Deafness_IsolatedAndComplex
Gene: FOXI1
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 - 09/10/2018Created: 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
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
Disputed evidence for enlarged vestibular aqueduct PMID: 19204907Created: 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 modelCreated: 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
Phenotypes for gene: FOXI1 were changed from Enlarged vestibular aqueduct, MIM# 600791 to autosomal recessive distal renal tubular acidosis MONDO:0018440
Publications for gene: FOXI1 were set to 29242249; 9843211; 17503324
Publications for gene: FOXI1 were set to 29242249; 9843211
Publications for gene: FOXI1 were set to 29242249; 9843211
Gene: foxi1 has been classified as Green List (High Evidence).
Publications for gene: FOXI1 were set to 29242249; 9843211
Publications for gene: FOXI1 were set to
Phenotypes for gene: FOXI1 were changed from sensorineural deafness and distal renal tubular acidosis to Enlarged vestibular aqueduct, MIM# 600791
Phenotypes for gene: FOXI1 were changed from to sensorineural deafness and distal renal tubular acidosis
Mode of inheritance for gene: FOXI1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
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