Disease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India

Valakunja H Ganaraja; Kiran Polavarapu; Mainak Bardhan; Veeramani Preethish-Kumar; Shingavi Leena; Ram M Anjanappa; Seena Vengalil; Saraswati Nashi; Gautham Arunachal; Swetha Gunasekaran; Dhaarini Mohan; Sanita Raju; Gopikrishnan Unnikrishnan; Akshata Huddar; Valasani Ravi-Kiran; Priya T Thomas; Atchayaram Nalini

doi:10.1055/s-0041-1736567

Disease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India

Glob Med Genet. 2021 Nov 9;9(1):34-41. doi: 10.1055/s-0041-1736567. eCollection 2022 Mar.

Authors

Valakunja H Ganaraja¹, Kiran Polavarapu^{1

2}, Mainak Bardhan¹, Veeramani Preethish-Kumar¹, Shingavi Leena¹, Ram M Anjanappa^{1

2}, Seena Vengalil¹, Saraswati Nashi¹, Gautham Arunachal³, Swetha Gunasekaran³, Dhaarini Mohan¹, Sanita Raju¹, Gopikrishnan Unnikrishnan¹, Akshata Huddar¹, Valasani Ravi-Kiran¹, Priya T Thomas⁴, Atchayaram Nalini¹

Affiliations

¹ Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.
² Division of Neurology, Department of Medicine, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, The Ottawa Hospital, Ottawa, Canada.
³ Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.
⁴ Department of Psychiatric Social Work, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.

Abstract

Calpainopathy is caused by mutations in the CAPN3 . There is only one clinical and genetic study of CAPN3 from India and none from South India. A total of 72 (male[M]:female [F] = 34:38) genetically confirmed probands from 72 independent families are included in this study. Consanguinity was present in 54.2%. The mean age of onset and duration of symptoms are 13.5 ± 6.4 and 6.3 ± 4.7 years, respectively. Positive family history occurred in 23.3%. The predominant initial symptoms were proximal lower limb weakness (52.1%) and toe walking (20.5%). At presentation, 97.2% had hip girdle weakness, 69.4% had scapular winging, and 58.3% had contractures. Follow-up was available in 76.4%, and 92.7% were ambulant at a mean age of 23.7 ± 7.6 years and duration of 4.5 years, remaining 7.3% became wheelchair-bound at 25.5 ± 5.7 years of age (mean duration = 13.5 ± 4.6), 4.1% were aged more than 40 years (duration range = 5-20). The majority remained ambulant 10 years after disease onset. Next-generation sequencing (NGS) detected 47 unique CAPN3 variants in 72 patients, out of which 19 are novel. Missense variants were most common occurring in 59.7% (homozygous = 29; Compound heterozygous = 14). In the remaining 29 patients (40.3%), at least one suspected loss of function variant was present. Common recurrent variants were c.2051-1G > T and c.2338G > C in 9.7%, c.1343G > A, c.802-9G > A, and c.1319G > A in 6.9% and c.1963delC in 5.5% of population. Large deletions were observed in 4.2%. Exon 10 mutations accounted for 12 patients (16.7%). Our study highlights the efficiency of NGS technology in screening and molecular diagnosis of limb-girdle muscular dystrophy with recessive form (LGMDR1) patients in India.

Keywords: CAPN3; LGMDR1; muscular dystrophy; next-generation sequencing.

The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).

Grants and funding

Funding None.