DHH

Summary

DHH (desert hedgehog signaling molecule, HGNC:2865) is a protein-coding gene on chromosome 12q13.12, encoding Desert hedgehog protein (O43323). The C-terminal part of the desert hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity.

This gene encodes a member of the hedgehog family. The hedgehog gene family encodes signaling molecules that play an important role in regulating morphogenesis. This protein is predicted to be made as a precursor that is autocatalytically cleaved; the N-terminal portion is soluble and contains the signalling activity while the C-terminal portion is involved in precursor processing. More importantly, the C-terminal product covalently attaches a cholesterol moiety to the N-terminal product, restricting the N-terminal product to the cell surface and preventing it from freely diffusing throughout the organism. Defects in this protein have been associated with partial gonadal dysgenesis (PGD) accompanied by minifascicular polyneuropathy. This protein may be involved in both male gonadal differentiation and perineurial development.

Source: NCBI Gene 50846 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 145 total — 12 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 41
• MANE Select transcript: NM_021044

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2865
Approved symbol	DHH
Name	desert hedgehog signaling molecule
Location	12q13.12
Locus type	gene with protein product
Status	Approved
Aliases	HHG-3, MGC35145
Ensembl gene	ENSG00000139549
Ensembl biotype	protein_coding
OMIM	605423
Entrez	50846

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000649637

RefSeq mRNA: 1 — MANE Select: NM_021044 NM_021044

CCDS: CCDS8779

Canonical transcript exons

ENST00000649637 — 3 exons

Exon	Start	End
ENSE00000938726	49091128	49091389
ENSE00003832677	49094210	49094801
ENSE00003837656	49086656	49090484

Expression profiles

Bgee: expression breadth ubiquitous, 123 present calls, max score 84.66.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3729 / max 62.2497, expressed in 129 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
130802	0.2428	86
130801	0.0779	29
130799	0.0275	14
130800	0.0247	9

Top tissues by expression

235 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tibial nerve	UBERON:0001323	84.66	gold quality
right testis	UBERON:0004534	76.71	gold quality
left testis	UBERON:0004533	75.92	gold quality
testis	UBERON:0000473	74.50	gold quality
sural nerve	UBERON:0015488	73.49	gold quality
adrenal tissue	UBERON:0018303	65.26	gold quality
parotid gland	UBERON:0001831	60.73	gold quality
heart right ventricle	UBERON:0002080	58.79	gold quality
colonic epithelium	UBERON:0000397	57.03	gold quality
adult organism	UBERON:0007023	56.71	gold quality
smooth muscle tissue	UBERON:0001135	56.68	gold quality
dorsal root ganglion	UBERON:0000044	56.35	silver quality
left coronary artery	UBERON:0001626	56.14	gold quality
metanephric glomerulus	UBERON:0004736	55.97	gold quality
decidua	UBERON:0002450	55.76	gold quality
coronary artery	UBERON:0001621	55.03	gold quality
vermiform appendix	UBERON:0001154	54.65	gold quality
right coronary artery	UBERON:0001625	53.18	gold quality
hindlimb stylopod muscle	UBERON:0004252	53.14	gold quality
cerebellar vermis	UBERON:0004720	52.33	gold quality
nasal cavity epithelium	UBERON:0005384	52.32	gold quality
apex of heart	UBERON:0002098	52.16	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	51.97	gold quality
gall bladder	UBERON:0002110	51.68	gold quality
right lung	UBERON:0002167	51.53	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	51.50	gold quality
caecum	UBERON:0001153	51.42	gold quality
right atrium auricular region	UBERON:0006631	51.22	gold quality
spinal cord	UBERON:0002240	51.04	gold quality
lower esophagus muscularis layer	UBERON:0035833	51.02	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.22

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR2, NR0B1, NR5A1, POU3F1, SOX10

miRNA regulators (miRDB)

114 targeting DHH, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-6817-3P	99.79	68.35	2126

Literature-anchored findings (GeneRIF, showing 21)

