T-cell immunodeficiency, congenital alopecia, and nail dystrophy

Summary

T-cell immunodeficiency, congenital alopecia, and nail dystrophy (MONDO:0011132) is a disease caused by FOXN1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FOXN1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 808
• Phenotypes (HPO): 5

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

5 HPO clinical features (Orphanet curated; top 5 by frequency):

HPO ID	Term	Frequency
HP:0001803	Nail pits	Very frequent (80-99%)
HP:0001807	Ridged nail	Very frequent (80-99%)
HP:0002721	Immunodeficiency	Very frequent (80-99%)
HP:0005403	Decreased total T cell count	Very frequent (80-99%)
HP:0005597	Congenital alopecia totalis	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	T-cell immunodeficiency, congenital alopecia, and nail dystrophy
Mondo ID	MONDO:0011132
MeSH	C536781
OMIM	601705
Orphanet	169095
DOID	DOID:0060769
SNOMED CT	720345008
UMLS	C1866426
MedGen	355713
GARD	0004358
Is cancer (heuristic)	no

Also known as: alopecia immunodeficiency · alymphoid cystic thymic dysgenesis · congenital alopecia and nail dystrophy associated with severe functional T-cell immunodeficiency · FOXN1 deficiency · Pignata Guarino syndrome · severe T-cell immunodeficiency-congenital alopecia-nail dystrophy syndrome · T-cell immunodeficiency, congenital alopecia and nail dystrophy · T-cell immunodeficiency, congenital alopecia, and nail dystrophy · winged helix deficiency

Data availability: 808 ClinVar variants · 55 ClinGen variant curations · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › combined immunodeficiency › severe combined immunodeficiency › T-cell immunodeficiency, congenital alopecia, and nail dystrophy

Related subtypes (10): recombinase activating gene 1 deficiency, recombinase activating gene 2 deficiency, janus kinase-3 deficiency, T-B- severe combined immunodeficiency, severe combined immunodeficiency due to CARMIL2 deficiency, immunodeficiency 79, familial severe combined immunodeficiency, severe combined immunodeficiency due to CD70 deficiency, T-B+ severe combined immunodeficiency, T+ B+ severe combined immunodeficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

