Hypogonadotropic hypogonadism 27 without anosmia

Summary

Hypogonadotropic hypogonadism 27 without anosmia (MONDO:0030684) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypogonadotropic hypogonadism 27 without anosmia
Mondo ID	MONDO:0030684
OMIM	619755
UMLS	C5676921
MedGen	1810165
GARD	0025611
Is cancer (heuristic)	no

Also known as: HH27 · hypogonadotropic hypogonadism 27 without anosmia

Data availability: 2 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › hypogonadism › hypogonadotropic hypogonadism › hypogonadotropic hypogonadism 27 without anosmia

Related subtypes (9): hypogonadotropic hypogonadism 23 with or without anosmia, hypogonadotropic hypogonadism 24 without anosmia, hypogonadotropic hypogonadism 10 with or without anosmia, hypogonadotropic hypogonadism 12 with or without anosmia, hypogonadotropic hypogonadism 13 with or without anosmia, congenital hypogonadotropic hypogonadism, Kallmann syndrome, hypogonadotropic hypogonadism 25 with anosmia, hypogonadotropic hypogonadism 26 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

2 retrieved; paginated sample, class counts are floors:

2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1803700	NM_006715.4(MAN2C1):c.351+3G>A	MAN2C1	Uncertain significance	criteria provided, single submitter
1326288	NM_005599.3(NHLH2):c.235C>T (p.Arg79Cys)	NHLH2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 2 · 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
NHLH2	Limited	Unknown	hypogonadotropic hypogonadism 27 without anosmia	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NHLH2	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
MAN2C1	Orphanet:528084	Non-specific syndromic intellectual disability

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
NHLH2	HGNC:7818	ENSG00000177551	Q02577	Helix-loop-helix protein 2	gencc,clinvar
MAN2C1	HGNC:6827	ENSG00000140400	Q9NTJ4	Alpha-mannosidase 2C1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NHLH2	Helix-loop-helix protein 2	Transcription factor which binds the E box motif 5’-CA[TC][AG]TG-3'.
MAN2C1	Alpha-mannosidase 2C1	Cleaves alpha 1,2-, alpha 1,3-, and alpha 1,6-linked mannose residues on cytoplasmic free oligosaccharides generated by N-glycoprotein degradation pathways.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Enzyme (other)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NHLH2	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, TAL-like
MAN2C1	Enzyme (other)	yes	3.2.1.24	Glyco_hydro_38_N, Gal_mutarotase_sf_dom, Glyco_hydro/deAcase_b/a-brl

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
buccal mucosa cell	1
dorsal motor nucleus of vagus nerve	1
superior vestibular nucleus	1
adenohypophysis	1
right lobe of thyroid gland	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NHLH2	116	tissue_specific	marker	buccal mucosa cell, dorsal motor nucleus of vagus nerve, superior vestibular nucleus
MAN2C1	230	ubiquitous	marker	right lobe of thyroid gland, adenohypophysis, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAN2C1	1,887
NHLH2	1,019

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MAN2C1	Q9NTJ4	94.84
NHLH2	Q02577	77.76

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 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
Lysosomal oligosaccharide catabolism	1	2855.0×	0.001	MAN2C1
Metabolism of carbohydrates and carbohydrate derivatives	1	120.2×	0.012	MAN2C1
Metabolism	1	11.6×	0.086	MAN2C1

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
hypothalamus gonadotrophin-releasing hormone neuron development	1	4213.0×	0.002	NHLH2
cell migration in hindbrain	1	2808.7×	0.002	NHLH2
ovulation cycle	1	1203.7×	0.002	NHLH2
mannose metabolic process	1	1053.2×	0.002	MAN2C1
male mating behavior	1	1053.2×	0.002	NHLH2
oligosaccharide catabolic process	1	766.0×	0.003	MAN2C1
peripheral nervous system development	1	290.6×	0.006	NHLH2
male gonad development	1	78.0×	0.019	NHLH2
central nervous system development	1	57.7×	0.023	NHLH2
apoptotic process	1	14.3×	0.082	NHLH2
positive regulation of transcription by RNA polymerase II	1	7.4×	0.142	NHLH2
regulation of transcription by RNA polymerase II	1	5.8×	0.164	NHLH2

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
NHLH2	0	0
MAN2C1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MAN2C1	3.2.1.24	alpha-mannosidase

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	MAN2C1
E	Difficult family or no structure, no drug	1	NHLH2

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)
NHLH2	0	—
MAN2C1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.