Monogenic hearing loss

Gene: FOXI1

After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed and remains BIALLELIC, autosomal or pseudoautosomal.

The review from North Thames GLH notes that no good recent evidence to support monoallelic/digenic inheritance and suggests keeping under review.

The review from North West GLH notes that biallelic inheritance is only applicable to hearing loss in ClinGen / OMIM - fits with KCNJ10 and SLC26A4.

Created: 5 Dec 2024, 8:33 p.m. | Last Modified: 5 Dec 2024, 8:38 p.m.

Panel Version: 4.62

The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before changing the mode of inheritance.

Created: 30 Jan 2023, 10:16 a.m. | Last Modified: 30 Jan 2023, 10:16 a.m.

Panel Version: 3.7

Green List (high evidence)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 3 Mar 2022, 1:19 p.m. | Last Modified: 3 Mar 2022, 1:19 p.m.

Panel Version: 2.221

Comment on list classification: Promoting this gene from red to amber. There are 2 homozygous and several heterozygous cases reported and it could be promoted to green after GMS review. Although most cases are syndromic hearing loss is a major feature. There is some debate about the whether it is homozygous only or also heterozygously inherited, however the homozygous cases are more convincing.

Created: 20 Sep 2020, 10:54 a.m. | Last Modified: 20 Sep 2020, 10:54 a.m.

Panel Version: 2.93

Associated with Enlarged vestibular aqueduct (EVA) #600791 (AR) in OMIM.

Pendred syndrome is the most common form of syndromic deafness. It is inherited in an autosomal recessive manner and has been associated with SLC26A4


PMID: 29242249 - Enerbäck et al 2018 - report In 2 unrelated consanguineous families from UAE and Iraq, in which they identified by WES 3 patients with homozygous missense mutations in FOXI1 (p.L146F and p.R213P) predicted to affect the highly conserved DNA binding domain. The phenotypic features include early-onset sensorineural deafness and distal renal tubular acidosis. The deafness was profound and associated with dilation of the vestibular aqueduct. In cultured cells, the mutations reduced the DNA binding affinity of FOXI1. They suggest that the lack of a family history in the patients reported by Yang et al 2007, argues against the pathogenicity of single heterozygous mutations, consistent with the apparent lack of a clinical phenotype in the parents of their patients.

PMID: 27997596 Liu et al 2016 - from 46 sporadic Chinese probands diagnosed with EVA they report two cases who were heterozygous for FOXI1 variants and carried no SLC26A4 or KCNJ10 variants. In one case the father also carried the variant. It is not stated whether the father was affected.

PMID: 17503324 - Yang et al 2007 - report 2 Pendred and 4 EVA patients with 5 different heterozygous mutations in FOXI1 that compromised its ability to activate SLC26A4 transcription. 1 of the EVA patients was a double heterozygote who also carried a heterozygous mutation in the SLC26A4 gene, however an unaffected sibling has the SLC26A4 E29Q mutation only. They also report 9 patients with Pendred syndrome or nonsyndromic EVA who were heterozygous for a -103T-C mutation upstream of SLC26A4 which significantly reduces FOXI1-binding affinity and affects transcription of SLC26A4.

PMID: 12642503 - Hulander et al 2003 - Show that in Foxi1-/- (Fkh10) mutant mice the endolymphatic compartment is severely dilated and that the mice are deaf. They also show that in Foxi1-/- mutants there is a complete lack of Pds (now known as SLC26A4) gene expression in the endolympahtic duct/sac epithelium.

PMID: 9843211 - Hulander et al 1998 - Fkh10-/- (now known as FOXI1) mice display behavioural abnormalities associated with vestibular dysfunction, and histological analysis showed gross structural malformation of the vestibulum as well as the cochlea

Created: 20 Sep 2020, 10:50 a.m. | Last Modified: 20 Sep 2020, 10:50 a.m.

Panel Version: 2.92

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• 17503324
• 29242249
• 12642503
• 9843211

Green List (high evidence)

Multiple families and a mouse model.

Created: 29 Jan 2020, 12:46 a.m. | Last Modified: 29 Jan 2020, 12:46 a.m.

Panel Version: 2.4

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Enlarged vestibular aqueduct 600791; deafness; renal tubular acidosis

Publications

• 29242249
• 9843211
• 17503324

Variants in this GENE are reported as part of current diagnostic practice

A new publication reporting on three families with early-onset sensorineural deafness and distal renal tubular acidosis.

Created: 19 Sep 2018, 3:44 p.m.

Comment on mode of inheritance: See PMID: 29242249

Created: 19 Sep 2018, 3:43 p.m.

Comment on mode of inheritance: PMID: 17503324 reports heterozygous mutations identified in patients with Pendred syndrome (PS) and nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA).

Created: 17 Feb 2016, 3:07 p.m.

Comment on list classification: Expert review suggests that this gene should be demoted from red to green as the evidence is not enough at this current time (only PMID: 17503324). Also seems to be a digenic mode of inheritance with mutations in the SLC26A4 gene.

Created: 17 Feb 2016, 2:57 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
#600791:Enlarged vestibular aqueduct[Hearing loss, sensorineuralVestibular abnormalities (variable)Enlarged vestibular aqueductCochlear malformation defect (Mondini dysplasia) (less common)]

Publications

• PMID:12642503
• 15173882
• 16932748
• 17503324
• 7957066
• 8825632
• 9843211

Red List (low evidence)

Very few convincing mutations

Created: 13 Oct 2015, 8:34 p.m.