Woodhouse-Sakati syndrome

Summary

Woodhouse-Sakati syndrome (MONDO:0009419) is a disease caused by DCAF17 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DCAF17 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 499
• Phenotypes (HPO): 35
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		25	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0000013	Hypoplasia of the uterus	Very frequent (80-99%)
HP:0000054	Micropenis	Very frequent (80-99%)
HP:0000135	Hypogonadism	Very frequent (80-99%)
HP:0000411	Protruding ear	Very frequent (80-99%)
HP:0000821	Hypothyroidism	Very frequent (80-99%)
HP:0000823	Delayed puberty	Very frequent (80-99%)
HP:0000824	Decreased response to growth hormone stimulation test	Very frequent (80-99%)
HP:0000831	Insulin-resistant diabetes mellitus	Very frequent (80-99%)
HP:0000842	Hyperinsulinemia	Very frequent (80-99%)
HP:0000938	Osteopenia	Very frequent (80-99%)
HP:0001256	Intellectual disability, mild	Very frequent (80-99%)
HP:0001260	Dysarthria	Very frequent (80-99%)
HP:0001266	Choreoathetosis	Very frequent (80-99%)
HP:0001268	Mental deterioration	Very frequent (80-99%)
HP:0001332	Dystonia	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0001596	Alopecia	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0003077	Hyperlipidemia	Very frequent (80-99%)
HP:0005135	Abnormal T-wave	Very frequent (80-99%)
HP:0008209	Premature ovarian insufficiency	Very frequent (80-99%)
HP:0008214	Decreased serum estradiol	Very frequent (80-99%)
HP:0008619	Bilateral sensorineural hearing impairment	Very frequent (80-99%)
HP:0008669	Abnormal spermatogenesis	Very frequent (80-99%)
HP:0008697	Hypoplasia of the fallopian tube	Very frequent (80-99%)
HP:0008734	Decreased testicular size	Very frequent (80-99%)
HP:0010464	Streak ovary	Very frequent (80-99%)
HP:0040171	Decreased serum testosterone concentration	Very frequent (80-99%)
HP:0100840	Aplasia/Hypoplasia of the eyebrow	Very frequent (80-99%)
HP:0000325	Triangular face	Occasional (5-29%)
HP:0000448	Prominent nose	Occasional (5-29%)
HP:0000674	Anodontia	Occasional (5-29%)
HP:0000709	Psychosis	Occasional (5-29%)
HP:0000738	Hallucinations	Occasional (5-29%)
HP:0040189	Scaling skin	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Woodhouse-Sakati syndrome
Mondo ID	MONDO:0009419
MeSH	C536742
OMIM	241080
Orphanet	3464
DOID	DOID:0112264
ICD-11	1893572805
SNOMED CT	237616002
UMLS	C0342286
MedGen	83337
GARD	0005592
Is cancer (heuristic)	no

Also known as: diabetes-hypogonadism-deafness-intellectual disability syndrome · extrapyramidal disorder, progressive, with primary hypogonadism, mental retardation, and alopecia · hypogonadism, alopecia, diabetes mellitus, mental retardation, deafness, and extrapyramidal syndrome · hypogonadism, diabetes mellitus, alopecia, intellectual disability, and electrocardiographic abnormalities · hypogonadism, diabetes mellitus, alopecia, mental retardation, and electrocardiographic abnormalities · woodhouse Sakati syndrome · Woodhouse-Sakati syndrome · woodhouse-Sakati syndrome

Data availability: 499 ClinVar variants · 6 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 › congenital hypogonadotropic hypogonadism › Woodhouse-Sakati syndrome

