SERKAL syndrome

Summary

SERKAL syndrome (MONDO:0012734) is a disease caused by WNT4 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: WNT4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 47
• Phenotypes (HPO): 15

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0000104	Renal agenesis	Obligate (100%)
HP:0001510	Growth delay	Obligate (100%)
HP:0001562	Oligohydramnios	Obligate (100%)
HP:0002089	Pulmonary hypoplasia	Obligate (100%)
HP:0012245	Sex reversal	Obligate (100%)
HP:0000036	Abnormality of the penis	Frequent (30-79%)
HP:0000047	Hypospadias	Frequent (30-79%)
HP:0000202	Orofacial cleft	Frequent (30-79%)
HP:0000776	Congenital diaphragmatic hernia	Frequent (30-79%)
HP:0000834	Abnormality of the adrenal glands	Frequent (30-79%)
HP:0001629	Ventricular septal defect	Frequent (30-79%)
HP:0001642	Pulmonic stenosis	Frequent (30-79%)
HP:0004794	Malrotation of small bowel	Frequent (30-79%)
HP:0005343	Hypoplasia of the bladder	Frequent (30-79%)
HP:0030680	Abnormal cardiovascular system morphology	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	SERKAL syndrome
Mondo ID	MONDO:0012734
MeSH	C567517
OMIM	611812
Orphanet	139466
NCIT	C123726
SNOMED CT	723720008
UMLS	C2678492
MedGen	394528
GARD	0010302
Is cancer (heuristic)	no

Also known as: 46,XX Sex reversal with dysgenesis of kidneys Adrenals and lungs · 46,XX SEX reversal with dysgenesis of kidneys, ADRENALS, and lungs · SERKAL · SERKAL syndrome · Sex reversion-kidneys, adrenal and lung dysgenesis syndrome

Data availability: 47 ClinVar variants · 5 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 XX gonadal dysgenesis › SERKAL syndrome

Related subtypes (10): ovarian dysgenesis 2, ovarian dysgenesis 3, ovarian dysgenesis 7, ovarian dysgenesis 1, ovarian dysgenesis 9, ovarian dysgenesis 10, ovarian dysgenesis 8, ovarian dysgenesis 5, ovarian dysgenesis 6, ovarian dysgenesis 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

47 retrieved; paginated sample, class counts are floors:

36 uncertain significance, 4 likely benign, 3 conflicting classifications of pathogenicity, 2 pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3897943	NM_030761.5(WNT4):c.872C>G (p.Thr291Arg)	WNT4	Pathogenic	no assertion criteria provided
6309	NM_030761.5(WNT4):c.341C>T (p.Ala114Val)	WNT4	Pathogenic	no assertion criteria provided
2819959	NM_030761.5(WNT4):c.875G>C (p.Arg292Thr)	WNT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3012437	NM_030761.5(WNT4):c.627C>T (p.His209=)	WNT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3580621	NM_030761.5(WNT4):c.697G>A (p.Ala233Thr)	WNT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1337432	NM_030761.5(WNT4):c.854G>A (p.Arg285His)	WNT4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1971047	NM_030761.5(WNT4):c.238T>C (p.Tyr80His)	WNT4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2144157	NM_030761.5(WNT4):c.277G>A (p.Asp93Asn)	WNT4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2442019	NM_030761.5(WNT4):c.881G>A (p.Arg294His)	WNT4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2478663	NM_030761.5(WNT4):c.1006G>A (p.Val336Ile)	WNT4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2628841	NM_030761.5(WNT4):c.667G>A (p.Ala223Thr)	WNT4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2729471	NM_030761.5(WNT4):c.957G>C (p.Gln319His)	WNT4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3470837	NM_030761.5(WNT4):c.257G>A (p.Arg86His)	WNT4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3580569	NM_030761.5(WNT4):c.935G>A (p.Gly312Asp)	WNT4	Uncertain significance	criteria provided, single submitter
3580574	NM_030761.5(WNT4):c.911A>G (p.Asp304Gly)	WNT4	Uncertain significance	criteria provided, single submitter
3580591	NM_030761.5(WNT4):c.845A>G (p.Gln282Arg)	WNT4	Uncertain significance	criteria provided, single submitter
3580597	NM_030761.5(WNT4):c.823C>T (p.Pro275Ser)	WNT4	Uncertain significance	criteria provided, single submitter
3580603	NM_030761.5(WNT4):c.819G>A (p.Leu273=)	WNT4	Uncertain significance	criteria provided, single submitter
3580610	NM_030761.5(WNT4):c.774C>T (p.Arg258=)	WNT4	Uncertain significance	criteria provided, single submitter
3580635	NM_030761.5(WNT4):c.633G>C (p.Val211=)	WNT4	Uncertain significance	criteria provided, single submitter
3580645	NM_030761.5(WNT4):c.610G>C (p.Val204Leu)	WNT4	Uncertain significance	criteria provided, single submitter
3580651	NM_030761.5(WNT4):c.607C>T (p.Arg203Trp)	WNT4	Uncertain significance	criteria provided, single submitter
3580656	NM_030761.5(WNT4):c.589-12C>T	WNT4	Uncertain significance	criteria provided, single submitter
3580665	NM_030761.5(WNT4):c.577G>T (p.Ala193Ser)	WNT4	Uncertain significance	criteria provided, single submitter
3580674	NM_030761.5(WNT4):c.466T>G (p.Ser156Ala)	WNT4	Uncertain significance	criteria provided, single submitter
3580679	NM_030761.5(WNT4):c.445+7G>A	WNT4	Uncertain significance	criteria provided, single submitter
3580687	NM_030761.5(WNT4):c.380C>T (p.Ala127Val)	WNT4	Uncertain significance	criteria provided, single submitter
3580695	NM_030761.5(WNT4):c.377G>A (p.Arg126Gln)	WNT4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3580702	NM_030761.5(WNT4):c.376C>T (p.Arg126Trp)	WNT4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3580712	NM_030761.5(WNT4):c.351G>A (p.Ser117=)	WNT4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 3 · 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
WNT4	Strong	Autosomal recessive	SERKAL syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WNT4	Orphanet:139466	SERKAL syndrome
WNT4	Orphanet:247768	Müllerian aplasia and hyperandrogenism
WNT4	Orphanet:2578	Mayer-Rokitansky-Küster-Hauser syndrome type 2

