Hypogonadotropic hypogonadism 5 with or without anosmia

Summary

Hypogonadotropic hypogonadism 5 with or without anosmia (MONDO:0012880) is a disease caused by CHD7 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: CHD7 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 718

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypogonadotropic hypogonadism 5 with or without anosmia
Mondo ID	MONDO:0012880
MeSH	C567220
OMIM	612370
DOID	DOID:0090084
UMLS	C3552553
MedGen	765467
GARD	0010773
Is cancer (heuristic)	no

Also known as: CHD7 hypogonadotropic hypogonadism · HH5 · hypogonadotropic hypogonadism 5 with or without anosmia · hypogonadotropic hypogonadism caused by mutation in CHD7 · KAL5 · Kallmann syndrome 5

Data availability: 718 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Kallmann syndrome › hypogonadotropic hypogonadism 5 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 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 14 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

600 retrieved; paginated sample, class counts are floors:

226 uncertain significance, 222 conflicting classifications of pathogenicity, 53 likely benign, 47 benign/likely benign, 21 pathogenic, 17 benign, 10 likely pathogenic, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
636326	NC_000008.11:g.228116G>C		Pathogenic	no assertion criteria provided
1028060	NM_017780.4(CHD7):c.6193C>T (p.Arg2065Cys)	CHD7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1032765	NM_017780.4(CHD7):c.519del (p.Pro174fs)	CHD7	Pathogenic	criteria provided, multiple submitters, no conflicts
158279	NM_017780.4(CHD7):c.1480C>T (p.Arg494Ter)	CHD7	Pathogenic	criteria provided, multiple submitters, no conflicts
158307	NM_017780.4(CHD7):c.6157C>T (p.Arg2053Ter)	CHD7	Pathogenic	criteria provided, multiple submitters, no conflicts
158320	NM_017780.4(CHD7):c.7891C>T (p.Arg2631Ter)	CHD7	Pathogenic	criteria provided, multiple submitters, no conflicts
1676546	NM_017780.4(CHD7):c.8546del (p.Glu2849fs)	CHD7	Pathogenic	criteria provided, single submitter
195978	NM_017780.4(CHD7):c.5405-17G>A	CHD7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2022	NM_017780.4(CHD7):c.3082A>G (p.Ile1028Val)	CHD7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2034	NM_017780.4(CHD7):c.2442+5G>C	CHD7	Pathogenic	criteria provided, single submitter
267364	NM_017780.4(CHD7):c.8458_8459del (p.Leu2820fs)	CHD7	Pathogenic	criteria provided, single submitter
267423	NM_017780.4(CHD7):c.3205C>T (p.Arg1069Ter)	CHD7	Pathogenic	criteria provided, multiple submitters, no conflicts
279762	NM_017780.4(CHD7):c.5029C>T (p.Arg1677Ter)	CHD7	Pathogenic	criteria provided, multiple submitters, no conflicts
3237465	NM_017780.4(CHD7):c.5397del (p.Phe1799fs)	CHD7	Pathogenic	criteria provided, single submitter
3238745	NM_017780.4(CHD7):c.5389G>T (p.Gly1797Ter)	CHD7	Pathogenic	criteria provided, single submitter
3384121	NM_017780.4(CHD7):c.2415dup (p.Met806fs)	CHD7	Pathogenic	criteria provided, single submitter
3393041	NM_017780.4(CHD7):c.6104-1G>C	CHD7	Pathogenic	criteria provided, single submitter
3595705	NM_017780.4(CHD7):c.2509_2512del (p.His837fs)	CHD7	Pathogenic	criteria provided, multiple submitters, no conflicts
4526201	NM_017780.4(CHD7):c.6247_6265del (p.Pro2083fs)	CHD7	Pathogenic	criteria provided, single submitter
4538411	NM_017780.4(CHD7):c.7164+1G>T	CHD7	Pathogenic	no assertion criteria provided
488680	NM_017780.4(CHD7):c.5968C>T (p.Gln1990Ter)	CHD7	Pathogenic	criteria provided, multiple submitters, no conflicts
620060	NM_017780.4(CHD7):c.7123del (p.Ser2375fs)	CHD7	Pathogenic	criteria provided, single submitter
690306	NM_017780.4(CHD7):c.3301T>C (p.Cys1101Arg)	CHD7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
818212	NM_017780.4(CHD7):c.8006dup (p.Pro2670fs)	CHD7	Pathogenic	criteria provided, single submitter
3238856	NM_017780.4(CHD7):c.1898C>A (p.Ser633Ter)	LOC126860403	Pathogenic	criteria provided, single submitter
1028059	NM_017780.4(CHD7):c.5C>A (p.Ala2Glu)	CHD7	Likely pathogenic	criteria provided, single submitter
1710203	NM_017780.4(CHD7):c.8094del (p.Met2699fs)	CHD7	Likely pathogenic	no assertion criteria provided
2503801	NC_000008.10:g.(61769448_61773462)_(61773685_61774754)del	CHD7	Likely pathogenic	criteria provided, single submitter
265994	NM_017780.4(CHD7):c.2731C>T (p.Leu911Phe)	CHD7	Likely pathogenic	no assertion criteria provided
3251907	NM_017780.4(CHD7):c.6371T>G (p.Phe2124Cys)	CHD7	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 5 · 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
CHD7	Strong	Autosomal dominant	hypogonadotropic hypogonadism 5 with or without anosmia	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CHD7	Orphanet:138	CHARGE syndrome
CHD7	Orphanet:39041	Omenn syndrome
CHD7	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
CHD7	Orphanet:478	Kallmann syndrome
SEMA3E	Orphanet:138	CHARGE 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
CHD7	HGNC:20626	ENSG00000171316	Q9P2D1	ATP-dependent chromatin remodeler CHD7	gencc,clinvar
SEMA3E	HGNC:10727	ENSG00000170381	O15041	Semaphorin-3E	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CHD7	ATP-dependent chromatin remodeler CHD7	ATP-dependent chromatin-remodeling factor, slides nucleosomes along DNA; nucleosome sliding requires ATP.
SEMA3E	Semaphorin-3E	Plays an important role in signaling via the cell surface receptor PLXND1.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CHD7	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
SEMA3E	Antibody/Immunoglobulin	yes		Semap_dom, Ig-like_dom, Immunoglobulin_dom

