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Deafness_IsolatedAndComplex

Gene: FOXI1

Green List (high evidence)

FOXI1 (forkhead box I1)
EnsemblGeneIds (GRCh38): ENSG00000168269
EnsemblGeneIds (GRCh37): ENSG00000168269
OMIM: 601093, Gene2Phenotype
FOXI1 is in 6 panels

3 reviews

Bryony Thompson (Royal Melbourne Hospital)

Green List (high evidence)

Distal renal tubular acidosis
PMID: 9843211, 12642503 - null mouse models display deafness and vestibular issues
PMID: 29242249 - distal renal tubular acidosis and sensorineural deafness with enlarged vestibular aqueduct (EVA) in 3 affected individuals in 2 consanguineous families with homozygous missense (L146F & R213P). Cases also had rickets, nephrocalcinosis, and medullary cysts. In vitro assays demonstrate reduced function for both variants.

Limited evidence - enlarged vestibular aqueduct (EVA) - Conflicting evidence for digenic inheritance (PMID: 17503324, 32447495). Only compelling evidence is double heterozygous mouse model. Original publication is from 2007. Many heterozygous missense reported, but no significant missense constraint in gene.
PMID: 17503324 - this study proposed SLC26A4 c.-103T>C silences FOXI1 transcription in multiple EVA cases, which lead to sequence FOXI1 as a candidate gene. 6 cases with Pendred syndrome and nonsyndromic EVA with missense/in-frame deletion, one case (G258E) also had a SLC26A4 missense (E29Q - LP) with digenic inheritance (both heterozygous parents were unaffected). All FOXI1 variants had reduced transcriptional activity in luciferase assays. G258E - 25 hets in gnomAD v2.1, N161del, G258R - 3 hets gnomAD v2.1, R267Q - 18 hets gnomAD v2.1, G335V - 3 hets gnomAD v2.1. Also, EVA occurs in the Slc26a4+/−; Foxi1+/− double-heterozygous mouse mutant
PMID: 30268946 - 1 heterozygous missense (p.Asp189Asn - 8 hets in gnomAD v2.1) identified in a EVA case. SLC26A4 also screened in this individual.
PMID: 27997596 - 1 EVA proband with a de novo missense (c.519C>A, p.His173Gln) & 1 EVA proband with missense (c.716C>T, p.Pro239Leu - 71 hets gnomAD v2.1) that was paternally inherited. All probands in the study were expected to have recessive disease and were also screened for variants in SLC26A4.
PMID: 22285650 - 716C>T (p.P239L) also identified in a proband with congenital severe SNHL with inner ear malformations, and a normal thyroid phenotype. Negative for SCL26A4 variants
PMID: 23965030 - c.367C > T p.Arg123Trp with SLC26A4 c.2219C > T p.Gly740Val in a case with hearing impairment and either goitre or EVA
PMID: 24860705 - identified a common variant in a Pendred syndrome case when investigating digenic inheritance, c.677C>T p.Thr226Ile - 1059 alleles in gnomAD v2.1 & 4 homozygotes
PMID: 32447495 - c.214C>A p.Pro72Thr (2 hets in gnomAD v2.1) identified in an EVA case with compound het SLC26A4 variants. FOXI1 variant derived from unaffected paternal transmission, which is evidence against digenic inheritance
PMID: 19204907 - this study disputes that SLC26A4 c.-103T>C exterts a pathogenic effect on FOXI1 transcription
Disputed classification by the ClinGen Hearing Loss GCEP, based on publication above - Classification - 09/10/2018
Created: 12 May 2022, 5:14 a.m. | Last Modified: 12 May 2022, 5:14 a.m.
Panel Version: 1.131

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
autosomal recessive distal renal tubular acidosis MONDO:0018440

Publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Comment on publications: Another six individuals reported in 17503324, though in one digenic inheritance was suggested.
Created: 2 Jan 2020, 4:14 a.m. | Last Modified: 2 Jan 2020, 4:14 a.m.
Panel Version: 0.193

Lilian Downie (Victorian Clinical Genetics Services)

Green List (high evidence)

Disputed evidence for enlarged vestibular aqueduct PMID: 19204907
Created: 3 Jul 2020, 4:26 a.m. | Last Modified: 3 Jul 2020, 4:26 a.m.
Panel Version: 0.358
2 unrelated families and a mouse model
Created: 31 Dec 2019, 1:09 a.m. | Last Modified: 31 Dec 2019, 1:09 a.m.
Panel Version: 0.65

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
sensorineural deafness and distal renal tubular acidosis

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Melbourne Genomics Health Alliance Deafness Flagship
  • Victorian Clinical Genetics Services
Phenotypes
  • autosomal recessive distal renal tubular acidosis MONDO:0018440
OMIM
601093
Clinvar variants
Variants in FOXI1
Penetrance
None
Publications
Panels with this gene

History Filter Activity

12 May 2022, Gel status: 3

Set Phenotypes

Bryony Thompson (Royal Melbourne Hospital)

Phenotypes for gene: FOXI1 were changed from Enlarged vestibular aqueduct, MIM# 600791 to autosomal recessive distal renal tubular acidosis MONDO:0018440

12 May 2022, Gel status: 3

Set publications

Bryony Thompson (Royal Melbourne Hospital)

Publications for gene: FOXI1 were set to 29242249; 9843211; 17503324

2 Jan 2020, Gel status: 3

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: FOXI1 were set to 29242249; 9843211

31 Dec 2019, Gel status: 3

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: FOXI1 were set to 29242249; 9843211

31 Dec 2019, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: foxi1 has been classified as Green List (High Evidence).

31 Dec 2019, Gel status: 3

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: FOXI1 were set to 29242249; 9843211

31 Dec 2019, Gel status: 3

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: FOXI1 were set to

31 Dec 2019, Gel status: 3

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: FOXI1 were changed from sensorineural deafness and distal renal tubular acidosis to Enlarged vestibular aqueduct, MIM# 600791

31 Dec 2019, Gel status: 3

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: FOXI1 were changed from to sensorineural deafness and distal renal tubular acidosis

31 Dec 2019, Gel status: 3

Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Mode of inheritance for gene: FOXI1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal

17 Nov 2019, Gel status: 3

Created, Added New Source, Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

gene: FOXI1 was added gene: FOXI1 was added to Deafness_MelbourneGenomics_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services,Melbourne Genomics Health Alliance Deafness Flagship Mode of inheritance for gene: FOXI1 was set to Unknown