, India

DOI: 10.3233/JND-210658

Journal: Journal of Neuromuscular Diseases, vol. 8, no. 4, pp. 525-535, 2021