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
cerebellar vermis	1
secondary oocyte	1
sural nerve	1
blood vessel layer	1
calcaneal tendon	1
cortical plate	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CHD7	269	ubiquitous	marker	secondary oocyte, cerebellar vermis, sural nerve
SEMA3E	197	broad	marker	cortical plate, calcaneal tendon, blood vessel layer

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CHD7	4,819
SEMA3E	917

Intra-cohort edges

A	B	Sources
CHD7	SEMA3E	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHD7	Q9P2D1	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SEMA3E	O15041	84.62

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Other semaphorin interactions	1	300.5×	0.015	SEMA3E
Semaphorin interactions	1	196.9×	0.015	SEMA3E
CHD6, CHD7, CHD8, CHD9 subfamily	1	74.2×	0.027	CHD7
Axon guidance	1	22.6×	0.055	SEMA3E
Nervous system development	1	21.5×	0.055	SEMA3E
Developmental Biology	1	7.2×	0.134	SEMA3E

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
right ventricular compact myocardium morphogenesis	1	8426.0×	0.005	CHD7
cranial nerve development	1	2808.7×	0.005	CHD7
olfactory nerve development	1	2808.7×	0.005	CHD7
regulation of growth hormone secretion	1	2808.7×	0.005	CHD7
gonadotrophin-releasing hormone neuronal migration to the hypothalamus	1	1404.3×	0.005	SEMA3E
chordate embryonic development	1	1404.3×	0.005	CHD7
female genitalia development	1	1203.7×	0.005	CHD7
nose development	1	1203.7×	0.005	CHD7
semicircular canal morphogenesis	1	1203.7×	0.005	CHD7
epithelium development	1	1053.2×	0.006	CHD7
olfactory behavior	1	936.2×	0.006	CHD7
genitalia development	1	842.6×	0.006	CHD7
atrioventricular canal development	1	766.0×	0.006	CHD7
adult heart development	1	601.9×	0.006	CHD7
cardiac septum morphogenesis	1	601.9×	0.006	CHD7
secondary palate development	1	601.9×	0.006	CHD7
ventricular trabecula myocardium morphogenesis	1	526.6×	0.006	CHD7
negative regulation of cell-matrix adhesion	1	443.5×	0.007	SEMA3E
aorta morphogenesis	1	443.5×	0.007	CHD7
innervation	1	443.5×	0.007	CHD7
face development	1	401.2×	0.007	CHD7
olfactory bulb development	1	383.0×	0.007	CHD7
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	337.0×	0.007	CHD7
negative chemotaxis	1	324.1×	0.007	SEMA3E
embryonic hindlimb morphogenesis	1	290.6×	0.008	CHD7
branching involved in blood vessel morphogenesis	1	263.3×	0.008	SEMA3E
blood circulation	1	255.3×	0.008	CHD7
adult walking behavior	1	247.8×	0.008	CHD7
positive regulation of multicellular organism growth	1	247.8×	0.008	CHD7
sprouting angiogenesis	1	240.7×	0.008	SEMA3E

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
CHD7	0	0
SEMA3E	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	1	SEMA3E
E	Difficult family or no structure, no drug	1	CHD7

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)
CHD7	0	—
SEMA3E	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.