SIX5 – Branchio-oto-renal syndrome

Branchio-oto-renal (BOR) syndrome is an autosomal dominant developmental disorder characterized by branchial arch anomalies, hearing loss, and renal malformations. Known causative genes include EYA1 and SIX1, with SIX5 emerging as a candidate based on its conserved interaction with EYA1. A targeted screen of 95 BOR patients identified four heterozygous missense mutations in five unrelated individuals (PMID:17357085). Despite the autosomal dominant inheritance pattern, no familial segregation data were reported for these variants.

Subsequent mutation screening of 140 BOR families did not reveal any pathogenic SIX5 variants, calling into question its prevalence in BOR (PMID:21280147). This large cohort study suggests that SIX5 contributes infrequently to BOR syndrome. No founder or recurrent alleles have been documented to date.

All reported SIX5 variants are missense changes: c.472G>A (p.Ala158Thr), c.886G>A (p.Ala296Thr), c.1093G>A (p.Gly365Arg), and c.1655C>T (p.Thr552Met) (PMID:17357085). No loss-of-function or splice-site mutations in SIX5 have been linked to BOR.

Functional assays demonstrated that two variants, p.Ala158Thr and p.Thr552Met, impair EYA1–SIX5 binding and reduce transcriptional activation of downstream targets, consistent with a haploinsufficiency mechanism (PMID:17357085). These in vitro data provide moderate support for pathogenicity.

However, the absence of SIX5 mutations in a large cohort and the lack of segregation data limit the strength of the association. While functional disruption is evident, only a handful of probands have been described, and replication is lacking. Key take-home: rare SIX5 missense variants may underlie BOR in EYA1/SIX1-negative cases, but the overall clinical utility remains limited.

References

• American journal of human genetics • 2007 • Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome. PMID:17357085
• Human Mutation • 2011 • Mutation screening of the EYA1, SIX1, and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations. PMID:21280147

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