Homozygosity mapping and whole exome sequencing reveal a novel ERCC8 mutation in a Chinese consanguineous family with unique cerebellar ataxia.

BACKGROUND: A consanguineous Chinese family was affected by an apparently novel autosomal recessive disorder characterized by cerebellar ataxia, cutaneous photosensitivity, and mild intellectual disability.

METHODS: The family was evaluated by homozygosity mapping, haplotype analysis, whole exome sequencing, and candidate gene mutation screening of the proband to identify the disease-associated gene and mutation. Bioinformatics methods were used to predict the functional significance of the mutated gene product. ERCC8 mutations and phenotypes were examined.

RESULTS: All three patients presented cerebellar ataxia, cutaneous photosensitivity, and mild intellectual disability. Whole genome and candidate region linkage analysis in the consanguineous family revealed a maximum logarithm of the odds score at 5q12.1. This homozygous region was confirmed by homozygosity mapping. The pathogenic missense mutation p.Gly257Arg affecting an evolutionary highly conserved amino acid was identified in ERCC8 at 5q12.1. Integrated application of whole exome sequencing and homozygosity mapping is an efficient approach for gene mapping and mutation identification in consanguineous families.

CONCLUSIONS: We identified a novel ERCC8 mutation and new unique disease phenotype. These results also confirmed the genotype-phenotype relationship between mutations in ERCC8 and clinical findings.