X-linked central congenital hypothyroidism with late-onset testicular enlargement

Summary

X-linked central congenital hypothyroidism with late-onset testicular enlargement (MONDO:0010475) is a disease caused by IGSF1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: IGSF1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 48

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		27	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked central congenital hypothyroidism with late-onset testicular enlargement
Mondo ID	MONDO:0010475
OMIM	300888
Orphanet	329235
DOID	DOID:0111140
NCIT	C130989
UMLS	C3550963
MedGen	763877
GARD	0017499
Is cancer (heuristic)	no

Also known as: CHTE · hypothyroidism Central and testicular enlargement · hypothyroidism, central, and testicular enlargement · hypothyroidism, central, and testicular enlargement, X-linked recessive · IGSF1 deficiency syndrome · Immunoglobulin superfamily member 1 deficiency syndrome · X-linked central congenital hypothyroidism with late-onset macroorchidism · X-linked central congenital hypothyroidism with late-onset testicular enlargement

Data availability: 48 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › X-linked central congenital hypothyroidism with late-onset testicular enlargement

Related subtypes (49): X-linked Opitz G/BBB syndrome, X-linked immunoneurologic disorder, X-linked adrenal hypoplasia congenita, X-linked lissencephaly with abnormal genitalia, X-linked severe congenital neutropenia, X-linked distal spinal muscular atrophy type 3, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, Aland island eye disease, X-linked erythropoietic protoporphyria, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, X-linked acrogigantism due to Xq26 microduplication, Wiskott-Aldrich syndrome, X-linked Alport syndrome, X-linked mandibulofacial dysostosis, X-linked chondrodysplasia punctata, choroideremia, cone dystrophy, X-linked, with tapetal-like sheen, diabetes insipidus, nephrogenic, X-linked, Dyggve-Melchior-Clausen syndrome, X-linked, dyskeratosis congenita, X-linked, X-linked hypohidrotic ectodermal dysplasia, X-linked Ehlers-Danlos syndrome, epidermodysplasia verruciformis, X-linked, exudative vitreoretinopathy 2, X-linked, Aarskog-Scott syndrome, X-linked, hemophilia A, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, hyper-IgM syndrome type 1, X-linked lymphoproliferative syndrome, macular dystrophy, X-linked, X-linked Emery-Dreifuss muscular dystrophy, X-linked myotubular myopathy, X-linked lethal multiple pterygium syndrome, X-linked retinoschisis, spondyloepiphyseal dysplasia tarda, X-linked, X-linked cerebellar ataxia, adrenoleukodystrophy, Charcot-Marie-Tooth disease type X, X-linked dominant disease, X-linked recessive disease, X-linked hypophosphatemic rickets, X-linked sideroblastic anemia 1, X-linked deafness, X-linked cone-rod dystrophy, X-linked congenital stationary night blindness, X-linked congenital hemolytic anemia, X-linked complex neurodevelopmental disorder, X-linked intellectual disability, leukemia, acute, X-linked

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

48 retrieved; paginated sample, class counts are floors:

