Deafness_IsolatedAndComplex

Gene: SIX5

Red List (low evidence)

ClinGEn expert review:
The SIX5 gene has been associated with autosomal dominant branchio-oto-renal syndrome using the ClinGen Clinical Validity Framework as of 4/20/2017. This association was made using case-level data only. At least 5 missense variants have been reported in humans. SIX5 was first associated with this disease in humans as early as 2007 (Hoskins et al.). Association has been reported in at least 6 probands in 2 publications (17357085, 24429398), however the reported variants are high in frequency in population databases, have no evidence of pathogenicity, and/or an alternate cause of disease has later been reported (21280147). This gene-disease association is supported by protein interaction and biochemical function studies (14704431, 17357085, 11950062). While EYA1 and SIX1 gene inactivation in mice leads to ear and kidney abnormalities, two independent SIX5 mouse models have cataracts and no ear or kidney abnormalities (10802667, 10802668). In summary, there is convincing evidence disputing the association between SIX5 and autosomal dominant branchio-oto-renal syndrome. More evidence is needed to either support or refute the role SIX5 plays in this disease.

Created: 28 Jan 2020, 11:07 p.m. | Last Modified: 28 Jan 2020, 11:07 p.m.

Panel Version: 0.254

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
branchio-oto-renal syndrome