Monogenic hearing loss

Gene: SIX5

Red List (low evidence)

This gene-disease association has been rated as 'DISPUTED' by ClinGen. 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). Two independent SIX5 mouse models have cataracts and no ear or kidney abnormalities (10802667, 10802668)

Created: 29 Jan 2020, 6:12 a.m. | Last Modified: 29 Jan 2020, 6:12 a.m.

Panel Version: 2.4

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Branchiootorenal syndrome 2, MIM#610896

Publications

• 17357085
• 24429398
• 21280147
• 14704431
• 17357085
• 11950062

Comment on list classification: Demoting from amber to red in view of ClinGen DISPUTED rating and no further reports of variants in SIX5 associated with hearing loss.

Created: 4 Nov 2020, 11:42 a.m. | Last Modified: 4 Nov 2020, 11:42 a.m.

Panel Version: 2.98

Comment on list classification: Upgrading from red to amber. Amber rating agreed at the GMS hearing specialist test group Webex on 2019-02-13

Created: 12 Jun 2019, 11:11 a.m.

Associated with Branchiootorenal syndrome 2 (610896) in OMIM and Gene2Phenotype (confirmed, monoallelic).

PMID: 17357085 - Hoskins et al. 2007 - screened a cohort of 95 patients with BOR for mutations in SIX5. Four different heterozygous missense mutations were identified in five individuals. All samples were negative for EYA1 or SIX1 mutations. 2 of the individuals had hearing loss (patients A477 and A500 with c.886G→A, A296T and c.1655C→T, T552M variants respectively). All sequence changes were absent in 150 healthy control individuals. In functional assays in yeast two-hybrids A296T showed a slight reduction in the interaction between SIX5 and Eya1 while T552M showed >2-fold reduction. EYA1 was the first gene to be linked to BOR and SIX5 homolog is known to interact with eya‐1 in Caenorhabditis elegans.

PMID: 21280147 - Krug et al 2011 - screened for EYA1, SIX1, and SIX5 mutations 140 patients from 124 families with BOR syndrome. The patient A500 from the Hoskins et al 2007 study was included in this cohort (Patient 1062 here). No likely disease causing SIX5 mutations were found. Two SIX5 variants were found but not considered as likely to cause the phenotype: one was found in controls, and the other, previously reported as a disease causing mutation in two families in Hoskins et al., 2007, was associated with a partial EYA1 deletion in the family that patient A500/1062 came from. They believe that the EYA1 deletion is responsible for the phenotype in this family, although cannot rule out the hypothesis that the SIX5 variant may modify the EYA1‐associated phenotype.

So in summary, Hoskins et al 2007 reported 2 BOR patients with hearing loss from unrelated families that had variants in SIX5. However, Krug et al 2011 later found that one of these two patients also had a partial EYA1 deletion. Also possible case of heterozygous nonsense variant in SIX5 in family with hearlng loss found by GOSH but unaffected father has the variant.

Created: 27 Feb 2019, 2:58 p.m.

I don't know

Heterozygous nonsense AD 1 family, father with normal hearing has the variant in our lab. 4 different pathogenic variants in HGMD associated with BOR, others with renal dysplasia/CAKUT. ? mark as amber Krug et al 2011 Hum Mutat 32(2): 183-190 screen a large BOR cohort and identify no SIX5 pathogenic variants and a 3 exon EYA1 deletion in one patient with a SIX5 missense, state that this calls into question the pathogenic role of SIX5 mutations

Created: 17 Feb 2019, 4:35 p.m.

Red List (low evidence)

Comment on list classification: Both reviewers agree this should be demoted from amber to red. PMID: 17357085 - reports heterozygous variants within this gene in patients with branchiootorenal syndrome (hearing loss was absent in two of the patients, and for one there was no data available). The association with hearing loss is therefore unclear.

Created: 23 Feb 2016, 11:46 a.m.

Red List (low evidence)

Mode of inheritance
Unknown

Phenotypes
#610896:Branchiootorenal syndrome 2[<omim version=1.0><clinicalSynopsisList>]

Publications

• PMID:10773454
• 10802667
• 10802668
• 11978764
• 14704431
• 15163633
• 17357085
• 21280147
• 7777532
• 8595416
• 9158137
• 9241282
• 9241283
• 9949207