Hypogonadotropic hypogonadism 14 with or without anosmia

Summary

Hypogonadotropic hypogonadism 14 with or without anosmia (MONDO:0013926) is a disease caused by WDR11 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: WDR11 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 36

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypogonadotropic hypogonadism 14 with or without anosmia
Mondo ID	MONDO:0013926
OMIM	614858
DOID	DOID:0090087
UMLS	C3540450
MedGen	761703
GARD	0015857
Is cancer (heuristic)	no

Also known as: HH14 · hypogonadotropic hypogonadism 14 with or without anosmia · hypogonadotropic hypogonadism caused by mutation in WDR11 · WDR11 hypogonadotropic hypogonadism

Data availability: 36 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Kallmann syndrome › hypogonadotropic hypogonadism 14 with or without anosmia

Related subtypes (17): hypogonadotropic hypogonadism 2 with or without anosmia, hypogonadotropic hypogonadism 3 with or without anosmia, hypogonadotropic hypogonadism 1 with or without anosmia, hypogonadotropic hypogonadism 4 with or without anosmia, hypogonadotropic hypogonadism 5 with or without anosmia, hypogonadotropic hypogonadism 6 with or without anosmia, hypogonadotropic hypogonadism 8 with or without anosmia, hypogonadotropic hypogonadism 9 with or without anosmia, hypogonadotropic hypogonadism 11 with or without anosmia, hypogonadotropic hypogonadism 15 with or without anosmia, hypogonadotropic hypogonadism 16 with or without anosmia, hypogonadotropic hypogonadism 17 with or without anosmia, hypogonadotropic hypogonadism 18 with or without anosmia, hypogonadotropic hypogonadism 19 with or without anosmia, hypogonadotropic hypogonadism 20 with or without anosmia, hypogonadotropic hypogonadism 21 with or without anosmia, hypogonadotropic hypogonadism 22 with or without anosmia

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

36 retrieved; paginated sample, class counts are floors:

19 uncertain significance, 9 benign, 5 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1687367	NM_018117.12(WDR11):c.163dup (p.Gln55fs)	WDR11	Likely pathogenic	criteria provided, single submitter
3061804	NM_018117.12(WDR11):c.3220_3223del (p.Asp1074fs)	WDR11	Likely pathogenic	no assertion criteria provided
4293190	NM_018117.12(WDR11):c.879+1G>T	WDR11	Likely pathogenic	criteria provided, single submitter
4538418	NM_018117.12(WDR11):c.458G>A (p.Trp153Ter)	WDR11	Likely pathogenic	no assertion criteria provided
928566	NM_018117.12(WDR11):c.1849G>T (p.Glu617Ter)	WDR11	Likely pathogenic	criteria provided, single submitter
1805596	NM_018117.12(WDR11):c.3665T>C (p.Ile1222Thr)	WDR11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
68842	NM_018117.12(WDR11):c.3450T>G (p.Phe1150Leu)	WDR11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1306011	NM_018117.12(WDR11):c.3553C>T (p.Arg1185Trp)	WDR11	Uncertain significance	criteria provided, multiple submitters, no conflicts
1337335	NM_018117.12(WDR11):c.76G>A (p.Ala26Thr)	WDR11	Uncertain significance	criteria provided, multiple submitters, no conflicts
1806341	NM_018117.12(WDR11):c.2321C>T (p.Ala774Val)	WDR11	Uncertain significance	criteria provided, single submitter
1895464	NM_018117.12(WDR11):c.1079G>A (p.Ser360Asn)	WDR11	Uncertain significance	criteria provided, single submitter
1979178	NM_018117.12(WDR11):c.403A>G (p.Ile135Val)	WDR11	Uncertain significance	criteria provided, multiple submitters, no conflicts
2369056	NM_018117.12(WDR11):c.394C>G (p.Leu132Val)	WDR11	Uncertain significance	criteria provided, multiple submitters, no conflicts
2584672	NM_018117.12(WDR11):c.3050T>A (p.Leu1017Gln)	WDR11	Uncertain significance	criteria provided, single submitter
2585361	NM_018117.12(WDR11):c.2149G>A (p.Ala717Thr)	WDR11	Uncertain significance	criteria provided, single submitter
3062082	NM_018117.12(WDR11):c.859A>G (p.Thr287Ala)	WDR11	Uncertain significance	criteria provided, single submitter
3376642	NM_018117.12(WDR11):c.1714G>A (p.Glu572Lys)	WDR11	Uncertain significance	criteria provided, single submitter
3590731	NM_018117.12(WDR11):c.3226G>A (p.Ala1076Thr)	WDR11	Uncertain significance	criteria provided, single submitter
3602594	NM_018117.12(WDR11):c.3023G>A (p.Gly1008Asp)	WDR11	Uncertain significance	criteria provided, single submitter
37309	NM_018117.12(WDR11):c.1303G>A (p.Ala435Thr)	WDR11	Uncertain significance	criteria provided, single submitter
3892881	NM_018117.12(WDR11):c.3660A>C (p.Glu1220Asp)	WDR11	Uncertain significance	criteria provided, single submitter
4293198	NM_018117.12(WDR11):c.1303G>C (p.Ala435Pro)	WDR11	Uncertain significance	criteria provided, single submitter
4531402	NM_018117.12(WDR11):c.1574G>A (p.Ser525Asn)	WDR11	Uncertain significance	criteria provided, single submitter
4531412	NM_018117.12(WDR11):c.1592C>G (p.Ser531Cys)	WDR11	Uncertain significance	criteria provided, multiple submitters, no conflicts
4538405	NM_018117.12(WDR11):c.2905G>A (p.Val969Met)	WDR11	Uncertain significance	no assertion criteria provided
4538423	NM_018117.12(WDR11):c.3418G>A (p.Val1140Met)	WDR11	Uncertain significance	no assertion criteria provided
1231978	NM_018117.12(WDR11):c.834G>A (p.Thr278=)	WDR11	Benign	criteria provided, multiple submitters, no conflicts
1246122	NM_018117.12(WDR11):c.3363C>G (p.Val1121=)	WDR11	Benign	criteria provided, multiple submitters, no conflicts
1249341	NM_018117.12(WDR11):c.1899A>T (p.Ala633=)	WDR11	Benign	criteria provided, multiple submitters, no conflicts
1261179	NM_018117.12(WDR11):c.199-7G>C	WDR11	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · Orphanet: 4 · 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
PHIP	Strong	Autosomal dominant	hypogonadotropic hypogonadism 14 with or without anosmia	15
WDR11	Strong	Autosomal dominant	hypogonadotropic hypogonadism 14 with or without anosmia	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WDR11	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
WDR11	Orphanet:478	Kallmann syndrome
WDR11	Orphanet:95496	Pituitary stalk interruption syndrome
PHIP	Orphanet:589905	PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WDR11	HGNC:13831	ENSG00000120008	Q9BZH6	WD repeat-containing protein 11	gencc,clinvar
PHIP	HGNC:15673	ENSG00000146247	Q8WWQ0	PH-interacting protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WDR11	WD repeat-containing protein 11	Involved in the Hedgehog (Hh) signaling pathway, is essential for normal ciliogenesis.
PHIP	PH-interacting protein	Probable regulator of the insulin and insulin-like growth factor signaling pathways.

