一个LAMA2基因复合杂合突变导致的肢带型肌营养不良症隐性23型家系的临床特征及遗传学分析

Clinical and molecular genetic analysis of a family with limb girdle muscular dystrophy caused by bi-allelic variants in LAMA2 gene

目的探讨1例表现为肢带型肌营养不良症(LGMD)患者的临床特征及遗传学特点。方法获取先证者的临床检查资料,采用全外显子组测序技术(WES)筛选患者的候选可疑致病突变,利用Mutation taster、SIFT、Polyphen2等有害性分析软件对候选突变位点进行功能预测。通过Sanger测序法对候选致病突变位点进行验证,并对该患者的临床特点进行分析。结果先证者临床表现为四肢远端肌肉萎缩及肌无力,血清肌酸激酶(CK)升高,肌电图提示肌源性损害。该家系中2例患者的LAMA2基因存在复合杂合突变,其中c.20_21insCCTC(p.Leu9Profs*42)杂合移码突变遗传自父亲,该突变为首次报道;c.C4591A(p.Pro1531Thr)杂合错义突变来自母亲,突变有害性分析表明两个突变位点均为有害突变。结论结合临床表现与基因检测结果,患者诊断为肢带型肌营养不良症隐性23型(LGMDR23)。LAMA2基因c.20_21insCCTC和c.C4591A复合杂合突变是患者的致病突变。本研究的病例为国内首次报道,进一步丰富了LAMA2基因的致病突变谱,为该病的临床诊断和基因检测提供更多参考依据。

Objective To explore the clinical and genetic characteristics of 1 case with limb-girdle muscular dystrophy. Methods Clinical data of the proband was collected. The suspected pathogenic mutation of proband was detected by whole exome sequencing(WES). And the candidate pathogenic mutations were analyzed by bioinformatics(Mutation taster,SIFT, Polyphen2). The suspected mutations of proband were verified by Sanger sequencing, and the clinical characteristics was analyzed. Results The clinical manifestations of the proband included muscle atrophy and muscle weakness in the distal extremities, serum creatine kinase(CK) increased, and electromyography suggested myogenic damage. WES revealed a compound heterozygous mutation in the LAMA2 gene existed in 2 cases. The c.20_21 insCCTC(p.L9 Pfs*42) heterozygous frameshift mutation was inherited from the father, which was reported for the first time. The c.C4591 A(p.Pro1531 Thr) heterozygous missense mutation came from the mother. Mutation harmfulness analysis showed that both mutations sites were harmful mutations. Conclusion Combined with clinical manifestations and genetic testing results, the patient was diagnosed as lamb-girdle muscular dystrophy recessive type 23(LGMDR23). LAMA2 gene c.20_21 insCCTC and c.C4591 A compound heterozygous mutations are the cause of the disease. The present study enriches the mutation spectrum of the LAMA2 gene and provides more evidence for clinical diagnosis and genetic counseling.