FOXI1

protein-coding

forkhead box I1, the group of Forkhead boxes

Gene summary

This gene belongs to the forkhead family of transcription factors, which is characterized by a distinct forkhead domain. This gene may play an important role in the development of the cochlea and vestibulum, as well as in embryogenesis. The encoded protein has been found to be required for the transcription of four subunits of a proton pump found in the inner ear, the kidney, and the epididymis. Mutations in this gene have been associated with deafness, autosomal recessive 4. [provided by RefSeq, Jan 2017]

Previous symbols:

FKHL10

MANE transcript

NM_012188.5

Inheritance

ClinVar variants

P:5U:139B:61

Top phenotype

Deafness, autosomal recessive 4, with enlarged vestibular aqueduct

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr5:170,105,897-170,109,734

External References & Databases

Ensembl (ENSG00000168269)

Transcript & Mutation Effects

hg38 • Region Span ~3.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive distal renal tubular acidosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018440

Submitter: PanelApp Australia

autosomal recessive nonsyndromic hearing loss 4LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0010933

Submitter: Labcorp Genetics (formerly Invitae)

hearing loss disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0005365

Submitter: ClinGen

FOXI1 was first associated with autosomal recessive hearing loss and renal tubular acidosis in 2017 (Enerback et al., PMID: 29242249). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, this gene-disease association was split from the FOXI1- enlarged vestibular aqueduct syndrome (EVA) association due to phenotypic concordance with the mouse model (Hulander et al., PMID:9843211). The split curation for autosomal recessive EVA has been curated separately. Additionally, digenic inheritance with variants in FOXI1 and SLC26A4 has been proposed in association with autosomal recessive enlarged vestibular aqueduct syndrome, which has been split in its own curation and is currently disputed (Yang et al. 2007 PMID:17503324). At least 2 missense variants have been reported in humans. Association is seen in at least 2 probands in 1 publication (PMID: 29242249). Variants in this gene segregated with disease in 1 additional family member. The mechanism for disease is unknown. The gene-disease association is also supported by a homozygous FOXI1 null mouse (PMID:9843211). Homozygous null mice were profoundly deaf with vestibular symptoms and histological examination of the inner ear revealed profound deformation. In summary, due to minimal genetic evidence in humans, there is limited evidence to support the FOXI1 and AR syndromic genetic deafness and renal tubular acidosis association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was approved by the ClinGen Hearing Loss Working Group on 2/27/2018. It was re-evaluated on 3/16/2022. As a result of this reevaluation, the classification did not change, and no new additional information was added to the curation.

enlarged vestibular aqueduct syndromeNO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0023069

Submitter: ClinGen

The FOXI1 gene has been associated with autosomal recessive enlarged vestibular aqueduct syndrome using the ClinGen Clinical Validity Framework as of 5/19/17. Association is seen in one proband with a de novo heterozygous missense variant (Liu et al. 2016 27997596). Association was also made in at least 5 probands with missense variants by Yang et al. 2007 (17503324). These associations were subsequently disputed by Choi et al. 2009 (DOI 10.1002/humu.21098). This gene-disease association is supported by expression studies and protein interaction studies. Of note, this gene has also been implicated in hearing loss and renal tubular acidosis. This been assessed separately. In summary, there is convincing evidence disputing the association between FOXI1 and autosomal recessive enlarged vestibular aqueduct syndrome. More evidence is needed to either support or refute the role FOXI1 plays in this disease. This classification was approved by the ClinGen Hearing Loss Working Group on 2/27/18.

autosomal recessive nonsyndromic hearing loss 4LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0010933

Submitter: Ambry Genetics

Pendred syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010134

Submitter: Orphanet

autosomal recessive distal renal tubular acidosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018440

Submitter: Orphanet

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 4, with enlarged vestibular aqueductAR

Manifestation: Audiologic/Otolaryngologic; Endocrine

Intervention: Audiologic/Otolaryngologic; Endocrine

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; In Pendred syndrome, awareness of the potential for thyroid abnormalities may be beneficial to allow early detection and appropriate management

Comments: Digenic inheritance (with SLC26A4) has been reported

Refs: 17503324

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FOXI1 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 122

Autosomal recessive nonsyndromic hearing loss 4Total: 87

not specifiedTotal: 67

FOXI1-related disorderTotal: 34

Pendred syndromeTotal: 8

Sensorineural hearing loss disorderTotal: 3

Hearing impairmentTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012188.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	51 clinvar	1 clinvar	56
missense		4 clinvar	133 clinvar	8 clinvar	1 clinvar	146
nonsense			1 clinvar			1
start loss						0
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	4	139	59	2	205

Highest pathogenic variant AF is 0.00002728161

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012188.5	RefSeq	NP_036320.2	2	MANE Select
ENST00000306268.8	Ensembl	ENSP00000304286.5	2	MANE Select
NM_144769.4	RefSeq	NP_658982.1	2	Standard
ENST00000449804.4	Ensembl	ENSP00000415483.2	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
foxi1	Danio rerio	Structure: radial glial cell Quality: disorganized abnormal

Gene / Model

Organism

Observed Phenotype

foxi1

Danio rerio

Structure: radial glial cell

Quality: disorganized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription by RNA polymerase II
anatomical structure morphogenesis
embryo development ending in birth or egg hatching
cell differentiation
inner ear morphogenesis

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA-binding transcription factor activity
DNA binding, bending

Cellular Component

nucleus
nucleolus
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000306268
Coding exons: 2
Length: 3827
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125740
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.728	201	232	0.866	0.0000144	2449
Missense (PolyPhen)		51	82.107	0.62114		876
Synonymous	0.0661	106	107	0.992	0.00000787	757
Loss of Function	2.51	1	9.25	0.108	3.97e-7	117

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional activator required for the development of normal hearing, sense of balance and kidney function. Required for the expression of SLC26A4/PDS, JAG1 and COCH in a subset of epithelial cells and the development of the endolymphatic system in the inner ear. Also required for the expression of SLC4A1/AE1, SLC4A9/AE4, ATP6V1B1 and the differentiation of intercalated cells in the epithelium of distal renal tubules (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.200

Intolerance Scores

LoFtool: 0.0345
RVIS EVS: -0.45
RVIS percentile EVS: 24.33

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.650

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium