Analysis The Characteristics Of Genetic Mutation In The Familial Emery-Dreifuss Muscular Dystrophy With Novel SYNE1 Gene Mutation

Background:Emery-Dreifuss muscular dystrophy(EDMD),characterized by the joint contracture,proximal muscle weakness,and cardiac abnormality,is a genetically heterogeneous disease occurring in X-linked and autosomal forms with varying gene mutations.Till date,EDMD has been associated with at least seven gene mutations,of which SYNE1 gene mutation is relatively less common.The SYNE1 gene has an autosomal dominant inheritance pattern and its mutations might result in defects in its expression product nesprin-1.This protein is ubiquitously expressed in multiple tissues and tether the outer membrane of the nuclear envelope(NE)to the cytoskeleton via interaction with F-actin,but particularly abundant in the striated muscles and cerebellum.Therefore,the SYNE1 gene mutations could cause EDMD4,and cerebellar ataxia theoretically,as well as,myogenic arthrogryposis multiplex congenita with features of EDMD and intellectual disability with spastic paraplegia and axonal neuropathy.In this study,we report a novel SYNE1 mutation in codon 2304 in a dominant pattern of muscular dystrophy with muscle weakness without significant cardiac abnormalities(“EDMD-like” phenotype).TTo the best of our knowledge,,this mutation(Gly2304Arg),which causes a glycine to arginine substitution,has never been reported.Materials and Methods:1?Clinical examination and neuroimaging of the captured target region and high-throughput sequencing were performed in a family of four generations.Muscle changes were evaluated using magnetic resonance imaging and muscle biopsies.Results:1?Target region capture sequencing yielded a novel missense mutation in codon 2304(G2304R),which is a heterozygous A to G point mutation at position 6910(c.6910A>G)in exon 46 of SYNE1 leading to a glycine-to-arginine substitution(p.Gly2304Arg).2?The mainly clinical manifestations of the proband are progressive muscle weakness,muscle atrophy,joint contracture,and without significant cardiac abnormalities3?The results were also identified by Sanger sequencing in three family members(?3??5??6)but not in the other four unaffected family members and 100 control subjects.Conclusions:1?This mutation is probably pathogenic and is the first of its kind reported in a familial EDMD-like.2?The mainly clinical manifestations of the proband are progressive muscle weakness,muscle atrophy,joint contracture of the peroneal muscles,and without significant cardiac abnormalities...