FOXN1

Summary

FOXN1 (forkhead box N1, HGNC:12765) is a protein-coding gene on chromosome 17q11.2, encoding Forkhead box protein N1 (O15353). Transcriptional regulator which regulates the development, differentiation, and function of thymic epithelial cells (TECs) both in the prenatal and postnatal thymus.

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.

Source: NCBI Gene 8456 — RefSeq curated summary.

At a glance

• Gene–disease (curated): T-cell immunodeficiency, congenital alopecia, and nail dystrophy (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 891 total — 52 pathogenic, 29 likely-pathogenic
• Phenotypes (HPO): 59
• Transcription factor: yes — 60 downstream targets (CollecTRI)
• MANE Select transcript: NM_001369369

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12765
Approved symbol	FOXN1
Name	forkhead box N1
Location	17q11.2
Locus type	gene with protein product
Status	Approved
Aliases	FKHL20
Ensembl gene	ENSG00000109101
Ensembl biotype	protein_coding
OMIM	600838
Entrez	8456

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000226247, ENST00000577936, ENST00000579795

RefSeq mRNA: 2 — MANE Select: NM_001369369 NM_001369369, NM_003593

CCDS: CCDS11232

Canonical transcript exons

ENST00000579795 — 9 exons

Exon	Start	End
ENSE00002693962	28506348	28506443
ENSE00002695549	28537117	28538900
ENSE00002697749	28523956	28524092
ENSE00002708355	28524503	28524967
ENSE00003974466	28534331	28534538
ENSE00003974467	28527251	28527361
ENSE00003974469	28534707	28535198
ENSE00003974470	28530749	28530845
ENSE00003974471	28529094	28529224

Expression profiles

Bgee: expression breadth broad, 75 present calls, max score 91.56.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3752 / max 91.1441, expressed in 60 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160040	0.2997	58
160039	0.0454	20
160041	0.0301	4

Top tissues by expression

250 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gingival epithelium	UBERON:0001949	91.56	gold quality
gingiva	UBERON:0001828	91.34	gold quality
upper leg skin	UBERON:0004262	91.25	gold quality
lower esophagus mucosa	UBERON:0035834	89.15	gold quality
skin of abdomen	UBERON:0001416	89.04	gold quality
skin of leg	UBERON:0001511	89.02	gold quality
penis	UBERON:0000989	87.90	gold quality
zone of skin	UBERON:0000014	87.52	gold quality
esophagus squamous epithelium	UBERON:0006920	87.24	gold quality
skin of hip	UBERON:0001554	85.78	gold quality
mammalian vulva	UBERON:0000997	83.38	gold quality
esophagus mucosa	UBERON:0002469	82.38	gold quality
nipple	UBERON:0002030	82.37	gold quality
epithelium of esophagus	UBERON:0001976	81.17	gold quality
oral cavity	UBERON:0000167	80.85	gold quality
squamous epithelium	UBERON:0006914	80.68	gold quality
pharyngeal mucosa	UBERON:0000355	75.80	gold quality
endometrium epithelium	UBERON:0004811	73.01	gold quality
vagina	UBERON:0000996	71.45	gold quality
frontal pole	UBERON:0002795	67.73	gold quality
paraflocculus	UBERON:0005351	67.37	gold quality
middle frontal gyrus	UBERON:0002702	67.31	gold quality
cerebellar vermis	UBERON:0004720	64.57	gold quality
thymus	UBERON:0002370	64.08	silver quality
tonsil	UBERON:0002372	62.84	gold quality
Brodmann (1909) area 10	UBERON:0013541	62.66	gold quality
body of tongue	UBERON:0011876	60.46	gold quality
esophagus	UBERON:0001043	58.86	gold quality
tongue	UBERON:0001723	56.88	gold quality
superior surface of tongue	UBERON:0007371	56.29	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.79

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

60 targets.