14 benign, 13 uncertain significance, 12 pathogenic, 5 likely pathogenic, 1 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033351	NM_001555.5(IGSF1):c.3550C>T (p.Arg1184Ter)	IGSF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1301901	NM_001555.5(IGSF1):c.3790C>T (p.Arg1264Ter)	IGSF1	Pathogenic	criteria provided, single submitter
3108778	NM_001555.5(IGSF1):c.1814_1836dup (p.Arg613delinsGlyArgThrTer)	IGSF1	Pathogenic	criteria provided, multiple submitters, no conflicts
3377347	NM_001555.5(IGSF1):c.461_486del (p.Gly154fs)	IGSF1	Pathogenic	criteria provided, single submitter
3377351	NM_001555.5(IGSF1):c.404_407del (p.Trp135fs)	IGSF1	Pathogenic	criteria provided, single submitter
39849	NM_001555.5(IGSF1):c.2123_2149del (p.Ala708_Lys716del)	IGSF1	Pathogenic	no assertion criteria provided
39850	NM_001555.5(IGSF1):c.2916G>A (p.Trp972Ter)	IGSF1	Pathogenic	no assertion criteria provided
39851	NM_001555.5(IGSF1):c.2233del (p.Glu745fs)	IGSF1	Pathogenic	no assertion criteria provided
39852	NM_001555.5(IGSF1):c.2573C>T (p.Ser858Phe)	IGSF1	Pathogenic	no assertion criteria provided
39853	NM_001555.5(IGSF1):c.3581dup (p.Glu1195fs)	IGSF1	Pathogenic	no assertion criteria provided
689654	NM_001555.5(IGSF1):c.2268dup (p.Arg757fs)	IGSF1	Pathogenic	no assertion criteria provided
689655	NM_001555.5(IGSF1):c.2303T>C (p.Leu768Pro)	IGSF1	Pathogenic	criteria provided, single submitter
807432	NM_001555.5(IGSF1):c.2407dup (p.His803fs)	IGSF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2440886	NM_001555.5(IGSF1):c.2042-1_2042del	IGSF1	Likely pathogenic	criteria provided, single submitter
2585310	NM_001555.5(IGSF1):c.1614G>A (p.Trp538Ter)	IGSF1	Likely pathogenic	criteria provided, single submitter
3764642	NM_001555.5(IGSF1):c.3868C>T (p.Arg1290Ter)	IGSF1	Likely pathogenic	criteria provided, single submitter
4291707	NM_001555.5(IGSF1):c.2816_2819dup (p.Tyr940Ter)	IGSF1	Likely pathogenic	criteria provided, single submitter
4755483	NM_001555.5(IGSF1):c.2036_2037insA (p.Thr680fs)	IGSF1	Likely pathogenic	criteria provided, single submitter
1803242	NM_001555.5(IGSF1):c.113C>T (p.Pro38Leu)	IGSF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
929812	NM_000136.3(FANCC):c.996+979_996+983del	AOPEP	Uncertain significance	no assertion criteria provided
1341740	NM_001555.5(IGSF1):c.1034G>A (p.Gly345Glu)	IGSF1	Uncertain significance	criteria provided, single submitter
1687248	NM_001555.5(IGSF1):c.3467T>A (p.Val1156Glu)	IGSF1	Uncertain significance	criteria provided, single submitter
1709444	NM_001555.5(IGSF1):c.2050C>A (p.Pro684Thr)	IGSF1	Uncertain significance	criteria provided, single submitter
2432835	NM_001555.5(IGSF1):c.3813T>G (p.Val1271=)	IGSF1	Uncertain significance	criteria provided, single submitter
2432836	NM_001555.5(IGSF1):c.1007G>A (p.Gly336Asp)	IGSF1	Uncertain significance	criteria provided, single submitter
2691000	NM_001555.5(IGSF1):c.1672C>T (p.Gln558Ter)	IGSF1	Uncertain significance	criteria provided, single submitter
3064973	NM_001555.5(IGSF1):c.3669C>G (p.Asn1223Lys)	IGSF1	Uncertain significance	criteria provided, single submitter
3065962	NM_001555.5(IGSF1):c.3061G>A (p.Gly1021Arg)	IGSF1	Uncertain significance	criteria provided, single submitter
3376288	NM_001555.5(IGSF1):c.2036G>C (p.Gly679Ala)	IGSF1	Uncertain significance	criteria provided, single submitter
4056791	NM_001555.5(IGSF1):c.2583C>G (p.Ser861Arg)	IGSF1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
IGSF1	Definitive	X-linked	X-linked central congenital hypothyroidism with late-onset testicular enlargement	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IGSF1	Orphanet:329235	X-linked central congenital hypothyroidism with late-onset testicular enlargement
FANCB	Orphanet:3412	VACTERL with hydrocephalus
FANCB	Orphanet:84	Fanconi anemia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IGSF1	HGNC:5948	ENSG00000147255	Q8N6C5	Immunoglobulin superfamily member 1	gencc,clinvar
AOPEP	HGNC:1361	ENSG00000148120	Q8N6M6	Aminopeptidase O	clinvar
FANCB	HGNC:3583	ENSG00000181544	Q8NB91	Fanconi anemia group B protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IGSF1	Immunoglobulin superfamily member 1	Seems to be a coreceptor in inhibin signaling, but seems not to be a high-affinity inhibin receptor.
AOPEP	Aminopeptidase O	Aminopeptidase which catalyzes the hydrolysis of amino acid residues from the N-terminus of peptide or protein substrates.
FANCB	Fanconi anemia group B protein	DNA repair protein required for FANCD2 ubiquitination.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Protease	1	12.2×	0.149
Antibody/Immunoglobulin	1	9.7×	0.149
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IGSF1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
AOPEP	Protease	yes		Peptidase_M1_dom, Peptidase_M1_C, ARM-type_fold
FANCB	Other/Unknown	no		FANCB

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
pituitary gland	1
right atrium auricular region	1
apex of heart	1
ascending aorta	1
right coronary artery	1
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IGSF1	194	broad	marker	pituitary gland, adenohypophysis, right atrium auricular region
AOPEP	224	ubiquitous	marker	apex of heart, right coronary artery, ascending aorta
FANCB	160	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FANCB	1,097
AOPEP	991
IGSF1	748

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FANCB	Q8NB91	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AOPEP	Q8N6M6	83.36
IGSF1	Q8N6C5	73.64

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 evidence-associated genes (1 with Reactome annotation).

Pathways 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.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Fanconi Anemia Pathway	1	278.5×	0.007	FANCB
PKR-mediated signaling	1	141.0×	0.007	FANCB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
replication-born double-strand break repair via sister chromatid exchange	1	936.2×	0.009	FANCB
negative regulation of activin receptor signaling pathway	1	468.1×	0.009	IGSF1
negative regulation of double-strand break repair via homologous recombination	1	208.1×	0.010	FANCB
immune response-regulating signaling pathway	1	151.8×	0.010	IGSF1
interstrand cross-link repair	1	144.0×	0.010	FANCB
positive regulation of double-strand break repair via homologous recombination	1	127.7×	0.010	FANCB
proteolysis	1	11.4×	0.092	AOPEP
regulation of DNA-templated transcription	1	10.5×	0.092	IGSF1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IGSF1	0	0
AOPEP	0	0
FANCB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
AOPEP	1	ADMET:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	2	IGSF1, AOPEP
E	Difficult family or no structure, no drug	1	FANCB

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
IGSF1	0	—
AOPEP	1	—
FANCB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.