三个FKRP基因变异所致的肢带型肌营养不良2I型家系的临床表现及遗传学分析

Analysis of clinical features and genetic variants in three Chinese pedigrees affected with Limb girdle muscular dystrophy type 2I

目的分析3个FKRP基因变异导致肢带型肌营养不良2I型(limb girdle muscular dystrophy type 2I,LGMD2I)家系的临床表型和基因变异特点。方法收集3例先证者的临床资料并对其进行肌肉活检。提取先证者及其家系成员的外周血样,采用全外显子组测序技术筛查先证者致病基因,确定可疑致病变异后对家系成员采用Sanger测序进行验证。结果先证者1和先证者2均存在双下肢无力的症状,其中先证者1行走能力丧失伴有肺通气功能障碍。先证者3存在下肢疼痛和剧烈运动后心悸、憋喘症状。3例先证者肌肉病理可见肌营养不良表现和α-抗肌萎缩相关糖蛋白分子的表达量降低。基因测序结果显示先证者1 FKRP基因存在c.545A>G(p.Y182C)和c.1391A>T(p.N464I)复合杂合变异,先证者2存在c.545A>G(p.Y182C)和c.941C>T(p.T314M)复合杂合变异,先证者3存在c.545A>G(p.Y182C)和c.161G>A(p.R54Q)复合杂合变异。C.545A>G(p.Y182C)、c.1391A>T(p.N464I)和c.941C>T(p.T314M)变异已有文献报道,c.161G>A(p.R54Q)变异尚未见报道。结论3个家系中患者的发病原因均为FKRP基因复合杂合变异。全外显子组测序对LGMD2I的诊断有重要价值。新的FKRP基因复合杂合变异位点的发现也丰富了该基因的变异谱。

Objective To analyze the clinical features and genetic variants of three Chinese pedigrees affected with Limb girdle muscular dystrophy type 2I(LGMD2I).Methods Clinical data and peripheral blood samples of the three probands and their family members were collected.Whole exome sequencing was carried out for the probands.Candidate variants were verified by Sanger sequencing of their family members.Results Probands 1 and 2 both featured weakness in the lower limbs.Proband 1 had lost walking ability and had pulmonary ventilation dysfunction.Proband 3 had lower limb pain,palpitations and asthma after exercise.Genetic sequencing revealed that proband 1 harbored compound heterozygous c.545A>G(p.Y182C)and c.1391A>T(p.N464I)variants of the FKRP gene,proband 2 harbored compound heterozygous c.545A>G(p.Y182C)and c.941C>T(p.T314M)variants of the FKRP gene,and proband 3 harbored compound heterozygous c.545A>G(p.Y182C)and c.161G>A(p.R54Q)variants.Among these,the c.161G>A(p.R54Q)variant was unreported previously.Conclusion Compound heterozygous variants of the FKRP gene probably underlay the LGMD2I in the three patients.Whole exome sequencing is crucial for the diagnosis of LGMD2I.The identification of the novel variant also broadened the mutational spectrum of the FKRP gene.