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

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.