Branchiootorenal Syndrome 2

A number sign (#) is used with this entry because of evidence that branchiootorenal syndrome-2 (BOR2) is caused by heterozygous mutation in the SIX5 gene (600963) on chromosome 19q13.

For a phenotypic description and a discussion of genetic heterogeneity of the branchiootorenal syndrome, see BOR1 (113650).

Clinical Features

Hoskins et al. (2007) reported 5 patients with a clinical diagnosis of BOR who carried heterozygous mutations in the SIX5 gene. One of the patients had bilateral dysplastic kidneys and a right preauricular tag but normal hearing. A second had bilateral cervical fistulas; right-sided hemifacial microsomia, preauricular sinus, and pinna malformation; hearing loss in both ears, with the right side more affected than the left; and bilateral renal dysplasia with diminished renal function. Another patient had cervical fistulas and hypoplastic kidneys, and a fourth had cervical fistulas, moderate to severe hearing loss in both ears, and left renal agenesis with a hypoplastic right kidney. Clinical data were unavailable in the fifth subject.

Molecular Genetics

Hoskins et al. (2007) identified 4 mutations in the SIX5 gene (600963) as a novel cause of BOR in 5 patients. The SIX5 gene was considered a good candidate for BOR owing to its similarity to SIX1 (601205), mutations in which cause branchiootic syndrome-3 (608389), and data on C. elegans on its direct interaction with eya-1 (601653), mutations in which also cause BOR (Li et al., 2004).

In 1 of the patients reported by Hoskins et al. (2007) as carrying a mutation in the SIX5 gene (T552M; 600963.0004), Krug et al. (2011) identified a mutation in the EYA1 gene, a deletion removing exons 3, 4, and 5. This patient's DNA had been tested for EYA1 mutations by direct sequencing, but not for abnormal copy number. This observation, in addition to the extreme rarity of SIX5 mutations, caused Krug et al. (2011) to reconsider the role of SIX5 in branchiootorenal syndrome etiology.