WNT5A – Autosomal Dominant Robinow Syndrome

Autosomal dominant Robinow syndrome is a rare skeletal dysplasia characterized by mesomelic limb shortening, distinctive facial features resembling a fetal face, genital hypoplasia, and vertebral anomalies. Heterozygous mutations in WNT5A have been repeatedly identified in individuals with this phenotype, including both familial and de novo cases, establishing WNT5A as the causative gene for the autosomal dominant form of Robinow syndrome ([MONDO:0008389]).

Clinical Validity

WNT5A demonstrates a Strong level of clinical validity for autosomal dominant Robinow syndrome. Pathogenic heterozygous WNT5A variants have been reported in five unrelated families comprising five probands, including two de novo occurrences and confirmed segregation in the original pedigree ([PMID:24716670], [PMID:19918918]). The recurrent identification of WNT5A mutations in independent cases and concordant phenotypes across kindreds support definitive causality.

Genetic Evidence

Inheritance mode: Autosomal dominant
Segregation: 2 additional affected relatives segregating WNT5A variant
Five probands with novel WNT5A missense mutations have been described in cohorts with autosomal dominant Robinow syndrome, including two de novo cases strengthening causality ([PMID:24716670]). The reported mutations disrupt conserved cysteines and other residues critical for ligand structure. One representative variant is c.206G>A (p.Cys69Tyr).

Variant Spectrum

Variants in WNT5A underlying this syndrome are exclusively heterozygous missense changes affecting highly conserved cysteine residues and tyrosines within the mature ligand. To date, four distinct cysteine-disrupting alleles and one tyrosine substitution have been reported, without evidence of loss-of-function truncating alleles, suggesting a dominant-negative or neomorphic effect.

Functional Evidence

Functional assays in zebrafish and Xenopus demonstrate that WNT5A missense mutations reduce noncanonical Wnt-5a signaling activity in vivo ([PMID:19918918]). Neomorphic dominant interference effects were further established by chicken embryo mandibular injections of WNT5A Cys83Ser and Cys182Arg variants, which disrupted chondrocyte polarity, migration, and JNK-PCP signaling despite preserved receptor binding ([PMID:28662348]). Together these studies provide Moderate experimental evidence for a dominant-negative mechanism in skeletal development.

Integration and Conclusion

Genetic and experimental findings converge to implicate heterozygous missense alterations in WNT5A as causal for autosomal dominant Robinow syndrome via disruption of noncanonical Wnt-PCP signaling. The consistent phenotypic presentation across unrelated families, de novo mutation occurrences, and mechanistic in vivo assays satisfy ClinGen criteria for a Strong gene–disease association. Further genotype–phenotype studies may refine variant interpretation and guide molecular diagnosis.

Key Take-home: Heterozygous missense mutations in WNT5A cause autosomal dominant Robinow syndrome through dominant-negative disruption of Wnt-5a–mediated planar cell polarity, supporting clinical genetic testing and potential pathway-directed interventions.

References

• Clinical genetics • 2015 • De novo WNT5A-associated autosomal dominant Robinow syndrome suggests specificity of genotype and phenotype [PMID:24716670]
• Developmental dynamics • 2010 • WNT5A mutations in patients with autosomal dominant Robinow syndrome [PMID:19918918]
• Journal of dental research • 2017 • Abnormal WNT5A Signaling Causes Mandibular Hypoplasia in Robinow Syndrome [PMID:28662348]

Evidence Based Scoring (AI generated)