Clinical manifestations and prenatal diagnosis of congenital muscular dystrophy

目的 对确诊的22例先天性肌营养不良(congenital muscular dystrophy,CMD)患儿进行临床特点总结,对先证者家庭进行遗传咨询,并对其23例再次妊娠的胎儿进行产前诊断.方法 分析2006年10月至2016年3月北京大学第一医院就诊的22例CMD患儿的病例资料.签署知情同意后,采集其中1 2例孕11～13周胎儿绒毛组织,及11例孕18～22周胎儿的羊水,提取基因组DNA,进行产前诊断.采用聚合酶链反应基因测序方法和多重连接探针扩增技术进行相关基因突变检测.采用短串联重复序列连锁分析鉴别是否有母血污染和胎儿生物学父母. 结果 (1)确诊的22例先证者中,1 3例为先天性肌营养不良1A型,均为LAMA2复合杂合突变.13例中,4例为野生型,7例为杂合子,2例携带与先证者相同复合杂合突变.(2)3例LMNA相关先天性肌营养不良先证者,均为LMNA新生突变,其中2例胎儿为野生型;1例胎儿携带与先证者相同致病突变,其母亲为突变嵌合体.(3)1例Ullrich先天性肌营养不良,为COL 6A2复合杂合突变,胎儿为野生型.(4)5例α-抗肌萎缩相关糖蛋白病,其中2例为肌-眼-脑病,为POMGn T1复合杂合突变,2例胎儿均为杂合子;1例为先天性肌营养不良1C型,为FKRP复合杂合突变,胎儿携带相同致病突变;1例为POMGnT1相关先天性肌营养不良伴智力障碍(congenital muscular dystrophywith mentalretardation,CMD-MR),为POMGnT1复合杂合突变,胎儿携带相同致病突变;1例为POMT1相关CMD-MR,为POMT1复合杂合突变,第1次产前诊断提示胎儿携带与先证者相同复合杂合致病突变,第2次产前诊断胎儿为杂合子. 结论 目前CMD尚无有效的治疗方法,需要对确诊的先证者家庭提供准确遗传咨询并进行有效的产前诊断,以期终止遗传链.Objective To summarize the clinical features of 22 probands diagnosed with congenital muscular dystrophy (CMD),and to provide genetic counseling and prenatal diagnosis for 23 fetuses of these pedigrees.Methods Data of 22 CMD patients who were treated in the Pediatric Department of Peking University First Hospital during October 2006 to March 2016 were analyzed.Informed written consents for participation in this study were obtained from the parents or guardians.Prenatal diagnosis was performed using DNA samples extracted from fetal villus cells of 12 cases at 11-13 gestational weeks and amniotic fluid of 11 cases at 18-22 gestational weeks.Direct DNA sequencing by polymerase chain reaction (PCR) and multiplex ligation-dependent probe amplification (MLPA) were used to detect CMD-related gene mutations.Linkage analysis of short tandem repeats (STRs) was used to identify maternal blood contamination and biological parents.Results Thirteen out of the 22 probands with CMD were diagnosed with congenital muscular dystrophy type 1 A (MDC1A),and all of them carried compound heterozygous mutations in LAMA2 gene.Prenatal diagnosis of 13 fetuses from these pedigrees found that four fetuses were wild-type,seven were heterozygotes and two carried the same mutations as their proband.Three probands with LMNA-related congenital muscular dystrophy (L-CMD) carried de novo mutations in LMNA gene.In these pedigrees,two fetuses were wild-type and one whose mother was mosaicism carried the same mutations as the proband.One proband with Ullrich congenital muscular dystrophy carried compound heterozygous mutations in COL6A2 gene and the fetus of the same pedigree was wild-type.Five probands were diagnosed with α-dystroglycanopathies.And among them,two cases of muscle-eye-brain disease (MEB) carried compound heterozygous mutations in POMGnT1 gene and the fetuses of the two peidgrees were heterozygotes;one case of congenital muscular dystrophy type 1C (MDC1C) had compound heterozygous mutations in FKRP gene and the fetus carried the same mutations;one patient diagnosed with POMGnT1-related congenital muscular dystrophy with mental retardation (CMD-MR) carried compound heterozygous mutations in POMGnT1 gene,and the fetus was positive for the same mutations;one proband with POMT1-related CMD-MR was positive for compound heterozygous mutations in POMT1 gene and the results of prenatal diagnosis for two fetuses of this pedigree showed that the first fetus had the same mutations as the proband,while the second was heterozygote.Conclusions No effective therapeutic method is available for CMD.Therefore,accurate genetic counseling and prenatal diagnosis are necessary to prevent CMD child from birth.国家自然科学基金; 国家重点基础研究发展计划; 北京市重点实验室: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 Diseases9669-6782