一个戈谢病Ⅱ型中国家系GBA基因突变分析及文献复习

Analysis and literature review of GBA gene mutations in a Chinese family with one member suffered from type 2 Gaucher disease

目的鉴定一个戈谢病Ⅱ型中国家系中GBA基因的致病性突变。方法收集1例戈谢病Ⅱ型10个月女性患儿的临床及家系资料,提取该先证者及其父母外周血DNA,采用PCR扩增GBA基因的11个外显子及剪接位点序列,对PCR产物进行直接测序;对先证者及其父亲的包含第6外显子变异位点的基因序列进行克隆测序。以"Gaucher disease""GBA"和"mutation"为检索词对dbSNP、ClinVar、HGMD和PubMed等数据库进行检索,收集并分析检索到的携带GBA c.680681delATinsGG突变的病例资料。结合该家系先证者的临床资料以及美国医学遗传学与基因组学学会和分子病理学协会(ACMG/AMP)的指南进行罕见突变的致病性鉴定。结果该家系先证者GBA基因有2个复合杂合性突变:遗传自父亲的第6外显子的c.680681delATinsGG(p.N227R)突变和遗传自母亲的第10外显子的c.1448T> C(p.L483P)突变。克隆测序验证了先证者及其父亲的c.680681位点有2种单体型:突变的GG和正常的AT。c.680681delATinsGG为罕见突变,尚未有研究对该突变进行致病性鉴定。随访显示先证者有运动、智力进行性减退以及惊厥发作和喂养困难,于出生后16个月因喂养时呛咳、窒息死亡。目前在数据库仅检索到2例患者携带该突变,其中1例患病资料缺乏,另外1例为中国戈谢病Ⅱ型患儿。根据ACMG/AMP的指南,该变异分类为"致病性的"。结论 GBA基因的c.680681delATinsGG和c.1448T> C复合杂合性突变导致该家系的先证者患病,c.680681delATinsGG为致病性突变,c.680681delATinsGG/c.1448T> C基因型与戈谢病Ⅱ型相关。

Objective To identify the pathogenic mutations of the GBA gene in a Chinese infant with type 2 Gaucher disease. Methods Clinical data and the family history of the proband, a 10-month-old affected female infant, were investigated. DNA was extracted from the peripheral blood of the proband and her parents. All 11 exons and the intron-exon splice sites of GBA gene were amplified by polymerase chain reaction(PCR). Mutations were detected by direct sequencing the PCR products. The DNA sequence containing exon 6 variant of the proband and her father were cloned and sequenced. Using the keywords of “Gaucher disease” “GBA gene” and “mutation”, relevant literatures were searched from dbSNP, ClinVar, HGMD, PubMed and other relevant databases. Phenotypic data of these patients with the GBA c.680_681delATinsGG mutation were collected and analyzed. The pathogenicity of the rare mutation was identified by the clinical manifestations of the proband in combination with the ACMG/AMP guidelines. Results The proband was found to be compound heterozygous for two mutations in the GBA gene: c.680_681delATinsGG(p.N227R)mutation in the exon 6 from her father and c.1448T > C(p.L483P)in the exon 10 from her mother. Cloning and sequencing verified both the proband and her father carried mutant GG and normal AT haplotypes at c.680_681 sites. The c.680_681delATinsGG is a rare mutation, and its pathogenicity has not been identified. Subsequent follow-up revealed that the proband developed progressive deterioration in physical activity and intelligence, convulsion and difficulty in feeding, and died of cough and suffocation due to feeding at 16 months after birth. At present, only 2 patients with this mutation have been retrieved, and clinical data were lacking in 1 case and the other case was a Chinese child with type 2 Gaucher disease. According to the ACMG/AMP guidelines, the variation was classified as “pathogenic”. Conclusions The compound heterozygous c.680_681delATinsGG(p.N227R) and c.1448T > C(p.L483P) mutations lead to the incidence of type 2 Gaucher disease in the proband.c.680_681del ATinsGG is a pathogenic mutation and c.680_681delATinsGG/c.1448T > C genotype is associated with type 2 Gaucher disease.