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Background <p>Weyers acrofacial dysostosis (WAD) is a rare autosomal dominant ciliopathy caused by heterozygous pathogenic variants in the <i>EVC2</i> gene. The classic phenotype includes short stature, dental anomalies, and nail dysplasia. To date, all reported causative variants are truncating mutations located within the last exon (exon 22). In contrast, pathogenic variants in other regions, particularly splice-site variants, remain poorly characterized. The co-occurrence of WAD and epilepsy has rarely been documented.</p> Methods <p>We performed exome sequencing in a proband with comorbid developmental and epileptic encephalopathy (DEE) and WAD features. A candidate splice-site variant was further investigated using an in vitro minigene splicing assay.</p> Results <p>Exome sequencing identified a <i>de novo</i> heterozygous splice-site variant in <i>EVC2</i> (c.451-1G &gt; T). Minigene analysis confirmed that this variant causes complete skipping of exon 4, predicted to lead to an in-frame deletion (p.Tyr151_Leu173del). To our knowledge, this is the first report of a pathogenic splice-site variant in this region of <i>EVC2</i> associated with WAD and DEE.</p> Conclusion <p>Our study expands the mutational spectrum of <i>EVC2</i>. It underscores the utility of exome sequencing coupled with functional assays for diagnosing complex cases.</p>

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A novel EVC2 splice-site variant expands the mutational and phenotypic spectrum of Weyers acrofacial dysostosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月10日

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  • Ai Chen,
  • Wenwen Zhang,
  • Pingping Long,
  • Ximin Chen,
  • Ayuan Zhang,
  • Hui Zhu,
  • Lan Zeng,
  • Fu Xiong,
  • Jin Wang,
  • Shuyao Zhu,
  • Ping Zhou

摘要

Background

Weyers acrofacial dysostosis (WAD) is a rare autosomal dominant ciliopathy caused by heterozygous pathogenic variants in the EVC2 gene. The classic phenotype includes short stature, dental anomalies, and nail dysplasia. To date, all reported causative variants are truncating mutations located within the last exon (exon 22). In contrast, pathogenic variants in other regions, particularly splice-site variants, remain poorly characterized. The co-occurrence of WAD and epilepsy has rarely been documented.

Methods

We performed exome sequencing in a proband with comorbid developmental and epileptic encephalopathy (DEE) and WAD features. A candidate splice-site variant was further investigated using an in vitro minigene splicing assay.

Results

Exome sequencing identified a de novo heterozygous splice-site variant in EVC2 (c.451-1G > T). Minigene analysis confirmed that this variant causes complete skipping of exon 4, predicted to lead to an in-frame deletion (p.Tyr151_Leu173del). To our knowledge, this is the first report of a pathogenic splice-site variant in this region of EVC2 associated with WAD and DEE.

Conclusion

Our study expands the mutational spectrum of EVC2. It underscores the utility of exome sequencing coupled with functional assays for diagnosing complex cases.