摘要目的 针对1个一级表兄妹婚配的常染色体隐性遗传共济失调汉族家系进行致病基因的定位和突变分析.方法 将该家系的6个成员作为研究对象,包括3个患病同胞、1个健康同胞以及他们的父母(表兄妹关系).排除家系患者FXN基因内含子区GAA三核苷酸纯合突变;采用全基因组单核苷酸多态性芯片扫描结合纯合性定位方法定位候选基因;在候选区域内进行致病基因突变分析.结果 通过纯合性定位初步锁定几个可能的致病基因候选区域:2p25.3、9q22.2-34.3、13q12.3-14.3和17p13,其中9q22.2-34.3区间包含共济失调伴眼动失用症2型致病基因SETX.突变分析显示该家系成员携带SETX基因3种错义突变和1种缺失突变,分别为c.3576T＞G(p.D1192E)、c.3754G＞ A(p.G1252R)、c.4156A＞ G(p.I1386V)和c.5084_5087delAGTC(p.Q1695_S1696del).3个患者携带上述4个位点纯合异常等位基因;其父母携带4个位点的杂合等位基因,正常同胞携带4个位点纯合正常等位基因.结论 我们首次在中国常染色体隐性遗传共济失调家系患者中发现SETX基因突变,患者为4种突变构成的单倍型,其中缺失突变c.5084_5087delAGTC(p.Q1695_S1696del)为新发现突变.本家系患者临床表型较轻,病程进展缓慢,无明显眼动失用,提示AOA2存在一定的临床变异.

abstractsObjective To identify the pathogenic gene for a Chinese Han consanguineous marriage family with autosomal recessive cerebellar ataxia by homozygosity mapping and mutation analysis.Methods Six members of the family were enrolled in this study,including 3 patients,the unaffected sibling and their parents of first cousin marriage.After excluding GAA repeats mutation of FXN gene,whole-genome single nucleotide polymorphism (SNP) microarray scanning and homozygosity mapping were performed to localize the candidate gene.The coding regions and intronic flanking sequences of the candidate genes were analyzed.Results Four candidate regions were identified,including 2p25.3,9q22.2-34.3,13q12.3-14.3 and 17p13.The SETX gene localizing in 9q22.2-34.3 that is responsible for ataxia with oculomotor apraxia 2 was analyzed at first.There were 4 mutations in exon 10,including three missense mutations (c.3576T ＞ G,p.D1192E ; c.3754G ＞ A,p.G1252R; c.4156A ＞ G,p.I1386V) and a deletion mutation (c.5084_5087delAGTC,p.Q1695_S1696del).Three patients were homozygous of the 4 mutations,an unaffected sibling was normal,and their parents were heterozygous of 4 mutations.Conclusions The pathogenic haplotype comprising four mutations of the SETX gene was identified in the consanguinity family.c.5084_5087delAGTC (p.Q1695_S1696del) is a novel mutation.The affected individuals of this family were characterized by mild phenotype and slow progress without oculomotor apraxia,indicating the clinical variability of the disease.