SIX1 – Branchio-oto-renal Syndrome

Branchio-oto-renal (BOR) syndrome (MONDO:0007029) is an autosomal dominant disorder characterized by branchial arch anomalies, hearing impairment, and renal malformations. While EYA1 mutations account for ~40% of cases, pathogenic variants in the homeobox gene SIX1 (HGNC:10887) underlie an additional subset of patients and define the DFNA23 locus for non-syndromic hearing loss in some kindreds (PMID:15141091).

Genetic evidence supports an Autosomal dominant inheritance mode with at least 4 unrelated probands carrying SIX1 variants in distinct families ([PMID:15141091]). Segregation of missense and truncating mutations with auditory and branchial phenotypes has been demonstrated in multi-generational pedigrees, including a Tunisian kindred with c.373G>A (p.Glu125Lys) (PMID:21700001).

The mutational spectrum comprises primarily missense substitutions within the Six and homeodomain regions, as well as rare truncating alleles. Recurrent variants include c.328C>T (p.Arg110Trp) and c.386A>C (p.Tyr129Ser), both impairing DNA binding. The novel variant c.373G>A (p.Glu125Lys) alters electrostatic potential at a conserved residue and has been observed in a family with isolated hearing loss and preauricular pits ([PMID:21700001]).

Functional assays demonstrate that SIX1 BOR-associated mutants disrupt the EYA1–SIX1–DNA complex, abrogate transcriptional activation of downstream targets, and in the case of p.Val17Glu abolish nuclear localization of the EYA1 co-factor (PMID:19497856). These data indicate mechanisms of haploinsufficiency and dominant-negative interference in early otic and branchial arch development.

Collectively, the evidence meets ClinGen criteria for a Moderate gene–disease association. Additional published functional studies exceed the ClinGen scoring cap but reinforce the pathogenic role of SIX1 variants in BOR syndrome.

Key Take-home: SIX1 mutations contribute a distinct diagnostic subset of BOR syndrome; targeted genetic testing informs clinical management and genetic counseling.

References

• Proceedings of the National Academy of Sciences of the United States of America | 2004 | SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. PMID:15141091
• The Journal of Biological Chemistry | 2009 | Biochemical and functional characterization of six SIX1 Branchio-oto-renal syndrome mutations. PMID:19497856
• European Journal of Medical Genetics | 2011 | A novel dominant mutation in SIX1, affecting a highly conserved residue, result in only auditory defects in humans. PMID:21700001

Evidence Based Scoring (AI generated)