Paediatric disorders - additional genes

Gene: WNT4

Green List (high evidence)

Comment on list classification: Comment on list classification: There are four 46,XX female individuals reported in literature with heterozygous missense variants in WNT4 and Müllerian-duct regression, primary amenorrhea, and hyperandrogenism, with no other congential anomalies (rated Amber on Differences in sex development). There are also 2 families reported with homozygous missense WNT4 variants and '46,XX Sex reversal with dysgenesis of kidneys Adrenals and lungs' (SERKAL) syndrome. Common clinical features included cleft lip/palate, renal agenesis, and congenital diaphragmatic hernia. Heterozygous parents were unaffected in these reports. There is good functional evidence from mouse models linking WNT4 deficiency to female sex reversal, renal malformations, and cleft palate. Based on available evidence, WNT4 can be rated Green on R27 Paediatric disorders - additional genes, with MOI set to BIALLELIC, autosomal or pseudoautosomal.

Created: 3 Nov 2026, 11:05 a.m. | Last Modified: 3 Nov 2026, 11:05 a.m.

Panel Version: 8.27

BIALLELIC REPORTS:
PMID: 40992710 Hernández-García et al., 2025
Study identified a consanguineous Afghan family with SERKAL syndrome. Parents were second cousins, healthy. First pregnancy was complicated by oligohydramnios and the male fetus was found to have unilateral renal agenesis. He died shortly after delivery. Their second pregnancy resulted in a miscarriage at 8 weeks gestation.
During the third pregnancy, ultrasound examination of a male fetus at 21 weeks gestation was suggestive of renal agenesis - pregnancy was terminated. Autopsy showed contractures, bilateral agenesis of the diaphragm, pulmonary hypoplasia, bilateral renal hypoplasia with cystic dysplasia, agenesis of the right adrenal, and marked hypoplasia of the left adrenal. Clinical trio exome showed the fetus was homozygous for WNT4: c.872C>G, p.(Thr291Arg). Variant not reported in gnomAD v4.1.2.
Functional evidence: Wnt4−/− mouse embryos do not have cleft lip and/or palate as seen in humans with SERKAL syndrome. Their palatal defects are limited to soft palate clefts. Ventricular septal defects were present in (8/18) of the Wnt4−/− mouse embryos / pups, and not present in any of the WT controls.

PMID: 18179883 Mandel et al., 2008
Described a consanguineous kindred in which a pair of siblings and their spouses had three pregnancies terminated at 19-24 weeks gestation due to ultrasound findings suggestive of renal agenesis. Autopsies performed on these fetuses revealed largely overlapping features that included 46,XX sex reversal and dysgenesis of the kidneys, adrenals, and lungs. Other reported anomalies included VSD and pulmonary artery stenosis (n = 1), congenital diaphragmatic hernia (n = 1), and orofacial clefting (n = 2). A homozygous WNT4 variant c.341C>T, p.(Ala114Val) was identified as causal. Variant not reported in gnomAD v4.1.2.

MONOALLELIC REPORTS:
PMID: 22503279 Chang et al., 2012
Study screened WNT4 for mutation in 189 Chinese women with Müllerian duct abnormalities. Only one novel synonymous mutation (c.1091G>A) in exon 5 and one known single-nucleotide polymorphism (rs16826648) in exon 2 were found. Authors conclude that "mutations in WNT4 are not responsible for Müllerian duct abnormalities in Chinese women".

PMID: 21377155 Philibert et al., 2011
Report of four 46,XX adolescent girls with Mayer-Rokitansky-Küster-Hauser syndrome and hyperandrogenism. Direct sequencing of WNT4 identified a new mutation c.697G>A, p.Ala233Thr in patient 1. This variant is present in a heterozygous state in 97 individuals in gnomAD v4.1.2, VUS/LB in ClinVar.

PMID: 18182450 Philibert et al., 2008
Report of a cohort of 28 adolescent French girls with primary amenorrhea and müllerian duct abnormalities. Only one individual presented with hyperandrogenism. This proband presented with primary amenorrhea and hyperandrogenism (severe acne and plasma testosterone: 1.8 vs. 1.2 nmol/liter in controls). She also presented with uterine hypoplasia and follicle depletion. WNT4: c.35T>C, p.Leu12Pro variant was identified. Present in 1 XX individual in gnomAD v4.1.2. Method: direct WNT4 sequencing.

PMID: 16959810 Biason-Lauber et al., 2007
Case report of a 19-year-old woman affected by primary amenorrhoea, absence of Müllerian ducts derivatives, clinical (acne and hirsutism) and biochemical (repeatedly high levels of testosterone) signs of androgen excess. Direct sequencing of WNT4 identified a heterozygous WNT4 p.Arg83Cys change.

PMID: 15317892 Biason-Lauber et al., 2004
Report of an 18yo 46,XX woman with Müllerian-duct regression and virilization, primary amenorrhea, and unilateral renal agenesis. Direct sequencing of WNT4 detected a heterozygous p.Glu226Gly variant (NM_030761.5: c.647A>G, p.Glu216Gly) - not in gnomAD v4. No mention of family history / variant segregation.

FUNCTIONAL EVIDENCE:
PMID: 15932923 Heikkilä et al., 2005 - Testosterone was found to be produced by the ovary of Wnt-4-deficient female mouse embryos and is also detected in the embryonic plasma. The results imply Wnt-4 signaling normally acts to suppress testosterone biosynthesis.
PMID: 9989404 Vainio et al., 1999 - mouse model; sexual development in males with a mutation in Wnt-4 appears to be normal; however, Wnt-4-mutant females are masculinized-the Mullerian duct is absent while the Wolffian duct continues to develop. Mice homozygous for a Wnt4 mutation died of kidney failure shortly after birth.

WNT4 is associated with AR SERKAL syndrome, OMIM:611812 and AD Mullerian aplasia and hyperandrogenism, OMIM:158330. Both associations are rated Strong on the DD G2P panel. Resources accessed 3rd Nov 2026.
Sources: Literature
Sources: Literature

Created: 3 Nov 2026, 10:57 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
SERKAL syndrome, OMIM:611812; SERKAL syndrome, MONDO:0012734; 46,XX Sex reversal with dysgenesis of kidneys Adrenals and lungs

Publications

• 9989404
• 15317892
• 15932923
• 16959810
• 18179883
• 18182450
• 21377155
• 22503279
• 40992710