FOXN1

protein-coding

forkhead box N1, the group of Forkhead boxes

Gene summary

Mutations in the winged-helix transcription factor gene at the nude locus in mice and rats produce the pleiotropic phenotype of hairlessness and athymia, resulting in a severely compromised immune system. This gene is orthologous to the mouse and rat genes and encodes a similar DNA-binding transcription factor that is thought to regulate keratin gene expression. A mutation in this gene has been correlated with T-cell immunodeficiency, the skin disorder congenital alopecia, and nail dystrophy. Alternative splicing in the 5' UTR of this gene has been observed. [provided by RefSeq, Jul 2008]

Previous symbols:

WHN
RONU

MANE transcript

NM_001369369.1

Inheritance

AD, AR, SD

ClinVar variants

P:84U:371B:286

Top phenotype

T-cell lymphopenia with or without nail dystrophy, autosomal dominant; T-cell immunodeficiency, congenital alopecia, and nail dystrophy; T-cell immunodeficiency with thymic aplasia

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr17:28,506,243-28,538,900

External References & Databases

Ensembl (ENSG00000109101)

Transcript & Mutation Effects

hg38 • Region Span ~32.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

T-cell immunodeficiency, congenital alopecia, and nail dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011132

Submitter: Orphanet

T-cell immunodeficiency, congenital alopecia, and nail dystrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011132

Submitter: Labcorp Genetics (formerly Invitae)

T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominantMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032928

Submitter: Ambry Genetics

T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032928

Submitter: Labcorp Genetics (formerly Invitae)

T-cell immunodeficiency, congenital alopecia, and nail dystrophySTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0011132

Submitter: PanelApp Australia

T-cell immunodeficiency, congenital alopecia, and nail dystrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011132

Submitter: G2P

T-cell immunodeficiency, congenital alopecia, and nail dystrophyDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0011132

Submitter: ClinGen

FOXN1 has been noted to be associated with the following disease entities: autosomal recessive T-cell immunodeficiency, congenital alopecia, and nail dystrophy (OMIM: 601705) and autosomal dominant T-cell lymphopenia, infantile, with or without nail dystrophy (OMIM: 618806). We found no definitive difference in the molecular mechanisms of these two, and there is significant overlap in their phenotypes suggestive of a disease spectrum. Therefore, per criteria outlined by the ClinGen Lumping and Splitting Working Group, these have been lumped into one disease entity, semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy. FOXN1 was first reported in relation to T-cell immunodeficiency, congenital alopecia, and nail dystrophy in 1999 (Frank et al., PMID: 10206641). In this report two siblings from a small village in southern Italy were identified as homozygous for the variant c.763C>T (p.R255*). In 2004, population screening of this Italian village identified 55 heterozygous carriers of p.R255* representing 6.5% of the individuals tested. Genealogical study of these individuals identified a common ancestor, and haplotype analysis supported this to be an ancestral founder variant (Adriani et al., PMID: 15180707). Additional study of some of these heterozygous adults in 2019 found several with a mild phenotype including nail dystrophy and CD8+ T cell lymphopenia (Bosticardo et al., PMID: 31447097). Eleven variants (missense, in-frame indel, nonsense, and frameshift) that have been reported in 9 probands in 8 publications (PMIDs: 10206641, 25173801, 30903456, 31566583, 20978268, 33464451, 31447097, 31151968) are included in this curation. These probands include those with biallelic pathogenic variants as well as those with monoallelic pathogenic variants. Probands with biallelic pathogenic variants have T-B+NK+ severe combined immunodeficiency (SCID). Some, but not all, have associated congenital alopecia and/or nail dystrophy (PMID: 10206641, 25173801, 30903456, 20978268, 31151968). The phenotype of those with monoallelic pathogenic variants is typically milder but spans a broad range from some who are apparently unaffected to others with only subtle features such as nail dystrophy to others with SCID (PMID: 31447097, 33464451, 31566583). It has been suggested that the heterozygotes’ CD4+ T cell lymphopenia normalizes in adulthood (PMID: 31447097). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by expression studies, functional assays, animal models, and rescue assays (PMIDs: 10206641, 8629026, 21507891, 7969402). FOXN1 encodes a protein that acts as a transcription factor and is expressed in both the thymus and skin (PMID: 10206641, 8629026). In human cells with biallelic pathogenic variants, there is a total blockage of CD4+ T cell maturation (PMID: 21507891). In mice, biallelic disruption of FOXN1 results in a “nude” phenotype characterized by hairlessness as well as athymia and immunodeficiency (PMID: 7969402, 8629026). Insertion of a wild-type FOXN1 transgene has been demonstrated to rescue this phenotype, restoring both thymus function and hair growth (PMID: 12016512). The mechanism of pathogenicity is reported to be loss of function. There was no experimental evidence supporting a dominant negative molecular mechanism at the time of curation. In summary, FOXN1 is definitively associated with semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID/CID GCEP on the meeting date October 21, 2021 (SOP Version 8).

