Congenital muscular dystrophies and congenital myopathies: A study of mutational pattern and phenotypic variability from a tertiary care hospital in India

Abstract

To characterize the genetic subtypes of Congenital muscular dystrophies (CMD) and Congenital myopathies (CM). A retrospective analysis of CMD and CM (2015–2019) confirmed by exome sequencing. Institutional Ethics Committee approval obtained for the study. CMD group: 15 patients; M:F = 2:3. Onset was congenital in Ullrich CMD(UCMD), FKRP and LAMA2, adult in Bethlem myopathy(BM) and variable in LMNA. Common findings: Contractures, limb girdle and facial weakness, elevated serum creatine kinase. Calf hypertrophy in LAMA2 and FKRP. UCMD (P1,2): Recessive nonsense(p.Gln104ter, p.Gln27ter) mutations in Col6A2 and Col6A3. BM (P3-7): P3-5 had dominant missense mutations in Col6A2(p.Gly564Arg), Col6A1(p.Gly269Ar) and Col12A1(p.Gly982Arg). Co6A3 nonsense(p.Arg59ter) and c.6309+3A>G(5'splice) mutations in P6,7. LAMA2 (P8,9): Compound heterozygous mutations(p.Lys1726ter|p.Arg2604ter; p.Arg2319ter|del 34-37ex): leukoencephalopathy and cerebellar cysts on imaging. LMNA (P10-14): Onset: infancy to 3rd decade. P10-13 had heterozygous missense mutations(p.Arg453Trp, p.Leu102Pro, p.Asn39His and p.Val440Met). Variable phenotypes: P10,11: EDMD, P12: LGMD, P13: RSS with DCM. P14 with biallelic (p.Glu124Argfs*3|p.Glu124Gln) mutations: EDMD with adult progeria features. FKRP (P15): Recessive(p.Pro448Leu) mutation: limb-girdle phenotype. CM group: 12 patients; M:F = 2:1. Infantile onset with motor delay in RYR1, DES and SEPN1. Ptosis was common in all except RYR1. RYR1 (P1-4): P1&2 had opthalmoparesis: compound heterozygous(p.Leu2963Pro| p.Ser783Leu; p.Glu4464Asp|p.Arg628His) mutations. P1 biopsy showed centronuclear myopathy(CNM). P3 had heterozygous(p.Gly3288Arg) mutation. P4 with CM and bullous skin lesions: concomitant RYR1 frameshift(p.Leu108SerfsTer10) and COL7A1 5’splice(c.8620+3G>A) mutations. DES (P5,6): Recessive truncating(p.Arg150Ter, p.Glu320ArgfsTer2) mutations. Variable phenotypes: P5: CM with dilated cardiomyopathy(DCM), P6: Congenital myasthenic syndrome(CMS). SEPN1 (P7,8): Rigid spine syndrome(RSS) with homozygous(p.Met525Arg, p.Ala195Thr) mutations. DNM2 (P9,10): Onset:11-12 years with limb-girdle weakness. Dominant(p.Glu368Lys, p.Val798Met) mutations. This study highlights the mutational pattern and challenging conundrums of genotype-phenotype correlations in CMD and CM.