• These data demonstrate that DHH is a key molecule in both male gonadal differentiation and perineurial formation in peripheral nerves (PMID:11990454)
• Importance of DHH in mammalian male sexual differentiation, providing extended evidence that DHH constitutes a key gene in gonadal differentiation (PMID:16390857)
• its signal transduction regulates tumor development. (review) (PMID:18788453)
• Hh signaling is important in the pathogenesis of B-CLL and, hence, may be a potential therapeutic target (PMID:19074837)
• We found no significant correlation between the expression of SOX9 and desert hedgehog, and neither SOX9 nor desert hedgehog expression was correlated to the histoprognostic grade in sarcomas. (PMID:21193222)
• Two cases have been described in Indian patients with 46,XY complete gonadal dysgenesis that could be attributable to mutations in the Desert hedgehog (DHH) gene leading to non-functional DHH protein. (PMID:21816240)
• Studies indicate that pathways of Hedgehog (Hh), Wnt and Notch, which regulate development during embryonic life and somatic stem cells (SCs) in the adult organism, can be reactivated in malignancies and support tumor-initiating cells (TIC) scompartment. (PMID:22123293)
• This study demonistrated that Desert hedgehog links transcription factor Sox10 to peripheral nerve development. (PMID:22514309)
• Mutations in DHH are associated with 46,XY pure gonadal dysgenesis and mixed gonadal dysgenesis. (PMID:23786321)
• Findings are unprecedented and indicate that the DHH-RHEBL1 fusion transcript is a novel recurrent feature in the changing landscape of CBFA2T3-GLIS2-positive childhood AML. (PMID:24127550)
• Single nucleotide polymorphism in the DHH gene is associated with bipolar disorder. (PMID:25517604)
• Mutations in DHH play a role in 46,XY gonadal dysgenesis and are associated with seminoma formation and a neuropathy with minifascicle formation. (PMID:25927242)
• Whole-exome sequencing revealed a homozygous variant in DHH leading to the p.Trp173Cys substitution. The relevant Trp residue is conserved, and its alteration was predicted to be deleterious. Molecular dynamics simulations showed that the mutation increases the conformational flexibility of the protein (PMID:28708305)
• Study describes two patients diagnosed with gonadal dysgenesis (GD), both harboring novel DHH compound heterozygous mutations p.[Tyr176*];[Asn337Lysfs*24] and p.[Tyr176*];[Glu212Lys]. While p.(Glu212Lys) retained 50% of its activity and led to a partially abolished DHH auto-processing, p.(Asn337Lysfs*24) resulted in a complete absence of auto-proteolysis. (PMID:30298535)
• Identify Dhh (desert hedgehog) as a downstream effector of Klf2, whose expression in endothelial cells is upregulated by shear stress and decreased by inflammatory cytokines. (PMID:30355159)
• Our findings suggest heterozygous DHH gene variants are unlikely to cause DSD, reaffirming that DHH is an autosomal recessive cause of 46,XY gonadal dysgenesis. (PMID:31018998)
• Defects in the DHH gene have been reported as a very rare cause of Disorders of sex development, and this report increases the number of 46,XY gonadal dysgenesis cases. (PMID:31240586)
• DHH pathogenic variants involved in 46,XY disorders of sex development differentially impact protein self-cleavage and structural conformation. (PMID:32504121)
• Mutations in the desert hedgehog (DHH) gene in the disorders of sexual differentiation and male infertility. (PMID:33712994)
• Distinctive functioning of STARD1 in the fetal Leydig cells compared to adult Leydig and adrenal cells. Impact of Hedgehog signaling via the primary cilium. (PMID:33864885)
• PKNOX1 acts as a transcription factor of DHH and promotes the progression of stomach adenocarcinoma by regulating the Hedgehog signalling pathway. (PMID:37864517)

Cross-species orthologs

24 orthologs

Organism	Symbol	Gene ID
danio_rerio	ihha	ENSDARG00000058733
danio_rerio	ihhb	ENSDARG00000058815
mus_musculus	Dhh	ENSMUSG00000023000
rattus_norvegicus	Dhh	ENSRNOG00000053675
drosophila_melanogaster	hh	FBGN0004644
caenorhabditis_elegans		WBGENE00001690
caenorhabditis_elegans		WBGENE00001691
caenorhabditis_elegans		WBGENE00001692
caenorhabditis_elegans		WBGENE00001693
caenorhabditis_elegans		WBGENE00001694
caenorhabditis_elegans		WBGENE00001695
caenorhabditis_elegans		WBGENE00001696
caenorhabditis_elegans		WBGENE00001697
caenorhabditis_elegans		WBGENE00001698
caenorhabditis_elegans		WBGENE00001699
caenorhabditis_elegans		WBGENE00001700
caenorhabditis_elegans		WBGENE00001702
caenorhabditis_elegans		WBGENE00001703
caenorhabditis_elegans		WBGENE00006949
caenorhabditis_elegans		WBGENE00006950
caenorhabditis_elegans		WBGENE00006951
caenorhabditis_elegans		WBGENE00006952
caenorhabditis_elegans		WBGENE00006953
caenorhabditis_elegans		WBGENE00006954