Target	Regulation
AFP
AKT1
AP1
AR
ATP7A
B3GNT9
BAZ2A
CARM1
CD79A
CDH1
CEL
CHD4
COL1A2
CYP7A1
DEUP1
DLL1	Unknown
DLL4	Unknown
DSC2	Unknown
DSG4	Repression
EGFR
EP400
ERBB2
ESR1
FOXN1
GLB1
H2AZ1
IBSP
IFNG
IL2
IL6

Upstream regulators (CollecTRI, top): AR, CTNNB1, ENO1, FOXN1, HOXC13, LEF1, SALL1, ZFPM1

Literature-anchored findings (GeneRIF, showing 22)

• Mutation of the FOXN1 gene is associated with congenital severe combined immunodeficiency associated with alopecia (PMID:15180707)
• These results establish a role for FOXN1 in initiation of terminal differentiation and implicate Akt in subsequent events. (PMID:15316080)
• Mechanisms and signaling pathways by which Foxn1 modulates keratinocyte differentiation in hair follicle and nail apparatus. Molecular and functional consequences of loss of function of Foxn1 protein in skin. Review. (PMID:16232301)
• Foxn1 is a sensitive and specific marker for thymoma and thymic carcinoma. (PMID:17592270)
• Foxn1/FGF2 pathway involved in instructing melanocytes where to place pigment. (PMID:17803914)
• study uncovered a positive regulatory loop between FGFR3 and FOXN1 that underlies a benign versus malignant skin tumor phenotype (PMID:19729838)
• role of FOXN1 in immunological disorders characterized by abnormal T-cell development or abnormal T-cell regulatory homeostasis [Review] (PMID:20429426)
• results show that FOXN1 is crucial for in utero T cell development, but not for B and NK cell differentiation (PMID:21507891)
• This is the first description of leucoderma occurring in a patient with Foxn1 deficiency, as well as the first report of this pigment abnormality following thymus transplantation. (PMID:22721479)
• The retinoid-related orphan receptor RORalpha promotes keratinocyte differentiation via FOXN1. (PMID:23922987)
• These results show that miR-18b and miR-518b are upstream controllers of FOXN1-directed epithelial lineage development. (PMID:24383669)
• Identification of a unique mutation in FOXN1 that led to severe combined immunodeficiency in a female infant is reported. (PMID:25173801)
• Whole-exome sequencing in a South American cohort links ALDH1A3, FOXN1 and RARB/retinoic acid regulation pathways to autism spectrum disorders. (PMID:26352270)
• FOXN1 founder Italian mutation identified in an indian newborn with severe combined immunodeficiency. (PMID:28636882)
• Here, by engineering a time-delayed feedback system of BMP inhibition in mouse embryos, the authors demonstrate that thymopoiesis irreversibly fails if Foxn1 gene expression does not occur during a defining time span in mid-gestation. They also reveal an epistatic interaction between the extent of BMP signalling and the gene dosage of Foxn1. (PMID:28819138)
• observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth. (PMID:31447097)
• FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans. (PMID:31566583)
• The crystal structure of human forkhead box N1 in complex with DNA reveals the structural basis for forkhead box family specificity. (PMID:31914405)
• Expanding the Nude SCID/CID Phenotype Associated with FOXN1 Homozygous, Compound Heterozygous, or Heterozygous Mutations. (PMID:33464451)
• Expression of BMP4 and FOXN1 in orthokeratinized odontogenic cyst compared to odontogenic keratocyst suggests an epidermal phenotype. (PMID:35527675)
• [Effects of FoxN1, p63 and AIRE on the process of age-related thymus involution: An update]. (PMID:36631020)
• Comprehensive phenotypic analysis of diverse FOXN1 variants. (PMID:37419334)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	foxn1	ENSDARG00000011879
mus_musculus	Foxn1	ENSMUSG00000002057
rattus_norvegicus	Foxn1	ENSRNOG00000010870
drosophila_melanogaster	jumu	FBGN0015396

