Branchio-oto-renal syndrome: The mutation spectrum inEYA1and its phenotypic consequences

Abstract

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.

Branchio–oto–renal syndrome: detection of EYA1 and SIX1 mutations in five out of six Danish families by combining linkage, MLPA and sequencing analyses

“…3 Six Danish families diagnosed with BOR participated in the study (Figure 1). Family 1, 21 3, 22 4, 22 5 6 and 6 22 have been described previously, whereas family 2 is new.…”

“…To test the MLPA-EYA1 kit, a DNA sample carrying an EYA1 deletion previously identified by other methods was reanalysed using the kit and the kit reliably detected the deletion (Supplementary Figure 1). In the present study, we planned -prior to sequencing (17 PCRs per patient) of EYA1 -to perform MLPA analysis (one ligation and one PCRs per patient), since deletions and duplications in EYA1 have been identified in up to 20% of EYA1 patients, 3 and when applied in this order, the two methods provide the most time-and cost-efficient strategy for the molecular diagnosis of EYA1.…”

“…2 Less frequent findings include preauricular tags (13%) and lacrimal duct aplasia (11%). 2 A set of diagnostic criteria was suggested by Chang et al 3 Based on clinical presentation, the prevalence of BOR was estimated to be 1:40 000, and to affect approximately 2% of profoundly deaf children. 4 Hearing loss is a crucial finding, presenting as sensorineural, conductive or mixed type with about equal distribution of the three types of hearing loss.…”

“…14 At least 116 different EYA1 mutations and rearrangements have been reported (isoform B). 3,15,16 By contrast, only few mutations have been reported in the SIX genes. Thus, so far, five unrelated families have been published with three different mutations in SIX1, 10,17 and five BOR individuals have been identified with four different SIX5 missense mutations.…”

“…14 Alternative splicing of EYA1 produces four transcript variants, expressing three different isoforms with the longest isoform having 18 exons. 3 Eya family members (Eya1 -4) are defined by a conserved B275 amino-acid C-terminal domain, referred to as the Eya domain and which possesses protein phosphatase activity. 18 Eya proteins, including Eya1, function as co-activators in transcriptional regulation by Dach proteins and Six proteins (including Six1 and Six5) during mammalian organogenesis.…”