Paralogs (2): IHH (ENSG00000163501), SHH (ENSG00000164690)

Protein

Protein identifiers

Desert hedgehog protein — O43323 (reviewed: O43323)

Alternative names: HHG-3

All UniProt accessions (1): O43323

UniProt curated annotations — full annotation on UniProt →

Function. The C-terminal part of the desert hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity. Both activities result in the cleavage of the full-length protein into two parts (N-product and C-product) followed by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-product (DHH-N). Both activities occur in the endoplasmic reticulum. Once cleaved, the C-product is degraded in the endoplasmic reticulum. Functions in cell-cell mediated juxtacrine signaling. Promotes endothelium integrity. Binds to PTCH1 receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes in endothelial cells. In Schwann cells, controls the development of the peripheral nerve sheath and the transition of mesenchymal cells to form the epithelium-like structure of the perineurial tube. The dually lipidated desert hedgehog protein N-product is essential for a variety of patterning events during development. Binds to the patched (PTCH1) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. Required for normal testis development and spermatogenesis, namely for the formation of adult-type Leydig cells and normal development of peritubular cells and seminiferous tubules. Activates primary cilia signaling on neighboring valve interstitial cells through a paracrine mechanism. May induce motor neurons in lateral neural tube and may have a polarizing activity. Prevents the desert hedgehog protein precursor binding to PTCH1.

Subunit / interactions. Multimer. Interacts with BOC and CDON. Interacts with HHIP.

Subcellular location. Cell membrane Endoplasmic reticulum membrane. Golgi apparatus membrane. Secreted. Cell membrane.

Post-translational modifications. Partially autoproteolyzed. The C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity. Both activities result in the cleavage of the full-length protein into two parts (N-product and C-product) followed by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-product (DHH-N). DHH-N is the active species, whereas the C-product is degraded in the endoplasmic reticulum. N-palmitoylation by HHAT is required for desert hedgehog protein N-product multimerization and full activity.

Disease relevance. 46,XY gonadal dysgenesis with minifascicular neuropathy (GDMN) [MIM:607080] An autosomal recessive disorder characterized by gonadal dysgenesis associated with polyneuropathy. Genital anomalies include the presence of a testis on one side and a streak or an absent gonad at the other, persistence of Muellerian duct structures, and a variable degree of genital ambiguity. The disease may be caused by variants affecting the gene represented in this entry. 46,XY sex reversal 7 (SRXY7) [MIM:233420] A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females. SRXY7 patients have no functional gonads. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. Binds calcium and zinc ions; this stabilizes the protein fold and is essential for protein-protein interactions mediated by this domain. The C-terminal domain regulates the auto-processing and controls the juxtacrine signaling.

Similarity. Belongs to the hedgehog family.

RefSeq proteins (1): NP_066382* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000320	Hedgehog_signalling_dom	Domain
IPR001657	Hedgehog	Family
IPR001767	Hedgehog_Hint	Domain
IPR003586	Hint_dom_C	Domain
IPR003587	Hint_dom_N	Domain
IPR009045	Zn_M74/Hedgehog-like	Homologous_superfamily
IPR036844	Hint_dom_sf	Homologous_superfamily
IPR050387	Hedgehog_Signaling	Family

Pfam: PF01079, PF01085

Catalyzed reactions (Rhea), 1 shown:

• glycyl-L-cysteinyl-[protein] + cholesterol + H(+) = [protein]-C-terminal glycyl cholesterol ester + N-terminal L-cysteinyl-[protein] (RHEA:59504)

UniProt features (41 total): binding site 12, strand 7, helix 7, site 4, sequence variant 3, chain 2, lipid moiety-binding region 2, signal peptide 1, mutagenesis site 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
2WFQ	X-RAY DIFFRACTION	1.85
3N1G	X-RAY DIFFRACTION	1.9
2WFR	X-RAY DIFFRACTION	1.95
2WG3	X-RAY DIFFRACTION	2.6
3N1Q	X-RAY DIFFRACTION	2.89