Related subtypes (24): brachytelephalangy-dysmorphism-Kallmann syndrome, hypogonadotropic hypogonadism 7 with or without anosmia, Prader-Willi syndrome, familial adrenal hypoplasia with absent pituitary luteinizing hormone, cerebellar ataxia-hypogonadism syndrome, CHARGE syndrome, ataxia-hypogonadism-choroidal dystrophy syndrome, Laurence-Moon syndrome, X-linked adrenal hypoplasia congenita, obesity due to prohormone convertase I deficiency, arhinia, choanal atresia, and microphthalmia, ANE syndrome, combined pituitary hormone deficiencies, genetic form, obesity due to congenital leptin deficiency, obesity due to leptin receptor gene deficiency, polyendocrine-polyneuropathy syndrome, hypogonadotropic hypogonadism-frontoparietal alopecia syndrome, hypogonadotropic hypogonadism-retinitis pigmentosa syndrome, Kallmann syndrome-heart disease syndrome, isolated congenital hypogonadotropic hypogonadism, Moebius syndrome-axonal neuropathy-hypogonadotropic hypogonadism syndrome, hypogonadotropic hypogonadism-severe microcephaly-sensorineural hearing loss-dysmorphism syndrome, Prader-Willi-like syndrome, Martsolf syndrome 1

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

499 retrieved; paginated sample, class counts are floors:

252 likely benign, 128 uncertain significance, 38 pathogenic, 36 benign, 21 conflicting classifications of pathogenicity, 13 likely pathogenic, 6 benign/likely benign, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069883	NM_025000.4(DCAF17):c.1091+2T>C	DCAF17	Pathogenic	criteria provided, single submitter
1454737	NM_025000.4(DCAF17):c.60C>A (p.Cys20Ter)	DCAF17	Pathogenic	criteria provided, single submitter
1679361	NM_025000.4(DCAF17):c.1488_1489del (p.Arg496fs)	DCAF17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
209146	NM_025000.4(DCAF17):c.436del (p.Ala147fs)	DCAF17	Pathogenic	criteria provided, multiple submitters, no conflicts
212711	NM_025000.4(DCAF17):c.270del (p.Lys90fs)	DCAF17	Pathogenic	no assertion criteria provided
216916	NM_025000.4(DCAF17):c.289dup (p.Ile97fs)	DCAF17	Pathogenic	criteria provided, multiple submitters, no conflicts
2694507	NM_025000.4(DCAF17):c.1038T>G (p.Tyr346Ter)	DCAF17	Pathogenic	criteria provided, single submitter
2706275	NM_025000.4(DCAF17):c.578dup (p.Arg194fs)	DCAF17	Pathogenic	criteria provided, single submitter
2708844	NM_025000.4(DCAF17):c.308G>A (p.Trp103Ter)	DCAF17	Pathogenic	criteria provided, single submitter
2717550	NM_025000.4(DCAF17):c.535C>T (p.Gln179Ter)	DCAF17	Pathogenic	criteria provided, single submitter
2733750	NM_025000.4(DCAF17):c.413del (p.Gly138fs)	DCAF17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734788	NM_025000.4(DCAF17):c.1068dup (p.His357fs)	DCAF17	Pathogenic	criteria provided, single submitter
2749940	NM_025000.4(DCAF17):c.673_674del (p.Ile225fs)	DCAF17	Pathogenic	criteria provided, single submitter
2771257	NM_025000.4(DCAF17):c.2T>C (p.Met1Thr)	DCAF17	Pathogenic	criteria provided, single submitter
2785333	NM_025000.4(DCAF17):c.705_706del (p.Leu235_Tyr236insTer)	DCAF17	Pathogenic	criteria provided, single submitter
2816473	NM_025000.4(DCAF17):c.894_906del (p.Gly299fs)	DCAF17	Pathogenic	criteria provided, single submitter
2821852	NM_025000.4(DCAF17):c.554_555del (p.His185fs)	DCAF17	Pathogenic	criteria provided, single submitter
2840402	NM_025000.4(DCAF17):c.1271del (p.Phe424fs)	DCAF17	Pathogenic	criteria provided, single submitter
2850434	NM_025000.4(DCAF17):c.539dup (p.Gly181fs)	DCAF17	Pathogenic	criteria provided, single submitter
2862216	NM_025000.4(DCAF17):c.1127del (p.Ser376fs)	DCAF17	Pathogenic	criteria provided, single submitter
2863695	NM_025000.4(DCAF17):c.1097T>A (p.Leu366Ter)	DCAF17	Pathogenic	criteria provided, single submitter
2917250	NM_025000.4(DCAF17):c.1052_1058del (p.Ala351fs)	DCAF17	Pathogenic	criteria provided, single submitter
2960660	NM_025000.4(DCAF17):c.1A>G (p.Met1Val)	DCAF17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3017478	NM_025000.4(DCAF17):c.1A>T (p.Met1Leu)	DCAF17	Pathogenic	criteria provided, single submitter
31580	NM_025000.4(DCAF17):c.387G>A (p.Trp129Ter)	DCAF17	Pathogenic	criteria provided, multiple submitters, no conflicts
31581	NM_025000.4(DCAF17):c.906G>A (p.Trp302Ter)	DCAF17	Pathogenic	criteria provided, multiple submitters, no conflicts
31582	NM_025000.4(DCAF17):c.341C>A (p.Ser114Ter)	DCAF17	Pathogenic	no assertion criteria provided
31583	NM_025000.4(DCAF17):c.127-3_127-1delinsAA	DCAF17	Pathogenic	no assertion criteria provided
3233372	NM_025000.4(DCAF17):c.127-1G>C	DCAF17	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3247167	NC_000002.11:g.(?172291088)(172315007_?)del	DCAF17	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 0 · 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
DCAF17	Strong	Autosomal recessive	Woodhouse-Sakati syndrome	6

