Clinical spectrum and genetic variations of <i>LMNA</i>-related muscular dystrophies in a large cohort of Chinese patients
Yanbin Fan, Dandan Tan, Danyu Song, Xu Zhang, Xingzhi Chang, Zhaoxia Wang, Cheng Zhang, H.S. Chan, Qixi Wu, Liwen Wu, Shuang Wang, Hui Yan, Ge Lin, Haipo Yang, Bing Mao, C. Bönnemann, Jingying Liu, Suxia Wang, Yun Yuan, Xiru Wu, Hong Zhang, Hui Xiong
Abstract
Background LMNA -related muscular dystrophy is caused by mutations in LMNA gene. We aimed to identify genetic variations and clinical features in a large cohort of Chinese patients with LMNA mutations in an attempt to establish genotype-phenotype correlation. Methods The clinical presentations of patients with LMNA -related muscular dystrophy were recorded using retrospective and prospective cohort study. LMNA mutation analysis was performed by Sanger sequencing or next-generation sequencing. Mosaicism was detected by personal genome machine amplicon deep sequencing for mosaicism. Results Eighty-four patients were identified to harbour LMNA mutations. Forty-one of those were diagnosed with LMNA -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 LMNA 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. Conclusions Our detailed clinical and genetic analysis of 84 patients with LMNA -related muscular dystrophy expands clinical spectrum and broadens genetic variations caused by LMNA mutations. We identified 21 novel and 29 known LMNA 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.