三个戊二酸血症Ⅰ型家系的临床及基因变异分析

Clinical and variation analysis of three Chinese families affected with glutaric acidemia type 1

目的通过对3个戊二酸血症Ⅰ型(glutaric acidemia type Ⅰ,GA-1)家系进行基因分析,探讨基因变异与表型的关系。方法提取3个家系3例先证者及其父母外周血基因组DNA,对戊二酰辅酶A脱氢酶(glutaryl-CoA dehydrogenase,GCDH)基因进行直接测序,确定GCDH基因变异类型。结果3例患者的临床表现差异大,具有相同基因型的不同患儿临床表现差异很大。测序结果显示家系1和家系2先证者均检测到GCDH基因c.1133C>T(p.A1a378Val)与c.1244-2A>C复合杂合变异,父母分别携带c.1133C>T(p.Ala378Val)变异和c.1244-2A>C变异。家系3先证者检测到GCDH基因c.339delT(p.Tyr113)与c.406G>T(p.Gly136Cys)复合杂合变异,父亲携带c.339delT变异,母亲携带c.406G>T变异。经检索HGMD数据库、dbSNP、千人基因组证实c.339delT及c.1133C>T变异为未报道过的新变异,生物学信息分析软件预测蛋白功能,提示均为致病性变异。结论新致病变异的检出,丰富了GCDH基因的突变谱;未发现GCDH基因型与临床表型相关的证据。

Objective To detect potential variation in glutaryl-CoA dehydrogenase (GCDH )gene among three Chinese families affected with glutaric acidemia typeⅠ(GA-1)and correlate the genotypes with phenotypes.Methods Genomic DNA was extracted from peripheral blood samples derived from three patients with GA-1 and their family members.The coding regions of the GCDH gene were amplified with PCR and subjected to Sanger sequencing.Results The clinical manifestation of the patients varied from macrocephaly to severe encephalopathy,with notable phenotypic difference between siblings carrying the same variant.In pedigrees 1 and 2,the probands have carried compound heterozygous variations c.1133 C>T(p.Ala378Val)and c.1244-2A> C,which were derived their fathers and mothers,respectively.In pedigree 3,the proband has carried compound heterozygous variation c.339delT (p.Tyr113)and c.406G>T (p.Gly136Cys).Among these,variations c.339delT and c.1133C>T were verified as novel by retrieval of dsSNP,HGMD and 1000 genome database.Bioinformatic analysis suggested that above variants can affect protein function and are probably pathogenic.Conclusion Above discovery has expanded the mutation spectrum of the GCDH gene.No correlation was found between the clinical phenotype and genotype of GA-1 patients.