Paralogs (41): FOXP3 (ENSG00000049768), FOXC1 (ENSG00000054598), FOXJ2 (ENSG00000065970), FOXF1 (ENSG00000103241), FOXM1 (ENSG00000111206), FOXP1 (ENSG00000114861), FOXO3 (ENSG00000118689), FOXA2 (ENSG00000125798), FOXA1 (ENSG00000129514), FOXJ1 (ENSG00000129654), FOXK2 (ENSG00000141568), FOXO1 (ENSG00000150907), FOXH1 (ENSG00000160973), FOXQ1 (ENSG00000164379), FOXK1 (ENSG00000164916), FOXD4 (ENSG00000170122), FOXA3 (ENSG00000170608), FOXB1 (ENSG00000171956), FOXR1 (ENSG00000176302), FOXL1 (ENSG00000176678), FOXC2 (ENSG00000176692), FOXE1 (ENSG00000178919), FOXS1 (ENSG00000179772), FOXL2 (ENSG00000183770), FOXO4 (ENSG00000184481), FOXD4L1 (ENSG00000184492), FOXD4L4 (ENSG00000184659), FOXD2 (ENSG00000186564), FOXI2 (ENSG00000186766), FOXE3 (ENSG00000186790), FOXD3 (ENSG00000187140), FOXD4L3 (ENSG00000187559), FOXR2 (ENSG00000189299), FOXJ3 (ENSG00000198815), FOXO6 (ENSG00000204060), FOXB2 (ENSG00000204612), FOXD4L5 (ENSG00000204779), FOXI3 (ENSG00000214336), FOXL3 (ENSG00000248767), FOXD1 (ENSG00000251493)

Protein

Protein identifiers

Forkhead box protein N1 — O15353 (reviewed: O15353)

Alternative names: Winged-helix transcription factor nude

All UniProt accessions (2): O15353, J3KRT9

UniProt curated annotations — full annotation on UniProt →

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. Plays a crucial role in the early prenatal stages of T-cell ontogeny.

Subcellular location. Nucleus.

Tissue specificity. Expressed in thymus.

Disease relevance. T-cell immunodeficiency, congenital alopecia, and nail dystrophy (TIDAND) [MIM:601705] A disorder characterized by the association of congenital alopecia, severe T-cell immunodeficiency, and ridging and pitting of all nails. The disease is caused by variants affecting the gene represented in this entry. T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant (TLIND) [MIM:618806] An autosomal dominant disorder characterized by decreased numbers of T cells, particularly cytotoxic CD8+ T cells, and increased susceptibility to recurrent infections, mainly respiratory viral infections. Additional features may include impaired thymic development, skin abnormalities, such as atopic dermatitis, and nail dystrophy. The disease is caused by variants affecting the gene represented in this entry. T-cell immunodeficiency with thymic aplasia (TIDTA) [MIM:242700] An autosomal recessive disorder characterized by selective hypo- or aplasia of the thymus, T-cell immunodeficiency due to impaired T-cell development, and increased susceptibility to viral infections. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (2): NP_001356298, NP_003584 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001766	Fork_head_dom	Domain
IPR030456	TF_fork_head_CS_2	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR047401	FH_FOXN1	Domain
IPR049624	FOXN1_4	Family

Pfam: PF00250

UniProt features (30 total): sequence variant 13, helix 6, region of interest 4, strand 3, compositionally biased region 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6EL8	X-RAY DIFFRACTION	1.61
5OCN	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15353-F1	54.44	0.18

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 240 (showing top): GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_EPITHELIUM_DEVELOPMENT, HNF3ALPHA_Q6, GAANYNYGACNY_UNKNOWN, GOBP_THYMIC_T_CELL_SELECTION, GOBP_T_CELL_HOMEOSTASIS, GOBP_LYMPHOCYTE_HOMEOSTASIS, GOBP_THYMUS_DEVELOPMENT, GOBP_REGULATION_OF_HAIR_CYCLE, chr17q11, GOBP_REGULATION_OF_HAIR_FOLLICLE_DEVELOPMENT, GOBP_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION

GO Biological Process (23): hair follicle development (GO:0001942), T cell lineage commitment (GO:0002360), regulation of transcription by RNA polymerase II (GO:0006357), defense response (GO:0006952), epidermis development (GO:0008544), animal organ morphogenesis (GO:0009887), keratinocyte differentiation (GO:0030216), positive regulation of epithelial cell differentiation (GO:0030858), nail development (GO:0035878), T cell homeostasis (GO:0043029), blood vessel morphogenesis (GO:0048514), positive regulation of hair follicle development (GO:0051798), lymphoid lineage cell migration into thymus (GO:0097535), thymus epithelium morphogenesis (GO:0097536), regulation of positive thymic T cell selection (GO:1902232), lymphocyte homeostasis (GO:0002260), regulation of DNA-templated transcription (GO:0006355), regulation of gene expression (GO:0010468), hemopoiesis (GO:0030097), cell differentiation (GO:0030154), regulation of T cell differentiation in thymus (GO:0033081), positive regulation of transcription by RNA polymerase II (GO:0045944), thymus development (GO:0048538)

