Branchio-oto-renal syndrome: the mutation spectrum in EYA1 and its phenotypic consequences

EYA1 mutations cause branchio-oto-renal (BOR) syndrome. These mutations include single nucleotide transitions and transversions, small duplications and deletions, and complex genomic rearrangements. The last cannot be detected by coding sequence analysis of EYA1. We sought to refine the clinical diagnosis of BOR syndrome by analyzing phenotypic data from families segregating EYA1 disease-causing mutations. Based on genotype-phenotype analyses, we propose new criteria for the clinical diagnosis of BOR syndrome. We found that in approximately 40% of persons meeting our criteria, EYA1 mutations were identified. Of these mutations, 80% were coding sequence variants identified by SSCP, and 20% were complex genomic rearrangements identified by a semiquantitative PCR-based screen. We conclude that genetic testing of EYA1 should include analysis of the coding sequence and a screen for complex rearrangements.