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Hearing loss

Gene: FOXI1

Amber List (moderate evidence)

FOXI1 (forkhead box I1)
EnsemblGeneIds (GRCh38): ENSG00000168269
EnsemblGeneIds (GRCh37): ENSG00000168269
OMIM: 601093, Gene2Phenotype
FOXI1 is in 3 panels

5 reviews

Eleanor Williams (Genomics England Curator)

Green List (high evidence)

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

Zornitza Stark (Australian Genomics)

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

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

Ellen McDonagh (Genomics England Curator)

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.

Jun Shen (Harvard Medical School)

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

Maria Bitner-Glindzicz (UCL)

Red List (low evidence)

Very few convincing mutations
Created: 13 Oct 2015, 8:34 p.m.

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Expert
  • Radboud University Medical Center, Nijmegen
  • Emory Genetics Laboratory
  • Illumina TruGenome Clinical Sequencing Services
Phenotypes
  • Nonsyndromic Hearing Loss, Mixed
  • #600791:Enlarged vestibular aqueduct
  • hearing loss
Tags
for-review
OMIM
601093
Clinvar variants
Variants in FOXI1
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

20 Sep 2020, Gel status: 2

Added Tag

Eleanor Williams (Genomics England Curator)

Tag for-review tag was added to gene: FOXI1.

20 Sep 2020, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: foxi1 has been classified as Amber List (Moderate Evidence).

19 Sep 2018, Gel status: 1

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for gene: FOXI1 were set to PMID:12642503; 15173882; 16932748; 17503324; 7957066; 8825632; 9843211

19 Sep 2018, Gel status: 1

Set mode of inheritance

Ellen McDonagh (Genomics England Curator)

Mode of inheritance for gene: FOXI1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal

17 Feb 2016, Gel status: 1

Gene classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

This gene has been classified as Red List (Low Evidence).

17 Feb 2016, Gel status: 1

Set Phenotypes

Ellen McDonagh (Genomics England Curator)

Phenotypes for FOXI1 were set to Nonsyndromic Hearing Loss, Mixed; #600791:Enlarged vestibular aqueduct; hearing loss

17 Feb 2016, Gel status: 1

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Mode of inheritance for FOXI1 was changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

17 Feb 2016, Gel status: 1

Gene classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

This gene has been classified as Red List (Low Evidence).

17 Feb 2016, Gel status: 3

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for FOXI1 were set to PMID:12642503; 15173882; 16932748; 17503324; 7957066; 8825632; 9843211

24 Jun 2015, Gel status: 3

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene FOXI1 was changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

24 Jun 2015, Gel status: 3

Added New Source

Ellen McDonagh (Genomics England Curator)

FOXI1 was added to Congenital hearing impairment (Profound/Severe)panel. Sources: Illumina TruGenome Clinical Sequencing Services,Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen,Expert

24 Jun 2015, Gel status: 3

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene FOXI1 was changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

24 Jun 2015, Gel status: 3

Added New Source

Ellen McDonagh (Genomics England Curator)

FOXI1 was added to Congenital hearing impairment (Profound/Severe)panel. Sources: Illumina TruGenome Clinical Sequencing Services,Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen,Expert

24 Jun 2015, Gel status: 2

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene FOXI1 was changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

24 Jun 2015, Gel status: 2

Added New Source

Ellen McDonagh (Genomics England Curator)

FOXI1 was added to Congenital hearing impairment (Profound/Severe)panel. Sources: Illumina TruGenome Clinical Sequencing Services,Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen,Expert

24 Jun 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

FOXI1 was added to Congenital hearing impairment (Profound/Severe)panel. Sources: Illumina TruGenome Clinical Sequencing Services,Emory Genetics Laboratory,Radboud University Medical Center, Nijmegen,Expert