Muscle disorders P-MU002. Mutation spectrum of congenital muscular dystrophies: A case series from India

Introduction. Congenital muscular dystrophies (CMD) are a group of neuromuscular disorders with clinical and genetic heterogeneity with onset at birth or infancy. Little is known about the genetic spectrum of CMD in India. Methods. A retrospective study on genetically confirmed CMDs (2015- 2019). Detailed phenotyping and Next Generation Sequencing (NGS) were done. Results. A total of 19 patients were classified into 5 subgroups based on the protein and gene defect. Ullrich CMD group=three patients, mean age of onset of 1year, M:F=2:1, clinically had motor delay and limb girdle weakness, proximal contractures, distal hypotonia, joint hyperextensibility, prominent calcaneum and velvety palms/soles. Homozygous mutations were found in COL6A2[c.310C>T(p.Gln104Ter), (c.2098G>A(p.Gly700Ser)), COL6A3[c.79C>T(p.Gln27Ter)] gene respectively. Bethlem myopathy=6 patients, mean age of onset=10 years, M:F= 2:4, had limb girdle weakness, prominent calf hypertrophy and contractures. Heterozygous mutations in COL6A1[c.805G>A; p.Gly269Arg], COL6A2{[c.655A>C(p.Met219Leu)], [c.1690G>C (p.Gly564Arg)]}; COL6A3{[c.6309+3A>G 5' splice site], [c.175C>T(p.Arg59Ter)]}; COL12A1[c.2944G>A (p.Gly982Arg)] respectively. Merosin deficient=5 patients, mean age of onset=4 years, M: F=2:3, had motor delay with limb girdle weakness, bifacial weakness, proximal and distal contractures, calf hypertrophy. Neuroimaging showed leukoencephalopathy with cerebellar cysts. Mutations were homozygous in LAMA2 gene in two patients [c.6350A>G] and exon 13 (c. 1823_1824del(p.Tyr608Ter) respectively and compound heterozygous in three [Exon,36- c.5176A>T(p.Lys1726Ter); Exon,56-c.7810C>T(p.Arg2604Ter)], (exon 8c.1176_1177del)p.Cys393TyrfsTer2), exon38(c.5476C>T(p.Arg1826Ter), [Exon,49- c.6955C>T(p.Arg2319Ter), CNVvariation(deletion)- exon,34-37]. Emery-Dreifuss Muscular dystrophy=3, mean age of onset of 10 years, M:F=1:2, had limb girdle pattern of weakness, elongated facies, neck and elbow contractures, kyphoscoliosis, scapular winging. Heterozygous mutations in LMNA gene seen in all 3 [c.115A>C (p.Asn39His)], [c.1357C>T(p.Arg453Trp)] and c.305T>C. CMD dystroglycanopathy with or without mental- retardation=two with onset in infancy, had motor delay, genetically had homozygous mutation in FKRP gene [c.1343C>T(p.Pro448Leu)] and POMT1(c.193G>A(p.Gly65Arg) Conclusion. This study describes a large cohort of genetically confirmed CMDs from a single center in India and demonstrates the genetic heterogeneity.