Nezelof syndrome

Summary

Nezelof syndrome (MONDO:0009451) is a disease with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 1
• ClinVar variants: 2
• Phenotypes (HPO): 36

Clinical features

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0005359	Aplasia of the thymus	Obligate (100%)
HP:0002719	Recurrent infections	Very frequent (80-99%)
HP:0005352	Severe T-cell immunodeficiency	Very frequent (80-99%)
HP:0005374	Cellular immunodeficiency	Very frequent (80-99%)
HP:0005403	Decreased total T cell count	Very frequent (80-99%)
HP:0031381	Decreased lymphocyte proliferation in response to mitogen	Very frequent (80-99%)
HP:0031397	Reduced proportion of naive T cells	Very frequent (80-99%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0002090	Pneumonia	Frequent (30-79%)
HP:0002718	Recurrent bacterial infections	Frequent (30-79%)
HP:0002960	Autoimmunity	Frequent (30-79%)
HP:0004798	Recurrent infection of the gastrointestinal tract	Frequent (30-79%)
HP:0031690	Opportunistic infection	Frequent (30-79%)
HP:0031691	Severe viral infection	Frequent (30-79%)
HP:0032169	Severe infection	Frequent (30-79%)
HP:0000964	Eczematoid dermatitis	Occasional (5-29%)
HP:0000010	Recurrent urinary tract infections	Occasional (5-29%)
HP:0000246	Sinusitis	Occasional (5-29%)
HP:0000389	Chronic otitis media	Occasional (5-29%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0001287	Meningitis	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002024	Malabsorption	Occasional (5-29%)
HP:0002716	Lymphadenopathy	Occasional (5-29%)
HP:0002726	Recurrent Staphylococcus aureus infections	Occasional (5-29%)
HP:0003472	Hypocalcemic tetany	Occasional (5-29%)
HP:0004844	Coombs-positive hemolytic anemia	Occasional (5-29%)
HP:0005366	Recurrent streptococcus pneumoniae infections	Occasional (5-29%)
HP:0005387	Combined immunodeficiency	Occasional (5-29%)
HP:0005401	Recurrent candida infections	Occasional (5-29%)
HP:0009098	Chronic oral candidiasis	Occasional (5-29%)
HP:0020101	Invasive fungal infection	Occasional (5-29%)
HP:0031430	Oligoclonal T cell expansion	Occasional (5-29%)
HP:0100646	Thyroiditis	Occasional (5-29%)
HP:0100806	Sepsis	Occasional (5-29%)
HP:0200122	Atypical or prolonged hepatitis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Nezelof syndrome
Mondo ID	MONDO:0009451
MeSH	C536288
OMIM	242700
Orphanet	83471
DOID	DOID:2012
ICD-10-CM	D81.4
ICD-11	215376282
SNOMED CT	55602000
UMLS	C0152094
MedGen	101814
GARD	0007201
Is cancer (heuristic)	no

Also known as: immune defect due to absence Of Thymus · Nezelof syndrome · Nezelof’s syndrome · T-lymphocyte deficiency

Data availability: 2 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › T-cell immunodeficiency › congenital T-cell immunodeficiency › Nezelof syndrome

Related subtypes (1): DiGeorge syndrome

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

2 retrieved; paginated sample, class counts are floors:

2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
827574	NM_001369369.1(FOXN1):c.933_936dup (p.Asp313fs)	FOXN1	Pathogenic	reviewed by expert panel
827575	NM_001369369.1(FOXN1):c.1089_1103del (p.Trp363_Pro368delinsCys)	FOXN1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

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

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	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.