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43323-F1	84.87	0.53

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (4): 198–199 (cleavage; by autolysis); 244 (involved in cholesterol transfer); 268 (involved in auto-cleavage); 271 (essential for auto-cleavage)

Ligand- & substrate-binding residues (12): 130; 132; 141; 148; 183; 90; 91; 91; 96; 126; 127; 127

Post-translational modifications (2): 23, 198

Mutagenesis-validated functional residues (1):

Position	Phenotype
23	loss of palmitoylation.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-373080	Class B/2 (Secretin family receptors)
R-HSA-5358346	Hedgehog ligand biogenesis
R-HSA-5362798	Release of Hh-Np from the secreting cell
R-HSA-5632681	Ligand-receptor interactions
R-HSA-5632684	Hedgehog ‘on’ state
R-HSA-5635838	Activation of SMO
R-HSA-5658034	HHAT G278V doesn’t palmitoylate Hh-Np
R-HSA-9690406	Transcriptional regulation of testis differentiation

MSigDB gene sets: 267 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_RESPONSE_TO_ESTRADIOL, KEGG_HEDGEHOG_SIGNALING_PATHWAY, LFA1_Q6, GOBP_MALE_SEX_DETERMINATION, GOBP_SEX_DETERMINATION, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_MALE_GAMETE_GENERATION, AAAYRNCTG_UNKNOWN, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_PROTEIN_MATURATION, GOBP_LEYDIG_CELL_DIFFERENTIATION, GOBP_REPRODUCTIVE_SYSTEM_DEVELOPMENT

GO Biological Process (17): osteoblast differentiation (GO:0001649), cell fate specification (GO:0001708), smoothened signaling pathway (GO:0007224), cell-cell signaling (GO:0007267), spermatid development (GO:0007286), regulation of gene expression (GO:0010468), protein autoprocessing (GO:0016540), male sex determination (GO:0030238), response to estradiol (GO:0032355), Leydig cell differentiation (GO:0033327), myelination (GO:0042552), response to estrogen (GO:0043627), positive regulation of smoothened signaling pathway (GO:0045880), regulation of steroid biosynthetic process (GO:0050810), self proteolysis (GO:0097264), proteolysis (GO:0006508), multicellular organism development (GO:0007275)

GO Molecular Function (9): patched binding (GO:0005113), calcium ion binding (GO:0005509), peptidase activity (GO:0008233), zinc ion binding (GO:0008270), cholesterol-protein transferase activity (GO:0140853), protein binding (GO:0005515), transferase activity (GO:0016740), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (8): Golgi membrane (GO:0000139), obsolete extracellular space (GO:0005615), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), extracellular region (GO:0005576), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signaling by Hedgehog	2
Hedgehog ‘on’ state	2
GPCR ligand binding	1
Hedgehog ligand biogenesis	1
Hh mutants abrogate ligand secretion	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell differentiation	2
catalytic activity, acting on a protein	2
catalytic activity	2
cellular anatomical structure	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
ossification	1
cell fate commitment	1
cellular developmental process	1
cell surface receptor signaling pathway	1
cell communication	1
signaling	1
germ cell development	1
spermatid differentiation	1
gene expression	1
regulation of macromolecule biosynthetic process	1
protein processing	1
multicellular organism development	1
sex determination	1
response to lipid	1
response to oxygen-containing compound	1
developmental process involved in reproduction	1
male gonad development	1
axon ensheathment	1
response to hormone	1
smoothened signaling pathway	1
regulation of smoothened signaling pathway	1
positive regulation of signal transduction	1
steroid biosynthetic process	1
regulation of steroid metabolic process	1
regulation of lipid biosynthetic process	1
proteolysis	1
protein metabolic process	1
multicellular organismal process	1
anatomical structure development	1
signaling receptor binding	1
metal ion binding	1
hydrolase activity	1
transition metal ion binding	1

Protein interactions and networks

STRING

1791 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DHH	PTCH1	Q13635	998
DHH	PTCH2	Q9Y6C5	995
DHH	HHIP	Q96QV1	965
DHH	SMO	Q99835	924
DHH	GLI1	P08151	832
DHH	GLI2	P10070	807
DHH	GLI3	P10071	799
DHH	SUFU	Q9UMX1	795
DHH	CDON	Q4KMG0	709
DHH	GAS1	P54826	697
DHH	SRY	Q05066	687
DHH	CYP17A1	P05093	640
DHH	CYP11A1	P05108	636
DHH	SOX9	P48436	624
DHH	NR5A1	Q13285	605

