Homozygosity mapping and mutation analysis of a consanguineous marriage family with autosomal recessive cerebellar ataxia

Objective 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. Key words: Autosomal recessive cerebellar ataxia; Consanguineous marriage; Homozygosity mapping; Oculomotor apraxia