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
WNT4	HGNC:12783	ENSG00000162552	P56705	Protein Wnt-4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WNT4	Protein Wnt-4	Ligand for members of the frizzled family of seven transmembrane receptors.

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)
WNT4	Other/Unknown	no		Wnt, Wnt4, Wnt_CS

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
decidua	1
islet of Langerhans	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WNT4	177	broad	marker	islet of Langerhans, decidua, type B pancreatic cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WNT4	2,347

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
WNT4	P56705	91.41

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Nephron development	1	878.5×	0.003	WNT4
Negative regulation of TCF-dependent signaling by WNT ligand antagonists	1	713.8×	0.003	WNT4
Transcriptional regulation of testis differentiation	1	713.8×	0.003	WNT4
WNT ligand biogenesis and trafficking	1	423.0×	0.004	WNT4
PCP/CE pathway	1	300.5×	0.005	WNT4
Class B/2 (Secretin family receptors)	1	190.3×	0.006	WNT4
TCF dependent signaling in response to WNT	1	117.7×	0.008	WNT4

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
female sex determination	1	16852.0×	6e-04	WNT4
negative regulation of testicular blood vessel morphogenesis	1	16852.0×	6e-04	WNT4
metanephric nephron morphogenesis	1	16852.0×	6e-04	WNT4
negative regulation of male gonad development	1	16852.0×	6e-04	WNT4
positive regulation of cortisol biosynthetic process	1	16852.0×	6e-04	WNT4
negative regulation of androgen biosynthetic process	1	16852.0×	6e-04	WNT4
embryonic epithelial tube formation	1	8426.0×	8e-04	WNT4
renal vesicle formation	1	8426.0×	8e-04	WNT4
metanephric tubule formation	1	8426.0×	8e-04	WNT4
positive regulation of aldosterone biosynthetic process	1	5617.3×	8e-04	WNT4
tertiary branching involved in mammary gland duct morphogenesis	1	5617.3×	8e-04	WNT4
positive regulation of dermatome development	1	5617.3×	8e-04	WNT4
somatotropin secreting cell differentiation	1	4213.0×	8e-04	WNT4
paramesonephric duct development	1	4213.0×	8e-04	WNT4
renal vesicle induction	1	4213.0×	8e-04	WNT4
meiotic nuclear division	1	4213.0×	8e-04	WNT4
negative regulation of testosterone biosynthetic process	1	4213.0×	8e-04	WNT4
negative regulation of steroid biosynthetic process	1	3370.4×	8e-04	WNT4
immature T cell proliferation in thymus	1	3370.4×	8e-04	WNT4
metanephric mesenchymal cell differentiation	1	3370.4×	8e-04	WNT4
pericyte cell differentiation	1	3370.4×	8e-04	WNT4
positive regulation of meiotic nuclear division	1	2808.7×	9e-04	WNT4
thyroid-stimulating hormone-secreting cell differentiation	1	2808.7×	9e-04	WNT4
mammary gland epithelium development	1	1872.4×	0.001	WNT4
Sertoli cell differentiation	1	1532.0×	0.002	WNT4
mesenchymal to epithelial transition	1	1532.0×	0.002	WNT4
negative regulation of wound healing	1	1296.3×	0.002	WNT4
regulation of cell-cell adhesion	1	1203.7×	0.002	WNT4
negative regulation of fibroblast growth factor receptor signaling pathway	1	1053.2×	0.002	WNT4
oocyte development	1	936.2×	0.002	WNT4

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
WNT4	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	WNT4

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)
WNT4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.