GO Molecular Function (7): transcription cis-regulatory region binding (GO:0000976), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	2
regulation of DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
hair cycle process	1
skin epidermis development	1
T cell differentiation	1
cell fate commitment	1
transcription by RNA polymerase II	1
response to stress	1
tissue development	1
anatomical structure morphogenesis	1
animal organ development	1
epidermal cell differentiation	1
skin development	1
epithelial cell differentiation	1
regulation of epithelial cell differentiation	1
positive regulation of cell differentiation	1
limb development	1
lymphocyte homeostasis	1
blood vessel development	1
tube morphogenesis	1
hair follicle development	1
positive regulation of developmental process	1
positive regulation of multicellular organismal process	1
regulation of hair follicle development	1
lymphoid lineage cell migration	1
morphogenesis of an epithelium	1
thymus development	1
regulation of T cell differentiation in thymus	1
positive thymic T cell selection	1
leukocyte homeostasis	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
gene expression	1
regulation of macromolecule biosynthetic process	1
cell development	1
cellular developmental process	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1

Protein interactions and networks

STRING

1720 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXN1	WNT5B	Q9H1J7	813
FOXN1	SUPT6H	Q7KZ85	752
FOXN1	AIRE	O43918	735
FOXN1	HOXC13	P31276	727
FOXN1	WNT10B	O00744	720
FOXN1	GCM2	O75603	710
FOXN1	WNT3	P56703	693
FOXN1	WNT4	P56705	674
FOXN1	PSMB11	A5LHX3	672
FOXN1	FZD7	O75084	660
FOXN1	HOXA3	O43365	648
FOXN1	RAG1	P15918	633
FOXN1	DLL4	Q9NR61	631
FOXN1	FZD8	Q9H461	623
FOXN1	PAX1	P15863	593

IntAct

41 interactions, top by confidence:

A	B	Type	Score
FOXN1	TSSK1B	psi-mi:“MI:0915”(physical association)	0.600
FOXN1	HOXA1	psi-mi:“MI:0915”(physical association)	0.560
FOXN1	SPATC1L	psi-mi:“MI:0915”(physical association)	0.560
FOXN1	PIN1	psi-mi:“MI:0915”(physical association)	0.560
FOXN1	TLE5	psi-mi:“MI:0915”(physical association)	0.560
FOXN1	DMRT3	psi-mi:“MI:0915”(physical association)	0.560
FOXN1	CDC23	psi-mi:“MI:0915”(physical association)	0.560
FOXN1	MAPKBP1	psi-mi:“MI:0915”(physical association)	0.560
FOXN1	TRAPPC6A	psi-mi:“MI:0915”(physical association)	0.560
FOXN1	CDA	psi-mi:“MI:0915”(physical association)	0.560
FOXN1	TRAF2	psi-mi:“MI:0915”(physical association)	0.560
FOXN1	LHX8	psi-mi:“MI:0915”(physical association)	0.560
FOXN1	FOXN1	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
TSSK1B	FOXN1	psi-mi:“MI:0915”(physical association)	0.000
HOXA1	FOXN1	psi-mi:“MI:0915”(physical association)	0.000
SPATC1L	FOXN1	psi-mi:“MI:0915”(physical association)	0.000
PIN1	FOXN1	psi-mi:“MI:0915”(physical association)	0.000
TLE5	FOXN1	psi-mi:“MI:0915”(physical association)	0.000
DMRT3	FOXN1	psi-mi:“MI:0915”(physical association)	0.000
CDC23	FOXN1	psi-mi:“MI:0915”(physical association)	0.000
MAPKBP1	FOXN1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (41): HOXD13 (Affinity Capture-MS), SMARCC2 (Affinity Capture-MS), TP53 (Affinity Capture-MS), ARNT (Affinity Capture-MS), SATB2 (Affinity Capture-MS), SMARCB1 (Affinity Capture-MS), SMARCE1 (Affinity Capture-MS), VARS (Affinity Capture-MS), ACTL6A (Affinity Capture-MS), HOXC13 (Affinity Capture-MS), SATB1 (Affinity Capture-MS), SIM2 (Affinity Capture-MS), TXNDC5 (Affinity Capture-MS), TTF2 (Affinity Capture-MS), LACTB (Affinity Capture-MS)

