Hypogonadotropic hypogonadism 21 with or without anosmia

Summary

Hypogonadotropic hypogonadism 21 with or without anosmia (MONDO:0014107) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypogonadotropic hypogonadism 21 with or without anosmia
Mondo ID	MONDO:0014107
OMIM	615271
DOID	DOID:0090093
UMLS	C3808986
MedGen	815316
GARD	0015933
Is cancer (heuristic)	no

Also known as: FLRT3 hypogonadotropic hypogonadism · HH21 · hypogonadotropic hypogonadism 21 with anosmia · hypogonadotropic hypogonadism 21 with or without anosmia · hypogonadotropic hypogonadism caused by mutation in FLRT3

Data availability: 6 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Kallmann syndrome › hypogonadotropic hypogonadism 21 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 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 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

6 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 1 benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
50865	NM_198391.3(FLRT3):c.1016A>G (p.Lys339Arg)	FLRT3	Pathogenic	no assertion criteria provided
1029224	NM_198391.3(FLRT3):c.1255A>T (p.Thr419Ser)	FLRT3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2441519	NM_198391.3(FLRT3):c.1727C>T (p.Ala576Val)	FLRT3	Uncertain significance	criteria provided, single submitter
3892327	NM_198391.3(FLRT3):c.1166C>T (p.Pro389Leu)	FLRT3	Uncertain significance	criteria provided, single submitter
1710063	NM_198391.3(FLRT3):c.999G>A (p.Met333Ile)	MACROD2	Uncertain significance	criteria provided, single submitter
1226971	NM_198391.3(FLRT3):c.1257C>T (p.Thr419=)	MACROD2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
FLRT3	Limited	Autosomal dominant	hypogonadotropic hypogonadism 21 with or without anosmia	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FLRT3	Orphanet:478	Kallmann 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
FLRT3	HGNC:3762	ENSG00000125848	Q9NZU0	Leucine-rich repeat transmembrane protein FLRT3	gencc,clinvar
MACROD2	HGNC:16126	ENSG00000172264	A1Z1Q3	ADP-ribose glycohydrolase MACROD2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FLRT3	Leucine-rich repeat transmembrane protein FLRT3	Functions in cell-cell adhesion, cell migration and axon guidance, exerting an attractive or repulsive role depending on its interaction partners.
MACROD2	ADP-ribose glycohydrolase MACROD2	Removes ADP-ribose from aspartate and glutamate residues in proteins bearing a single ADP-ribose moiety.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Antibody/Immunoglobulin	1	14.6×	0.135
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FLRT3	Antibody/Immunoglobulin	yes		LRRNT, Cys-rich_flank_reg_C, Leu-rich_rpt
MACROD2	Enzyme (other)	yes	3.1.1.106	Macro_dom, Macro_dom-like

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
endothelial cell	2
lower lobe of lung	1
pericardium	1
buccal mucosa cell	1
epithelial cell of pancreas	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FLRT3	248	ubiquitous	marker	endothelial cell, lower lobe of lung, pericardium
MACROD2	214	ubiquitous	marker	endothelial cell, buccal mucosa cell, epithelial cell of pancreas

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FLRT3	1,353
MACROD2	926

Intra-cohort edges

A	B	Sources
FLRT3	MACROD2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MACROD2	A1Z1Q3	4
FLRT3	Q9NZU0	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Downstream signaling of activated FGFR1	1	543.8×	0.004	FLRT3
Signaling by ROBO receptors	1	124.1×	0.008	FLRT3

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
proepicardium cell migration involved in pericardium morphogenesis	1	8426.0×	0.002	FLRT3
purine nucleoside metabolic process	1	2808.7×	0.002	MACROD2
peptidyl-glutamate ADP-deribosylation	1	2808.7×	0.002	MACROD2
protein de-ADP-ribosylation	1	1685.2×	0.003	MACROD2
embryonic morphogenesis	1	766.0×	0.005	FLRT3
head development	1	601.9×	0.005	FLRT3
obsolete cell-cell adhesion via plasma-membrane adhesion molecules	1	561.7×	0.005	FLRT3
synaptic membrane adhesion	1	290.6×	0.007	FLRT3
neuron projection extension	1	263.3×	0.007	FLRT3
response to axon injury	1	255.3×	0.007	FLRT3
fibroblast growth factor receptor signaling pathway	1	142.8×	0.012	FLRT3
positive regulation of synapse assembly	1	122.1×	0.013	FLRT3
synapse assembly	1	115.4×	0.013	FLRT3
response to bacterium	1	96.8×	0.014	MACROD2
neuron projection development	1	61.1×	0.021	FLRT3
axon guidance	1	45.3×	0.026	FLRT3
brain development	1	39.8×	0.027	MACROD2
heart development	1	39.4×	0.027	FLRT3
DNA damage response	1	26.8×	0.037	MACROD2

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
FLRT3	0	0
MACROD2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MACROD2	4	Binding:2, Toxicity:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MACROD2	3.1.1.106	O-acetyl-ADP-ribose deacetylase

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	2	FLRT3, MACROD2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
FLRT3	0	—
MACROD2	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.