Submission Details

The association between the SIX1 gene and autosomal dominant branchio-oto-renal syndrome (AD BOR) has been classified as Definitive using the ClinGen Cllinical Validity Framework as of 11/21/16. The first case was published in 2004 by Ruf et al. Some affected individuals do not have any renal phenotype, and are sometimes considered to have branchio-otic syndrome. Mutai 2013 reported a mother and child with the p.Arg110Trp variant in SIX1, which was previously reported in a family with BOR syndrome, who did not have any other clinical features of BOR other than hearing loss. The association with nonsyndromic hearing loss, however, has not been replicated. In a family reported by Salam et al. 2000 with linkage to a novel autosomal dominant nonsyndromic hearing loss locus DFNA23, Ruf 2004 later identified a missense variant in SIX1, but also that an affected individual had progressive renal failure, indicating this family may have actually had BOR syndrome. Functional studies indicate that SIX1 interacts with EYA1, the most common cause of BOR syndrome, and that pathogenic variants in SIX1 impair the protein's ability to bind EYA1 or to bind DNA (Ruf et al. 2004, Patrick et al. 2009) and two mouse models of BOR syndrome have been generated (Zheng et al. 2003, Bosman et al. 2009). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern for BOR and autosomal dominant nonsyndromic hearing loss. Therefore, all of the disease entitites have been lumped into one disease entity, AD BOR. In summary, SIX1 is definitively associated with AD BOR. This classification was approved by the ClinGen Hearing Loss Working Group on 6/22/2017.