ESM2 similar proteins: A0A1W2PQ73, A1YF16, A1YG93, A2RU54, A5PKG8, O02786, O14813, O15353, O35602, O43638, O57601, P13297, P19419, P28360, P35548, P41969, P42580, P43687, P49640, P50223, P50548, P52946, P52950, P63156, P63157, P70459, P78413, Q03358, Q14549, Q2VL78, Q2VL79, Q2VL82, Q2VL83, Q2VL84, Q2VL85, Q2VL86, Q2VL87, Q2VL88, Q5NSW5, Q61575

Diamond homologs: A0A8V0YY16, A1L1S5, A2BGM5, A8MTJ6, B5RHS5, D3Z120, O00358, O00409, O15353, O54743, O60129, O70220, O88470, O93529, P32027, P32028, P32030, P32314, P42128, P55316, P56260, P58012, Q00939, Q12946, Q12947, Q12948, Q12951, Q13461, Q1A1A1, Q1A1A2, Q1A1A3, Q1A1A4, Q1A1A5, Q1A1A6, Q28BS5, Q28D67, Q28F43, Q28G71, Q28H65, Q28HT3

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
HOXC13	“up-regulates quantity by expression”	FOXN1	“transcriptional regulation”
FOXN1	“down-regulates quantity by repression”	DSG4	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

891 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	52
Likely pathogenic	29
Uncertain significance	395
Likely benign	356
Benign	31

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1048525	NM_001369369.1(FOXN1):c.1370del (p.His457fs)	Pathogenic
1067142	NM_001369369.1(FOXN1):c.1327del (p.Met444fs)	Pathogenic
1070970	NM_001369369.1(FOXN1):c.723C>G (p.Tyr241Ter)	Pathogenic
1074340	NM_001369369.1(FOXN1):c.1316del (p.Leu439fs)	Pathogenic
1075865	NM_001369369.1(FOXN1):c.823del (p.Ser275fs)	Pathogenic
1360931	NM_001369369.1(FOXN1):c.455del (p.Pro152fs)	Pathogenic
1417126	NM_001369369.1(FOXN1):c.64G>T (p.Glu22Ter)	Pathogenic
1454677	NM_001369369.1(FOXN1):c.690dup (p.Phe231fs)	Pathogenic
1457907	NM_001369369.1(FOXN1):c.1459_1460del (p.Thr487fs)	Pathogenic
2016991	NM_001369369.1(FOXN1):c.1431del (p.His478fs)	Pathogenic
2087766	NM_001369369.1(FOXN1):c.1021del (p.Arg341fs)	Pathogenic
2088121	NM_001369369.1(FOXN1):c.340C>T (p.Arg114Ter)	Pathogenic
2424707	NC_000017.10:g.(?26861752)(26869835_?)del	Pathogenic
2498699	NM_001369369.1(FOXN1):c.1318C>T (p.Gln440Ter)	Pathogenic
2704556	NM_001369369.1(FOXN1):c.6del (p.Ser3fs)	Pathogenic
2704650	NM_001369369.1(FOXN1):c.118C>T (p.Gln40Ter)	Pathogenic
2716400	NM_001369369.1(FOXN1):c.1324_1336del (p.Leu442fs)	Pathogenic
2751542	NM_001369369.1(FOXN1):c.98_114del (p.Leu33fs)	Pathogenic
2780381	NM_001369369.1(FOXN1):c.246C>A (p.Cys82Ter)	Pathogenic
2815940	NM_001369369.1(FOXN1):c.1064del (p.Lys355fs)	Pathogenic
2820427	NM_001369369.1(FOXN1):c.1220C>G (p.Ser407Ter)	Pathogenic
2823406	NM_001369369.1(FOXN1):c.1151del (p.Leu384fs)	Pathogenic
2831369	NM_001369369.1(FOXN1):c.62del (p.Gly21fs)	Pathogenic
2856279	NM_001369369.1(FOXN1):c.1314_1315dup (p.Leu439fs)	Pathogenic
3251406	NM_001369369.1(FOXN1):c.1216_1247dup (p.Gly418fs)	Pathogenic
3367209	NM_001369369.1(FOXN1):c.880G>A (p.Val294Ile)	Pathogenic
3389391	NM_001369369.1(FOXN1):c.1178del (p.Gly393fs)	Pathogenic
3643502	NM_001369369.1(FOXN1):c.1238del (p.Leu413fs)	Pathogenic
3661380	NM_001369369.1(FOXN1):c.806dup (p.Pro272fs)	Pathogenic
3722792	NM_001369369.1(FOXN1):c.1465dup (p.Gln489fs)	Pathogenic

