Phenotype and genotype analysis of congenital muscular dystrophy with early rigid spine caused by SEPN1 mutation

目的 分析先天性肌营养不良伴早期脊柱强直(RSMD1)患儿的临床特征,并行致病基因突变研究.方法 收集2例RSMD1患儿临床资料,对患儿进行肌肉活检;提取外周血基因组DNA,利用外显子靶向捕获结合二代测序技术对先证者进行遗传性肌病相关致病基因突变检测,确定基因突变的类型.结果 2例患儿起病隐匿,进展缓慢,自幼运动发育落后,肌无力,肌张力减低,肌病面容,均可独立行走,跑跳慢.例1,女,4岁,竖头不稳,漏斗胸,脊柱前凸,反复肺部感染,血清肌酸激酶(CK)轻度升高,肌肉MRI提示肌肉弥散受损,肌肉活检未见显著病理改变,基因检测发现SEPN1复合杂合突变c.7_8insGGGCC(p.Arg5 Glyfs)和c.1167delC(p.His389fs).例2,男,13岁,脊柱侧弯,存在睡眠呼吸障碍,血清CK正常,肌肉活检提示慢性肌肉病样病理改变.发现SEPN1复合杂合突变c.233delC(p.Ser78fs)和c.1384T＞ C(p.Sec462Arg).2例患儿的突变分别来自其父母,均为未报道过的新突变.结论 通过分子遗传学分析,确诊2例SEPN1突变导致的RSMD1,为这些家庭的遗传咨询提供了可能.对早期肌无力尤其是颈轴肌无力和肌张力低下,脊柱强直、脊柱前侧凸伴严重呼吸功能不全,而四肢关节挛缩不明显的患者,应分析SEPN1基因.基因检测是确诊RSMD1最可靠的方法.Objective To analyze the clinical features of congenital muscular dystrophy with early rigid spine (rigid spine with muscular dystrophy type 1,RSMD1),and study the gene mutation.Methods Clinical data of the probands and the parents of 2 cases RSMD1 were collected.Skeletal muscle biopsies were performed on the probands for pathological diagnosis.Genomic DNA was extracted from peripheral blood leucocytes,and the virulence gene was detected by exon trapping and next generation sequencing technology to determine the gene mutation and confirm the pathogenicity.Results Two patients were presented with delayed motor development,a myopathic face,high palatine arches,and muscle weakness,hypotonia,with normal or mildly increased serum creatine kinase (CK) level.Case 1 was a 4 years old girl.She had neck extensor weakness,koilosternia,lordosis,repeat pulmonary infection,slightly high serum CK level,muscle MRI presented diffuse involvement and muscle biopsy had less significant pathological changes.Case 2 was a 13-year-old boy.He had scoliosis and respiratory insufficiency.His muscle biopsy indicated chronic myopathic changes with normal serum CK level.SEPN1 gene analysis results showed they had unreported compound heterozygote mutations,c.7_8insGGGCC (p.Arg5Glyfs),c.1167delC (p.His389fs) and c.233delC (p.Ser78fs),c.1384T ＞ C (p.Sec462Arg) respectively.The mutations in 2 patients were inherited from their parents respectively,and all were unreported novel mutations.Conclusions Two cases of RSMD1 are genetically identified and genetic counseling of the family can be possible.Patients,who have delay in motor milestone with cervicoaxial weakness early in life,spinal stiffness without limb joint contractures,progressive respiratory insufficiency,early nocturnal hypoventilation in a person who is still ambulatory,should be considered to detect SEPN1 mutation.Genetic analysis is the most reliable method for diagnosing RSMD1.国家自然科学基金; 国家重点基础研究发展计划; 儿科遗传性疾病分子诊断与研究北京市重点实验室(Z141107004414036)National Natural Science Foundation of China; National Key Basic Research Program of China; Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases中国科技核心期刊(ISTIC)中国科学引文数据库(CSCD)171347-13513