46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome

Summary

46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome (MONDO:0011766) is a disease caused by DHH (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DHH (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 5
• Phenotypes (HPO): 26

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0000013	Hypoplasia of the uterus	Very frequent (80-99%)
HP:0000026	Male hypogonadism	Very frequent (80-99%)
HP:0000055	Abnormality of female external genitalia	Very frequent (80-99%)
HP:0000133	Gonadal dysgenesis	Very frequent (80-99%)
HP:0000142	Abnormality of the vagina	Very frequent (80-99%)
HP:0000786	Primary amenorrhea	Very frequent (80-99%)
HP:0000789	Infertility	Very frequent (80-99%)
HP:0000837	Increased circulating gonadotropin level	Very frequent (80-99%)
HP:0001271	Polyneuropathy	Very frequent (80-99%)
HP:0001315	Reduced tendon reflexes	Very frequent (80-99%)
HP:0002460	Distal muscle weakness	Very frequent (80-99%)
HP:0003130	Abnormal peripheral myelination	Very frequent (80-99%)
HP:0003134	Abnormality of peripheral nerve conduction	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0003409	Distal sensory impairment of all modalities	Very frequent (80-99%)
HP:0003434	Sensory ataxic neuropathy	Very frequent (80-99%)
HP:0007141	Sensorimotor neuropathy	Very frequent (80-99%)
HP:0008214	Decreased serum estradiol	Very frequent (80-99%)
HP:0008715	Testicular dysgenesis	Very frequent (80-99%)
HP:0008723	Gonadal dysgenesis with female appearance, male	Very frequent (80-99%)
HP:0010464	Streak ovary	Very frequent (80-99%)
HP:0040171	Decreased serum testosterone concentration	Very frequent (80-99%)
HP:0045010	Abnormality of peripheral nerves	Very frequent (80-99%)
HP:0000150	Gonadoblastoma	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0003376	Steppage gait	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome
Mondo ID	MONDO:0011766
MeSH	C567773
OMIM	607080
Orphanet	168563
DOID	DOID:0051055
UMLS	C5436061
MedGen	1727162
GARD	0017034
Is cancer (heuristic)	no

Also known as: 46XY gonadal dysgenesis with minifascicular neuropathy

Data availability: 5 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › hypogonadism › gonadal dysgenesis › 46,XY complete gonadal dysgenesis › 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome

Related subtypes (11): 46,XY sex reversal 4, 46,XY sex reversal 7, 46,XY sex reversal 2, 46,XY sex reversal 3, 46,XY sex reversal 5, 46,XY sex reversal 6, 46,XY disorder of sex development due to testicular 17,20-desmolase deficiency, 46,XY sex reversal 9, 46,XY sex reversal 10, 46,XY sex reversal 1, 46,XY sex reversal 11

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

5 retrieved; paginated sample, class counts are floors:

5 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
5010	NM_021044.4(DHH):c.2T>C (p.Met1Thr)	DHH	Pathogenic	no assertion criteria provided
560406	NM_021044.4(DHH):c.371G>A (p.Arg124Gln)	DHH	Pathogenic	criteria provided, single submitter
981234	NM_021044.4(DHH):c.304-572_492dup	DHH	Pathogenic	no assertion criteria provided
981235	NM_021044.4(DHH):c.519G>T (p.Trp173Cys)	DHH	Pathogenic	no assertion criteria provided
981236	NM_021044.4(DHH):c.554C>A (p.Ser185Ter)	DHH	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
DHH	Strong	Autosomal recessive	46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DHH	Orphanet:168563	46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome
DHH	Orphanet:242	46,XY complete gonadal dysgenesis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DHH	HGNC:2865	ENSG00000139549	O43323	Desert hedgehog protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DHH	Desert hedgehog protein	The C-terminal part of the desert hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DHH	Other/Unknown	no		Hedgehog_signalling_dom, Hedgehog, Hedgehog_Hint

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
left testis	1
right testis	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DHH	123	tissue_specific	yes	tibial nerve, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DHH	1,849

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DHH	O43323	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 1 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
HHAT G278V doesn’t palmitoylate Hh-Np	1	2284.0×	0.002	DHH
Release of Hh-Np from the secreting cell	1	1427.5×	0.002	DHH
Ligand-receptor interactions	1	1427.5×	0.002	DHH
Transcriptional regulation of testis differentiation	1	713.8×	0.003	DHH
Activation of SMO	1	634.4×	0.003	DHH
Hedgehog ligand biogenesis	1	211.5×	0.006	DHH
Class B/2 (Secretin family receptors)	1	190.3×	0.006	DHH
Hedgehog ‘on’ state	1	158.6×	0.006	DHH

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of steroid biosynthetic process	1	1532.0×	0.003	DHH
self proteolysis	1	1532.0×	0.003	DHH
male sex determination	1	1404.3×	0.003	DHH
Leydig cell differentiation	1	1203.7×	0.003	DHH
protein autoprocessing	1	648.1×	0.005	DHH
cell fate specification	1	526.6×	0.005	DHH
positive regulation of smoothened signaling pathway	1	421.3×	0.005	DHH
response to estrogen	1	343.9×	0.005	DHH
myelination	1	251.5×	0.007	DHH
response to estradiol	1	198.3×	0.008	DHH
smoothened signaling pathway	1	181.2×	0.008	DHH
spermatid development	1	145.3×	0.009	DHH
osteoblast differentiation	1	121.2×	0.010	DHH
regulation of gene expression	1	83.4×	0.013	DHH
cell-cell signaling	1	69.6×	0.014	DHH

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
DHH	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	DHH

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DHH	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.