SpliceAI

1903 predictions. Top by Δscore:

Variant	Effect	Δscore
17:28506441:CAGGT:C	donor_loss	1.0000
17:28506442:AGGT:A	donor_loss	1.0000
17:28506443:GGTA:G	donor_loss	1.0000
17:28506444:GTA:G	donor_loss	1.0000
17:28506445:T:A	donor_loss	1.0000
17:28524964:CCTGG:C	donor_loss	1.0000
17:28524966:TGGT:T	donor_loss	1.0000
17:28524969:T:A	donor_loss	1.0000
17:28527246:AGCAG:A	acceptor_gain	1.0000
17:28527247:GCAGG:G	acceptor_gain	1.0000
17:28530745:TCA:T	acceptor_loss	1.0000
17:28530746:CA:C	acceptor_loss	1.0000
17:28530747:A:AG	acceptor_gain	1.0000
17:28530747:AGCAT:A	acceptor_loss	1.0000
17:28530748:G:GG	acceptor_gain	1.0000
17:28530748:GC:G	acceptor_gain	1.0000
17:28530748:GCA:G	acceptor_gain	1.0000
17:28530748:GCAT:G	acceptor_gain	1.0000
17:28530748:GCATC:G	acceptor_gain	1.0000
17:28530842:CAAG:C	donor_loss	1.0000
17:28530843:AAGG:A	donor_loss	1.0000
17:28530844:AGGTG:A	donor_loss	1.0000
17:28530845:GGTG:G	donor_loss	1.0000
17:28530846:GTGA:G	donor_loss	1.0000
17:28534320:T:TA	acceptor_gain	1.0000
17:28534325:C:A	acceptor_gain	1.0000
17:28534326:G:A	acceptor_gain	1.0000
17:28534327:GCA:G	acceptor_loss	1.0000
17:28534328:CA:C	acceptor_loss	1.0000
17:28534329:A:AG	acceptor_gain	1.0000

AlphaMissense

4179 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:28529205:A:G	K271E	1.000
17:28529206:A:T	K271I	1.000
17:28529207:A:C	K271N	1.000
17:28529207:A:T	K271N	1.000
17:28529208:C:A	P272T	1.000
17:28529208:C:T	P272S	1.000
17:28529209:C:A	P272H	1.000
17:28529209:C:G	P272R	1.000
17:28529214:T:G	Y274D	1.000
17:28529218:C:T	S275F	1.000
17:28529220:T:C	Y276H	1.000
17:28529221:A:G	Y276C	1.000
17:28530754:T:A	L279H	1.000
17:28530754:T:C	L279P	1.000
17:28530757:T:A	I280N	1.000
17:28530757:T:G	I280S	1.000
17:28530765:G:C	A283P	1.000
17:28530766:C:A	A283D	1.000
17:28530769:T:A	L284H	1.000
17:28530769:T:C	L284P	1.000
17:28530793:T:C	L292P	1.000
17:28530799:T:A	V294D	1.000
17:28530807:A:T	I297F	1.000
17:28530808:T:A	I297N	1.000
17:28530808:T:C	I297T	1.000
17:28530808:T:G	I297S	1.000
17:28530810:T:C	Y298H	1.000
17:28530810:T:G	Y298D	1.000
17:28530816:T:C	F300L	1.000
17:28530817:T:C	F300S	1.000

