Branchiootic Syndrome 3

A number sign (#) is used with this entry because branchiootic syndrome-3 is caused by mutation in the SIX1 gene (601205).

For a phenotypic description and a discussion of genetic heterogeneity of branchiootic syndrome, see BOS1 (602588).

Mapping

Ruf et al. (2003) mapped a locus for branchiootic syndrome to 14q21.3-q24.3, which they designated BOS3. Mapping was achieved by a genomewide search in a large Anglo-Saxon Australian pedigree with more than 40 affected subjects. The highest multipoint lod score was 4.81 for marker D14S980. In contrast to the pedigree described by Kumar et al. (2000) (BOS2; 120502) in which hearing loss was diagnosed in 50% of the affected subjects, deafness seemed to be a major feature in the pedigree reported by Ruf et al. (2003). As 25% of the patients showed association with branchial arch defects, a nonsyndromic form of deafness was unlikely. The finding of lacrimal duct stenosis, a common association in both branchiootorenal (BOR; 113650) and branchiootic syndromes, further confirmed the diagnosis of BOS. The hearing loss varied in form, severity, frequency, and age of onset among the different family members and even between the ears of 1 patient, a characteristic feature of BOR and BOS. EYA2 (601654) and EYA3 (601655) were excluded as sites of mutations causing BOS3 in this kindred because these 2 genes are located on chromosomes 20 and 1, respectively. Mutations in another member of the EYA gene family, EYA4 (603550), is responsible for late-onset deafness (601316).

Molecular Genetics

Ruf et al. (2004) located the SIX1, SIX4 (606342), and SIX6 (606326) genes, which act within a genetic network of EYA and PAX genes to regulate organogenesis, within a 33-Mb critical interval on chromosome 14q23. By direct sequencing of exons in these genes, they identified 2 different mutations in the SIX1 gene in 3 kindreds with branchiootic syndrome-3 (601205.0001-601205.0002).

In 7 affected individuals from a large 5-generation Danish family with branchiootic syndrome, Sanggaard et al. (2007) identified heterozygosity for a missense mutation in the SIX1 gene (601205.0004). All affected individuals had hearing impairment, and some had branchial and preauricular defects. There were no subjective complaints indicating renal disease, and no renal anomalies were detected in the 3 affected individuals who underwent renal ultrasound. The mutation was not found in unaffected family members or in 140 control chromosomes.