EVC2 – Weyers Acrofacial Dysostosis

Weyers acrofacial dysostosis (WAD) is an ultra-rare autosomal dominant ciliopathy characterized by mild short stature, postaxial polydactyly, nail dysplasia, and dysplastic teeth. Heterozygous truncating variants in the last exon of EVC2 define a distinct allelic disorder from Ellis-van Creveld syndrome, with dominant inheritance and retention of residual protein function.

Genetic evidence for EVC2 in WAD is strong. Three independent heterozygous truncating variants were first reported in individuals with WAD ([PMID:19876929]); two additional families harboring distinct last-exon nonsense changes were described subsequently ([PMID:23220543]); and a novel C-terminal truncating variant was identified in a multigenerational WAD pedigree ([PMID:38531627]). These heterozygous variants segregate with disease in an autosomal dominant pattern and are absent outside the critical exon 22 region.

The variant spectrum in WAD is dominated by premature termination codons clustering in exon 22, including c.2938G>T (p.Glu980Ter) which removes the final 43 amino acids and abolishes critical protein–protein interactions. A recurrent founder variant c.942G>A (p.Trp314Ter) has also been observed in unrelated families, supporting a mutational hotspot in the terminal coding exon.

Functional studies demonstrate that EVC2 C-terminal truncations fail to localize to the basal bodies of primary cilia and significantly impair Hedgehog pathway activation in vitro, mirroring the WAD phenotype in cellular assays ([PMID:19876929]). Murine and cell-based models confirm a dominant-negative mechanism, with truncated Evc2 proteins sequestering EvC complex components and smoothened (SMO), thereby diminishing Hh ligand response.

No conflicting evidence has been reported to date. The concordance of genetic segregation, recurrent variant clustering, and robust functional impairment supports a strong gene–disease relationship. Key take-home: targeted screening of EVC2 exon 22 for heterozygous truncating variants is essential for definitive diagnosis, genetic counseling, and prenatal testing in suspected WAD.

References

• American journal of medical genetics. Part C, Seminars in medical genetics • 2009 • Ellis-van Creveld syndrome and Weyers acrodental dysostosis are caused by cilia-mediated diminished response to hedgehog ligands. PMID:19876929
• European journal of medical genetics • 2013 • Novel and recurrent EVC and EVC2 mutations in Ellis-van Creveld syndrome and Weyers acrofacial dyostosis. PMID:23220543
• Journal of medical genetics • 2024 • Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis. PMID:38531627

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