IntAct

13 interactions, top by confidence:

A	B	Type	Score
HHIP	DHH	psi-mi:“MI:0407”(direct interaction)	0.650
DHH	BOC	psi-mi:“MI:0407”(direct interaction)	0.560
DHH	CDON	psi-mi:“MI:0407”(direct interaction)	0.560
DHH	HSPA5	psi-mi:“MI:0914”(association)	0.530
HHIP	DHH	psi-mi:“MI:0915”(physical association)	0.400
DHH	NME6	psi-mi:“MI:0914”(association)	0.350
DHH	MANBA	psi-mi:“MI:0914”(association)	0.350

BioGRID (45): RPIA (Affinity Capture-MS), TSSC1 (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), WBSCR16 (Affinity Capture-MS), FKBP14 (Affinity Capture-MS), NME6 (Affinity Capture-MS), RPIA (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), FKBP14 (Affinity Capture-MS), CCDC132 (Affinity Capture-MS), WBSCR16 (Affinity Capture-MS), TSSC1 (Affinity Capture-MS), SEMG1 (Affinity Capture-MS), GPX8 (Affinity Capture-MS), SEPN1 (Affinity Capture-MS)

ESM2 similar proteins: A1A4L8, A2BDX3, A4RPM5, A5GFZ6, A6NK58, B4FAT0, B4NXF7, B6TNK6, O19179, O43323, O95396, O95571, P19971, P55203, P85971, Q02846, Q05922, Q08DH8, Q0VFH3, Q14BV6, Q17CA7, Q1WNP0, Q3KQV9, Q3TW96, Q3UQ84, Q561R2, Q58E95, Q5PQQ1, Q5ZKI2, Q61488, Q66JK4, Q6PAT0, Q7PY41, Q86U10, Q8AWD2, Q8NFV4, Q8VBZ0, Q8VDG5, Q923K4, Q96EY9

Diamond homologs: B3LV44, B3P7F8, B4G2I8, B4HFB7, B4JTF5, B4K4M0, B4LZT9, B4NJP3, B4PN49, B4R1D8, O13215, O13220, O13226, O13234, O13235, O13238, O13240, O13241, O13243, O13247, O13250, O13253, O43323, P56674, P79682, P79691, P79693, P79696, P79709, P79711, P79712, P79715, P79717, P79719, P79729, P79838, P79839, P79850, P79852, P79853

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

145 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	7
Uncertain significance	81
Likely benign	25
Benign	15

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
1685695	NM_021044.4(DHH):c.1004T>C (p.Leu335Pro)	Pathogenic
4281675	NM_021044.4(DHH):c.680C>T (p.Ala227Val)	Pathogenic
5010	NM_021044.4(DHH):c.2T>C (p.Met1Thr)	Pathogenic
5011	NM_021044.4(DHH):c.485T>C (p.Leu162Pro)	Pathogenic
5012	NM_021044.4(DHH):c.1086del (p.Leu363fs)	Pathogenic
560406	NM_021044.4(DHH):c.371G>A (p.Arg124Gln)	Pathogenic
561187	NM_021044.4(DHH):c.528C>A (p.Tyr176Ter)	Pathogenic
561188	NM_021044.4(DHH):c.1011del (p.Asn337fs)	Pathogenic
561189	NM_021044.4(DHH):c.528C>G (p.Tyr176Ter)	Pathogenic
981234	NM_021044.4(DHH):c.304-572_492dup	Pathogenic
981235	NM_021044.4(DHH):c.519G>T (p.Trp173Cys)	Pathogenic
981236	NM_021044.4(DHH):c.554C>A (p.Ser185Ter)	Pathogenic
265768	NM_021044.4(DHH):c.1027T>C (p.Cys343Arg)	Likely pathogenic
2690584	NM_021044.4(DHH):c.825dup (p.Ala276fs)	Likely pathogenic
3029074	NM_021044.4(DHH):c.566-2A>G	Likely pathogenic
4081310	NM_021044.4(DHH):c.30del (p.Cys11fs)	Likely pathogenic
4281630	NM_021044.4(DHH):c.802A>G (p.Thr268Ala)	Likely pathogenic
4281674	NM_021044.4(DHH):c.734G>C (p.Arg245Pro)	Likely pathogenic
561190	NM_021044.4(DHH):c.634G>A (p.Glu212Lys)	Likely pathogenic