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
DCAF17	HGNC:25784	ENSG00000115827	Q5H9S7	DDB1- and CUL4-associated factor 17	gencc,clinvar
METTL8	HGNC:25856	ENSG00000123600	Q9H825	tRNA N(3)-cytidine methyltransferase METTL8, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DCAF17	DDB1- and CUL4-associated factor 17	May function as a substrate receptor for CUL4-DDB1 E3 ubiquitin-protein ligase complex.
METTL8	tRNA N(3)-cytidine methyltransferase METTL8, mitochondrial	Mitochondrial S-adenosyl-L-methionine-dependent methyltransferase that mediates N(3)-methylcytidine modification of residue 32 of the tRNA anticodon loop of mitochondrial tRNA(Ser)(UCN) and tRNA(Thr).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DCAF17	Other/Unknown	no		DCAF17
METTL8	Other/Unknown	no		METTL2/6/8-like, SAM-dependent_MTases_sf, Methyltransf_25

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
adrenal tissue	1
cortical plate	1
male germ line stem cell (sensu Vertebrata) in testis	1
buccal mucosa cell	1
calcaneal tendon	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DCAF17	220	ubiquitous	yes	cortical plate, male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue
METTL8	263	ubiquitous	marker	primordial germ cell in gonad, buccal mucosa cell, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DCAF17	1,488
METTL8	1,140

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DCAF17	Q5H9S7	87.38
METTL8	Q9H825	73.00

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Neddylation	1	47.4×	0.021	DCAF17

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
tRNA C3-cytosine methylation	1	4213.0×	0.002	METTL8
mitochondrial tRNA modification	1	1685.2×	0.002	METTL8
mRNA metabolic process	1	842.6×	0.003	METTL8
positive regulation of mitochondrial translation	1	561.7×	0.003	METTL8
acrosome assembly	1	227.7×	0.006	DCAF17
cell morphogenesis	1	78.8×	0.015	DCAF17
protein ubiquitination	1	20.7×	0.048	DCAF17

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
DCAF17	0	0
METTL8	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	0
E	Difficult family or no structure, no drug	2	DCAF17, METTL8

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)
DCAF17	0	—
METTL8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05522374	Not specified	RECRUITING	TIRCON International NBIA Registry