303 likely benign, 231 uncertain significance, 29 pathogenic, 13 benign, 13 likely pathogenic, 7 conflicting classifications of pathogenicity, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1048525	NM_001369369.1(FOXN1):c.1370del (p.His457fs)	FOXN1	Pathogenic	reviewed by expert panel
1067142	NM_001369369.1(FOXN1):c.1327del (p.Met444fs)	FOXN1	Pathogenic	criteria provided, single submitter
1070970	NM_001369369.1(FOXN1):c.723C>G (p.Tyr241Ter)	FOXN1	Pathogenic	reviewed by expert panel
1074340	NM_001369369.1(FOXN1):c.1316del (p.Leu439fs)	FOXN1	Pathogenic	criteria provided, single submitter
1075865	NM_001369369.1(FOXN1):c.823del (p.Ser275fs)	FOXN1	Pathogenic	criteria provided, single submitter
1360931	NM_001369369.1(FOXN1):c.455del (p.Pro152fs)	FOXN1	Pathogenic	criteria provided, single submitter
1417126	NM_001369369.1(FOXN1):c.64G>T (p.Glu22Ter)	FOXN1	Pathogenic	criteria provided, single submitter
1454677	NM_001369369.1(FOXN1):c.690dup (p.Phe231fs)	FOXN1	Pathogenic	criteria provided, single submitter
1457907	NM_001369369.1(FOXN1):c.1459_1460del (p.Thr487fs)	FOXN1	Pathogenic	criteria provided, single submitter
2016991	NM_001369369.1(FOXN1):c.1431del (p.His478fs)	FOXN1	Pathogenic	criteria provided, single submitter
2087766	NM_001369369.1(FOXN1):c.1021del (p.Arg341fs)	FOXN1	Pathogenic	criteria provided, single submitter
2088121	NM_001369369.1(FOXN1):c.340C>T (p.Arg114Ter)	FOXN1	Pathogenic	reviewed by expert panel
2424707	NC_000017.10:g.(?26861752)(26869835_?)del	FOXN1	Pathogenic	criteria provided, single submitter
2704556	NM_001369369.1(FOXN1):c.6del (p.Ser3fs)	FOXN1	Pathogenic	criteria provided, single submitter
2704650	NM_001369369.1(FOXN1):c.118C>T (p.Gln40Ter)	FOXN1	Pathogenic	criteria provided, single submitter
2716400	NM_001369369.1(FOXN1):c.1324_1336del (p.Leu442fs)	FOXN1	Pathogenic	criteria provided, single submitter
2751542	NM_001369369.1(FOXN1):c.98_114del (p.Leu33fs)	FOXN1	Pathogenic	criteria provided, single submitter
2780381	NM_001369369.1(FOXN1):c.246C>A (p.Cys82Ter)	FOXN1	Pathogenic	reviewed by expert panel
2815940	NM_001369369.1(FOXN1):c.1064del (p.Lys355fs)	FOXN1	Pathogenic	criteria provided, single submitter
2820427	NM_001369369.1(FOXN1):c.1220C>G (p.Ser407Ter)	FOXN1	Pathogenic	criteria provided, single submitter
2823406	NM_001369369.1(FOXN1):c.1151del (p.Leu384fs)	FOXN1	Pathogenic	criteria provided, single submitter
2831369	NM_001369369.1(FOXN1):c.62del (p.Gly21fs)	FOXN1	Pathogenic	criteria provided, single submitter
2856279	NM_001369369.1(FOXN1):c.1314_1315dup (p.Leu439fs)	FOXN1	Pathogenic	criteria provided, single submitter
3367209	NM_001369369.1(FOXN1):c.880G>A (p.Val294Ile)	FOXN1	Pathogenic	reviewed by expert panel
3643502	NM_001369369.1(FOXN1):c.1238del (p.Leu413fs)	FOXN1	Pathogenic	criteria provided, single submitter
3661380	NM_001369369.1(FOXN1):c.806dup (p.Pro272fs)	FOXN1	Pathogenic	criteria provided, single submitter
3722792	NM_001369369.1(FOXN1):c.1465dup (p.Gln489fs)	FOXN1	Pathogenic	criteria provided, single submitter
3726217	NM_001369369.1(FOXN1):c.804_805del (p.Phe269fs)	FOXN1	Pathogenic	criteria provided, single submitter
3729790	NM_001369369.1(FOXN1):c.1184del (p.Pro395fs)	FOXN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1199408	NM_001369369.1(FOXN1):c.1364_1367del (p.Tyr455fs)	FOXN1	Likely pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FOXN1	Definitive	Autosomal recessive	T-cell immunodeficiency, congenital alopecia, and nail dystrophy	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FOXN1	Orphanet:169095	Severe combined immunodeficiency due to FOXN1 deficiency
FOXN1	Orphanet:676039	Combined immunodeficiency due to FOXN1 haploinsufficiency
FOXN1	Orphanet:83471	T-cell immunodeficiency with thymic aplasia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FOXN1	HGNC:12765	ENSG00000109101	O15353	Forkhead box protein N1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FOXN1	Forkhead box protein N1	Transcriptional regulator which regulates the development, differentiation, and function of thymic epithelial cells (TECs) both in the prenatal and postnatal thymus.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FOXN1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_2, WH-like_DNA-bd_sf

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingiva	1
gingival epithelium	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FOXN1	75	tissue_specific	yes	gingival epithelium, gingiva, upper leg skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FOXN1	1,802

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FOXN1	O15353	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lymphoid lineage cell migration into thymus	1	8426.0×	6e-04	FOXN1
thymus epithelium morphogenesis	1	8426.0×	6e-04	FOXN1
regulation of positive thymic T cell selection	1	8426.0×	6e-04	FOXN1
T cell lineage commitment	1	3370.4×	0.001	FOXN1
nail development	1	2407.4×	0.001	FOXN1
positive regulation of hair follicle development	1	2407.4×	0.001	FOXN1
positive regulation of epithelial cell differentiation	1	1872.4×	0.001	FOXN1
blood vessel morphogenesis	1	802.5×	0.002	FOXN1
T cell homeostasis	1	455.5×	0.004	FOXN1
hair follicle development	1	383.0×	0.004	FOXN1
keratinocyte differentiation	1	247.8×	0.005	FOXN1
defense response	1	216.1×	0.005	FOXN1
epidermis development	1	210.7×	0.005	FOXN1
animal organ morphogenesis	1	191.5×	0.006	FOXN1
regulation of transcription by RNA polymerase II	1	11.7×	0.086	FOXN1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FOXN1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	FOXN1

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FOXN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.