SpliceAI

512 predictions. Top by Δscore:

Variant	Effect	Δscore
12:49091108:C:CT	donor_gain	1.0000
12:49091121:A:AC	donor_gain	1.0000
12:49091122:C:CC	donor_gain	1.0000
12:49091125:TACCA:T	donor_loss	1.0000
12:49091126:A:AT	donor_loss	1.0000
12:49091127:CCAG:C	donor_gain	1.0000
12:49091133:TTG:T	donor_gain	1.0000
12:49091145:TGG:T	donor_gain	1.0000
12:49091385:CAACG:C	acceptor_gain	1.0000
12:49091388:CG:C	acceptor_gain	1.0000
12:49094204:CCTTA:C	donor_loss	1.0000
12:49094205:CTTAC:C	donor_loss	1.0000
12:49094206:TTACC:T	donor_loss	1.0000
12:49094207:TA:T	donor_loss	1.0000
12:49094208:A:AG	donor_loss	1.0000
12:49094209:C:CG	donor_loss	1.0000
12:49090484:TC:T	acceptor_loss	0.9900
12:49090485:C:CC	acceptor_gain	0.9900
12:49090485:C:CG	acceptor_loss	0.9900
12:49090486:T:A	acceptor_loss	0.9900
12:49091107:ACCAC:A	donor_gain	0.9900
12:49091108:CCACC:C	donor_gain	0.9900
12:49091109:C:CT	donor_gain	0.9900
12:49091109:CACCC:C	donor_gain	0.9900
12:49091111:C:A	donor_gain	0.9900
12:49091122:CTGTA:C	donor_gain	0.9900
12:49091126:A:AC	donor_gain	0.9900
12:49091127:C:CC	donor_gain	0.9900
12:49091130:G:C	donor_gain	0.9900
12:49091190:T:TA	donor_gain	0.9900

AlphaMissense

2494 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:49091148:A:T	V182D	1.000
12:49091384:A:C	C103W	1.000
12:49091146:G:C	H183D	0.999
12:49091180:G:C	F171L	0.999
12:49091180:G:T	F171L	0.999
12:49091181:A:G	F171S	0.999
12:49091182:A:G	F171L	0.999
12:49091188:C:G	A169P	0.999
12:49091196:G:T	A166E	0.999
12:49091247:A:T	I149N	0.999
12:49091263:C:G	G144R	0.999
12:49091306:C:A	W129C	0.999
12:49091306:C:G	W129C	0.999
12:49091308:A:G	W129R	0.999
12:49091308:A:T	W129R	0.999
12:49091325:A:T	L123Q	0.999
12:49091339:C:A	W118C	0.999
12:49091339:C:G	W118C	0.999
12:49091341:A:G	W118R	0.999
12:49091341:A:T	W118R	0.999
12:49091364:A:C	L110W	0.999
12:49091385:C:T	C103Y	0.999
12:49094249:C:A	K88N	0.999
12:49094249:C:G	K88N	0.999
12:49094252:G:C	F87L	0.999
12:49094252:G:T	F87L	0.999
12:49094253:A:C	F87C	0.999
12:49094253:A:G	F87S	0.999
12:49094254:A:G	F87L	0.999
12:49094273:G:C	N80K	0.999

dbSNP variants (sampled 300 via entrez): RS1000390211 (12:49091692 GAGA>G), RS1000405530 (12:49092324 C>G), RS1000467744 (12:49087240 A>G), RS1000540740 (12:49086872 C>T), RS1001560888 (12:49088326 G>A,C), RS1001665033 (12:49095340 G>C), RS1001826941 (12:49090545 A>G), RS1002153370 (12:49090891 G>A,C), RS1002413696 (12:49095055 T>C), RS1002468806 (12:49090188 G>A), RS1003012059 (12:49096305 G>A), RS1003552810 (12:49095554 C>A,T), RS1003926058 (12:49091927 G>A), RS1004621822 (12:49096287 G>C), RS1004631293 (12:49088540 C>T)

Disease associations

OMIM: gene MIM:605423 | disease phenotypes: MIM:233420, MIM:607080

GenCC curated gene-disease

Disease	Classification	Inheritance
46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome	Strong	Autosomal recessive
46,XY complete gonadal dysgenesis	Supportive	Autosomal dominant

