DYNC1Hl基因p.P776L突变致常染色体显性遗传脊肌萎缩症一家系分析

Pedigree analysis of DYNCIH1p.P776L mutation in a family with spinal muscular atrophy

目的分析常染色体显性脊肌萎缩症一家系的临床及电生理特点,并对患者及其家系进行致病基因突变分析。方法为了明确先证者双下肢近端萎缩、无力的致病原因,对患者的家系展开调查,采集了12名先证者家系成员的Il缶床资料,并对先证者及其母亲进行实验室化验、肌电图+F波+H反射、脊柱及双下肢x线、头颅MRI及脊髓MRI等检查;进一步对先证者血样进行人类全外显子测序,并按照2015年美国医学遗传学与基因组学学会(AcMc)和美国分子病理学会(AMP)的基因变异解读标准和指南做致病性分析,且对其及其家属进行一代验证。结果家系调查发现,该家系12人中存在7例双下肢近端无力患者,3例主要表现为双下肢肌肉萎缩,1例以高弓足为主要表型,其余患者主要表现为双下肢近端无力;先证者及其母亲肌电图检查考虑为脊髓前角病变;6例均存在DYNCIHl基因(exon8,c.2327C>T,p.P776L)突变患者,考虑变异来源于先证者外祖母,根据ACMG和AMP指南考虑强致病性突变。结论我们在6例患者中鉴定出了DYNClHl基因p.P776L的致病性突变,且该突变存在共分离现象、其表型存在个体差异,这种发现对于研究中国人群脊肌萎缩具有重要意义。

Objective To analyze the clinical and electrophysiological features in a family with spinal muscular atrophy (SMA),and assess the probable causative gene mutations for the family.Methods To identify the nosogenesis of the proband with weakness and atrophy in the double lower proximal limbs, clinical data of his 12 family members were collected,and the proband and his mother were selected for clinical examinations,including laboratory tests,electromyogram (EMG),F-wave,H-reflex,X-ray of the spine and double lower limbs,brain and spinal cord magnetic resonance imaging,etc.Moreover,human whole exome sequencing was performed on blood sample from the proband,then its deleterious effects were assessed according to the Standards and guidelines for the interpretation of sequence variants,a joint consensus recommendation of the American College of Medical Genomics (ACMG)and the Association for Molecular Pathology (AMP).Subsequently,the strong pathogenic mutation was validated by Sanger sequencing.Results Familial investigation showed seven of 12family members presented with weakness in the double lower proximal limbs.Among them,three had the main manifestation of atrophy in the double lower proximal limbs,one had high arched foot as the main presentation,and the others had weakness in the double lower proximal limbs.EMG studies showed the abnormal results in the anterior horn of the spinal cord.The strong pathogenic mutation in DYNC1H1gene (exon8,c.2327C>T,p.P776L)was identified from the proband according to ACMG and AMP guidelines.Sanger sequencing revealed six patients had this variant and it was passed mainly from his maternal grandmother.Conclusions A pathogenic mutation of the DYNC1H1p.P776L in six Chinese pedigrees which cosegregated with SMA was identified.There existedindividual differences in clinical presentations.This finding may have important implications for the study of SMA in Chinese patients.