Whole-exome sequencing identifies USH2A mutations in a pseudo-dominant Usher syndrome family

Usher syndrome (USH) is an autosomal recessive (AR) multi-sensory degenerative disorder leading to deaf-blindness. USH is clinically subdivided into three subclasses, and 10 genes have been identified thus far. Clinical and genetic heterogeneities in USH make a precise diagnosis difficult. A dominant-like USH family in successive generations was identified, and the present study aimed to determine the genetic predisposition of this family. Whole-exome sequencing was performed in two affected patients and an unaffected relative. Systematic data were analyzed by bioinformatic analysis to remove the candidate mutations via step-wise filtering. Direct Sanger sequencing and co-segregation analysis were performed in the pedigree. One novel and two known mutations in the USH2A gene were identified, and were further confirmed by direct sequencing and co-segregation analysis. The affected mother carried compound mutations in the USH2A gene, while the unaffected father carried a heterozygous mutation. The present study demonstrates that whole-exome sequencing is a robust approach for the molecular diagnosis of disorders with high levels of genetic heterogeneity.