Mondo (4): disorder of sexual differentiation (MONDO:0002145), 46,XY sex reversal 7 (MONDO:0009301), 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome (MONDO:0011766), 46,XY complete gonadal dysgenesis (MONDO:0010765)

Orphanet (3): Difference of sex development (Orphanet:90771), 46,XY complete gonadal dysgenesis (Orphanet:242), 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome (Orphanet:168563)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000013	Hypoplasia of the uterus
HP:0000026	Male hypogonadism
HP:0000037	Male pseudohermaphroditism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000055	Abnormal female external genitalia morphology
HP:0000133	Gonadal dysgenesis
HP:0000142	Abnormal vagina morphology
HP:0000147	Polycystic ovaries
HP:0000150	Gonadoblastoma
HP:0000786	Primary amenorrhea
HP:0000789	Infertility
HP:0000815	Hypergonadotropic hypogonadism
HP:0000837	Increased circulating gonadotropin level
HP:0001265	Hyporeflexia
HP:0001271	Polyneuropathy
HP:0001315	Reduced tendon reflexes
HP:0001761	Pes cavus
HP:0002460	Distal muscle weakness
HP:0003130	Abnormal peripheral myelination
HP:0003134	Abnormality of peripheral nerve conduction
HP:0003202	Skeletal muscle atrophy
HP:0003376	Steppage gait
HP:0003380	Decreased number of peripheral myelinated nerve fibers
HP:0003409	Distal sensory impairment of all modalities
HP:0003434	Sensory ataxic neuropathy
HP:0003577	Congenital onset
HP:0006886	Impaired distal vibration sensation
HP:0006937	Impaired distal tactile sensation
HP:0007141	Sensorimotor neuropathy

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001482_8	Lumbar spine bone mineral density	1.000000e-15
GCST002783_440	Body mass index	2.000000e-06
GCST002783_516	Body mass index	1.000000e-06
GCST008103_109	Bipolar disorder	4.000000e-06
GCST010703_9	Brain morphology (MOSTest)	8.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D012734	Disorders of Sex Development	C12.050.351.875.253; C12.200.706.316; C12.800.316; C16.131.939.316; C19.391.119
D006061	Gonadal Dysgenesis, 46,XY	C12.050.351.875.253.096.687; C12.050.351.875.253.309.388; C12.200.706.316.096.687; C12.200.706.316.309.388; C12.800.316.096.687; C12.800.316.309.388; C16.131.939.316.096.687; C16.131.939.316.309.388; C19.391.119.096.687; C19.391.119.309.388
C565537	46,XY Gonadal Dysgenesis, Complete or Partial, DHH-Related (supp.)
C567773	46,Xy Gonadal Dysgenesis, Partial, With Minifascicular Neuropathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Diazinon	increases methylation	1
Oxygen	decreases expression	1
Smoke	decreases expression	1

Clinical trials (associated diseases)

12 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03718234	PHASE1	COMPLETED	Subcutaneous Hydrocortisone Children With Congenital Adrenal Hyperplasia
NCT00485186	Not specified	WITHDRAWN	Gene Polymorphisms Influencing Steroid Synthesis and Action
NCT01875640	Not specified	COMPLETED	Decision Support for Parents Receiving Information About Child’s Rare Disease
NCT02784184	Not specified	UNKNOWN	COPENHAGEN Minipuberty Study
NCT03102554	Not specified	ENROLLING_BY_INVITATION	Genetics of Differences of Sex Development and Hypospadias
NCT03283852	Not specified	RECRUITING	Identifying New Genetic Causes to Development Disorders
NCT04195490	Not specified	UNKNOWN	Evaluation of Outcomes of Feminizing Genitoplasty in Children With Disorders of Sex Development
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04717349	Not specified	RECRUITING	Data Collection Study of Pediatric and Adolescent Gynecology Conditions
NCT05058781	Not specified	RECRUITING	Minipuberty in Infants Born With Potential Hypogonadism Hypogonadotrope
NCT06692049	Not specified	RECRUITING	Gonadal Tissue Cryopreservation for Fertility Preservation in Children with a Disorder of Sex Development
NCT06989593	Not specified	RECRUITING	Breaking Silence Through Story: A Narrative Medicine Intervention for Parents of Children With Urogenital Conditions