Clinical spectrum and genetic variations of <i>LMNA</i>-related muscular dystrophies in a large cohort of Chinese patients.

Abstract

<i>LMNA</i>-related muscular dystrophy is caused by mutations in <i>LMNA</i> gene. We aimed to identify genetic variations and clinical features in a large cohort of Chinese patients with <i>LMNA</i> mutations in an attempt to establish genotype-phenotype correlation. The clinical presentations of patients with <i>LMNA</i>-related muscular dystrophy were recorded using retrospective and prospective cohort study. <i>LMNA</i> mutation analysis was performed by Sanger sequencing or next-generation sequencing. Mosaicism was detected by personal genome machine amplicon deep sequencing for mosaicism. Eighty-four patients were identified to harbour <i>LMNA</i> mutations. Forty-one of those were diagnosed with <i>LMNA</i>-related congenital muscular dystrophy (L-CMD), 32 with Emery-Dreifuss muscular dystrophy (EDMD) and 11 with limb-girdle muscular dystrophy type 1B (LGMD1B). We identified 21 novel and 29 known <i>LMNA</i> mutations. Two frequent mutations were identified: c.745C>T and c.1357C>T. A correlation between the location of mutation and the clinical phenotype was observed: mutations affecting the head and coil 2A domains mainly occurred in L-CMD, while the coil 2B and Ig-like domains mainly related to EDMD and LGMD1B. We found somatic mosaicism in one parent of four probands. Muscle biopsies revealed 11 of 20 biopsied L-CMD exhibited inflammatory changes, and muscle cell ultrastructure showed abnormal nuclear morphology. Our detailed clinical and genetic analysis of 84 patients with <i>LMNA</i>-related muscular dystrophy expands clinical spectrum and broadens genetic variations caused by <i>LMNA</i> mutations. We identified 21 novel and 29 known <i>LMNA</i> mutations and found two frequent mutations. A correlation between the location of mutation and the clinical severity was observed. Preliminary data suggested that low-dose corticosteroid treatment may be effective.