FOXN1

Chr 17ARAD

forkhead box N1

Also known as: FKHL20, RONU, TIDAND, TIDTA, TLIND, WHN

NCBI Gene: 8456 ENSG00000109101 UniProt: O15353

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]

Primary Disease Associations & Inheritance

?T-cell immunodeficiency with thymic aplasiaMIM #242700

T-cell immunodeficiency, congenital alopecia, and nail dystrophyMIM #601705

T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominantMIM #618806

600

ClinVar variants

Pathogenic / LP

0.94

pLI score· haploinsufficient

Active trials

Clinical Summary— FOXN1

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Gene-Disease Validity (ClinGen)

T-cell immunodeficiency, congenital alopecia, and nail dystrophy · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.94). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

55 Pathogenic / Likely Pathogenic· 233 VUS of 600 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.35LOEUF

pLI 0.942

Z-score 3.78

OE 0.13 (0.06–0.35)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.66Z-score

OE missense 0.91 (0.83–0.99)

350 obs / 386.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.13 (0.06–0.35)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.83–0.99)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97

0≤1.21.6

LoF obs/exp: 3 / 22.2Missense obs/exp: 350 / 386.4Syn Z: 0.35