Clinical Genomic Database (CGD)

T-cell lymphopenia with or without nail dystrophy, autosomal dominant; T-cell immunodeficiency, congenital alopecia, and nail dystrophy; T-cell immunodeficiency with thymic aplasiaAD/AR

Manifestation: Allergy/Immunology/Infectious; Dermatologic

Intervention: Allergy/Immunology/Infectious

Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; BMT has been reported in cell immunodeficiency, congenital alopecia, and nail dystrophy, but has not been described as curative in T-cell lymphopenia with or without nail dystrophy, autosomal dominant; In T-cell immunodeficiency with thymic aplasia, thymus transplantation has been reported as curative

Refs: 8911612; 10206641; 15180707; 18339010; 20429426; 20864124; 21507891; 31447097; 31566583

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FOXN1 variants in ClinVar

13 Conditions Cataloged

T-cell immunodeficiency, congenital alopecia, and nail dystrophyTotal: 778

Inborn genetic diseasesTotal: 108

not providedTotal: 80

not specifiedTotal: 48

FOXN1-related disorderTotal: 37

T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominantTotal: 35

FOXN1-related disordersTotal: 8

Severe combined immunodeficiency diseaseTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001369369.1. 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			8 clinvar	264 clinvar	2 clinvar	274
missense	2 clinvar	6 clinvar	348 clinvar	19 clinvar	1 clinvar	376
nonsense	10 clinvar	5 clinvar	1 clinvar			16
start loss						0
frameshift	36 clinvar	20 clinvar	10 clinvar			66
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar	4 clinvar			9
Total	49	35	371	283	3	741

Highest pathogenic variant AF is 0.0000068155427

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001369369.1	RefSeq	NP_001356298.1	8	MANE Select
ENST00000579795.6	Ensembl	ENSP00000464645.1	8	MANE Select
NM_003593.3	RefSeq	NP_003584.2	8	Standard
ENST00000226247.2	Ensembl	ENSP00000226247.2	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
foxn1	Danio rerio	Structure: thymus Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

foxn1

Danio rerio

Structure: thymus

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

hair follicle development
T cell lineage commitment
regulation of transcription by RNA polymerase II
transcription by RNA polymerase II
defense response

Molecular Function

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

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000226247
Coding exons: 8
Length: 32654
Individuals with no LoFs: 125709
Homozygous LoFs: 0
Heterozygous LoFs: 39
Defined: 125748
p: 0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.657	350	386	0.906	0.0000228	4147
Missense (PolyPhen)		63	98.636	0.63871		1218
Synonymous	0.353	172	178	0.966	0.0000121	1400
Loss of Function	3.78	3	22.2	0.135	0.00000104	268

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.0015	0.0015	notable
East Asian	0.000054	0.000054	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional regulator which regulates the development, differentiation, and function of thymic epithelial cells (TECs) both in the prenatal and postnatal thymus. Acts as a master regulator of the TECs lineage development and is required from the onset of differentiation in progenitor TECs in the developing fetus to the final differentiation steps through which TECs mature to acquire their full functionality. Regulates, either directly or indirectly the expression of a variety of genes that mediate diverse aspects of thymus development and function, including MHC Class II, DLL4, CCL25, CTSL, CD40 and PAX1. Regulates the differentiation of the immature TECs into functional cortical TECs (cTECs) and medullary TECs (mTECs). Essential for maintenance of mTECs population in the postnatal thymus. Involved in the morphogenesis and maintenance of the three-dimensional thymic microstructure which is necessary for a fully functional thymus. Plays an important role in the maintenance of hematopoiesis and particularly T lineage progenitors within the bone marrow niche with age. Essential for the vascularization of the thymus anlage. Promotes the terminal differentiation of epithelial cells in the epidermis and hair follicles, partly by negatively regulating the activity of protein kinase C (By similarity). Plays a crucial role in the early prenatal stages of T-cell ontogeny (PubMed:21507891). {ECO:0000250|UniProtKB:Q61575, ECO:0000269|PubMed:21507891}.;

Recessive Scores

pRec: 0.245

Intolerance Scores

LoFtool: 0.0592
RVIS EVS: -0.22
RVIS percentile EVS: 37.7

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0312

Gene Damage Prediction

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