Mutation pattern in 606 Duchenne muscular dystrophy children with a comparison between familial and non-familial forms: a study in an Indian large single-center cohort

• Published in: Journal of neurology Vol. 266; no. 9; pp. 2177 - 2185
• Main Authors: Polavarapu, Kiran, Preethish-Kumar, Veeramani, Sekar, Deepha, Vengalil, Seena, Nashi, Saraswati, Mahajan, Niranjan P., Thomas, Priya Treesa, Sadasivan, Arun, Warrier, Manjusha, Gupta, Anupam, Arunachal, Gautham, Debnath, Monojit, Keerthipriya, Muddasu Suhasini, Pradeep-Chandra-Reddy, Chevula, Puttegowda, Arpitha, John, Anu P., Tavvala, Ajitha, Gunasekaran, Swetha, Sathyaprabha, Talakad N., Chandra, Sadanandavalli Retnaswami, Kramer, Boris, Delhaas, Tammo, Nalini, Atchayaram
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-09-2019; Springer Nature B.V
• Subjects: Alternative splicing; Child; Child, Preschool; Children; Cohort Studies; Databases, Genetic - trends; Duchenne's muscular dystrophy; Dystrophin; Genetic counseling; Humans; India - epidemiology; Male; Medicine; Medicine & Public Health; Muscular dystrophy; Muscular Dystrophy, Duchenne - diagnosis; Muscular Dystrophy, Duchenne - epidemiology; Muscular Dystrophy, Duchenne - genetics; Mutation; Mutation - genetics; Neurology; Neuroradiology; Neurosciences; Next-generation sequencing; Original Communication; Retrospective Studies; India; Mutation; Duchenne muscular dystrophy; Familial; India
• ISSN: 0340-5354; 1432-1459
• DOI: 10.1007/s00415-019-09380-3

Introduction
Duchenne muscular dystrophy (DMD) is induced by a wide spectrum of mutations such as exon deletions, duplications and small mutations in the dystrophin gene. This is the first study on the mutational spectrum in a cohort of DMD children from India, with an emphasis to compare the mutations in familial and sporadic forms.
Results
Multiplex ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS) identified 525 and 70 cases of DMD, respectively, while 11 cases showed absent dystrophin staining with no mutations detected. Families with two or more affected males contributed to 12% of the entire cohort. The mutations comprised of exonic deletions in 492/606 (81.2%), duplications in 33/606 (5.4%) and small mutations (point mutations and INDELs) in 70/606 (11.5%) cases. MLPA identified significantly more larger mutations in sporadic (88.2%) than in familial cases (75.3%). The mutations in NGS were: [nonsense = 40 (57.1%); frameshift = 17 (24.3%); splice variant = 12 (17.1%)]. Nonsense mutations were more common in familial than in sporadic cases: 17.8% vs 10.7%. The familial group reported an earlier onset of disease (2.8 ± 1.7 years) as compared to sporadic cases (3.8 ± 1.6 years).
Conclusion
MLPA could identify mutations in a high percentage of our DMD children. The preponderance of small mutations was noted to be distinctly higher in the familial group. Intriguingly, the familial form of DMD formed a small percentage of the entire cohort. The reasons could be increasing awareness among parents and physicians with early identification of DMD cases, genetic counseling and prenatal testing.