Protein-family classification

Druggable: 0 · Difficult: 2 · 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
Scaffold/PPI	2	17.3×	0.003

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WDR11	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
PHIP	Scaffold/PPI	no		Bromodomain, WD40_rpt, WD40/YVTN_repeat-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
epithelium of nasopharynx	1
nasopharynx	1
bronchial epithelial cell	1
epithelium of bronchus	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WDR11	287	ubiquitous	marker	epithelium of nasopharynx, nasopharynx, calcaneal tendon
PHIP	302	ubiquitous	marker	bronchial epithelial cell, epithelium of bronchus, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PHIP	3,057
WDR11	1,088

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PHIP	Q8WWQ0	146
WDR11	Q9BZH6	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RHOBTB2 GTPase cycle	1	237.9×	0.006	PHIP
RHOH GTPase cycle	1	154.3×	0.006	WDR11

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete vesicle tethering to Golgi	1	1685.2×	0.009	WDR11
positive regulation of insulin-like growth factor receptor signaling pathway	1	601.9×	0.009	PHIP
head development	1	601.9×	0.009	WDR11
regulation of protein phosphorylation	1	561.7×	0.009	PHIP
regulation of smoothened signaling pathway	1	312.1×	0.011	WDR11
regulation of cell morphogenesis	1	312.1×	0.011	PHIP
positive regulation of mitotic nuclear division	1	271.8×	0.011	PHIP
negative regulation of extrinsic apoptotic signaling pathway	1	210.7×	0.012	PHIP
insulin receptor signaling pathway	1	110.9×	0.020	PHIP
multicellular organism growth	1	68.5×	0.027	WDR11
cytoskeleton organization	1	66.3×	0.027	PHIP
regulation of cell shape	1	61.5×	0.027	PHIP
heart development	1	39.4×	0.039	WDR11
cilium assembly	1	36.8×	0.039	WDR11
intracellular protein transport	1	32.4×	0.041	WDR11
negative regulation of apoptotic process	1	17.4×	0.069	PHIP
positive regulation of cell population proliferation	1	16.8×	0.069	PHIP
positive regulation of DNA-templated transcription	1	14.0×	0.078	PHIP
positive regulation of transcription by RNA polymerase II	1	7.4×	0.137	PHIP
regulation of transcription by RNA polymerase II	1	5.8×	0.164	PHIP

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
WDR11	0	0
PHIP	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
PHIP	17	Binding:17

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	WDR11, PHIP

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
WDR11	0	—
PHIP	17	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.