dbSNP variants (sampled 300 via entrez): RS1000159441 (17:28507269 C>G,T), RS1000232116 (17:28536170 A>C), RS1000390494 (17:28521661 C>G,T), RS1000468696 (17:28535923 C>G), RS1000494758 (17:28506036 G>A), RS1000648766 (17:28520833 A>G), RS1000762823 (17:28521916 G>A), RS1000841942 (17:28518214 C>A,T), RS1001099030 (17:28532945 G>A), RS1001326827 (17:28526916 G>A), RS1001356175 (17:28524897 C>T), RS1001393283 (17:28518588 C>A,T), RS1001471136 (17:28511584 A>G), RS1001536898 (17:28532608 A>C), RS1001587000 (17:28536319 A>G)

Disease associations

OMIM: gene MIM:600838 | disease phenotypes: MIM:601705, MIM:618806, MIM:209850, MIM:242700

GenCC curated gene-disease

Disease	Classification	Inheritance
T-cell immunodeficiency, congenital alopecia, and nail dystrophy	Definitive	Autosomal recessive
T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
T-cell immunodeficiency, congenital alopecia, and nail dystrophy	Definitive	SD

Mondo (5): T-cell immunodeficiency, congenital alopecia, and nail dystrophy (MONDO:0011132), T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant (MONDO:0032928), severe combined immunodeficiency (MONDO:0015974), autism (MONDO:0005260), Nezelof syndrome (MONDO:0009451)

Orphanet (4): Severe combined immunodeficiency due to FOXN1 deficiency (Orphanet:169095), Combined immunodeficiency due to FOXN1 haploinsufficiency (Orphanet:676039), Severe combined immunodeficiency (Orphanet:183660), T-cell immunodeficiency with thymic aplasia (Orphanet:83471)

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000246	Sinusitis
HP:0000389	Chronic otitis media
HP:0000821	Hypothyroidism
HP:0000964	Eczematoid dermatitis
HP:0000999	Pyoderma
HP:0001047	Atopic dermatitis
HP:0001287	Meningitis
HP:0001433	Hepatosplenomegaly
HP:0001508	Failure to thrive
HP:0001596	Alopecia
HP:0001803	Nail pits
HP:0001807	Ridged nail
HP:0001888	Decreased total lymphocyte count
HP:0002014	Diarrhea
HP:0002024	Malabsorption
HP:0002028	Chronic diarrhea
HP:0002090	Pneumonia
HP:0002097	Emphysema
HP:0002110	Bronchiectasis
HP:0002716	Lymphadenopathy
HP:0002718	Recurrent bacterial infections
HP:0002719	Recurrent infections
HP:0002721	Immunodeficiency
HP:0002726	Recurrent Staphylococcus aureus infections
HP:0002788	Recurrent upper respiratory tract infections
HP:0002960	Autoimmunity
HP:0002972	Reduced delayed hypersensitivity

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003995_31	Tonsillectomy	1.000000e-08
GCST005014_182	Tonsillectomy	1.000000e-08
GCST009377_4	Bone mineral density	1.000000e-06
GCST009377_7	Bone mineral density	8.000000e-06
GCST009698_110	Metabolite levels	8.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007924	tonsillectomy risk measurement
EFO:0007620	volumetric bone mineral density

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D016511	Severe Combined Immunodeficiency	C16.320.798.750; C16.614.815; C18.452.284.800; C20.673.795.750
C536781	T-cell immunodeficiency, congenital alopecia and nail dystrophy (supp.)
C536288	Thymic aplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Forkhead box TFs

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases reaction, increases expression, decreases expression	2
CGP 52608	affects binding, increases reaction	1
U 0126	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
Arsenic	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Methylcholanthrene	affects binding, increases reaction	1
Sodium Dodecyl Sulfate	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	decreases expression	1
Lactic Acid	affects expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A2C1	SEES3-1V human FOXN1, clone1	Embryonic stem cell	Male
CVCL_A2C2	SEES3-1V human FOXN1, clone2	Embryonic stem cell	Male
CVCL_A2C3	SEES3-1V human FOXN1, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT01420627	PHASE3	COMPLETED	EZN-2279 in Patients With ADA-SCID
NCT06940570	PHASE3	SUSPENDED	Methadone as an Alternative Treatment for Children Underdoing HSCT
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder