Novel mutations in EVC cause aberrant splicing in Ellis-van Creveld syndrome

Area of Science:

• Genetics
• Molecular Biology
• Medical Genetics

Background:

• Ellis-van Creveld syndrome (EvC) is a rare genetic disorder affecting skeletal growth, nails, teeth, and sometimes the heart.
• It is caused by mutations in the EVC or EVC2 genes, with similar phenotypes observed for both.
• Weyers acrofacial dysostosis is a related, milder disorder also linked to these genes.

Purpose of the Study:

• To perform a clinical and molecular analysis of a Chinese family with Ellis-van Creveld syndrome.
• To identify the specific genetic mutations responsible for the syndrome in this family.
• To elucidate the molecular mechanisms by which these mutations lead to the disease.

Main Methods:

• Clinical examination and molecular analysis of a Chinese family.
• DNA sequencing of the EVC and EVC2 genes.
• In vitro minigene expression assay, RT-PCR, and sequencing to analyze splicing defects.

Main Results:

• Two novel heterozygous splice site mutations in the EVC gene (c.384+5G>C and c.1465-1G>A) were identified.
• The c.384+5G>C mutation created a cryptic splice site, and c.1465-1G>A caused exon 11 skipping.
• Both mutations resulted in in-frame abnormal transcripts, likely affecting protein function.
• This is the first report of EVC mutations causing EvC syndrome in the Chinese population.

Conclusions:

• Novel splice site mutations in the EVC gene are responsible for Ellis-van Creveld syndrome in this Chinese family.
• These mutations alter pre-mRNA splicing, leading to abnormal transcripts and contributing to the disease's pathogenesis.
• The findings expand the understanding of EvC syndrome genetics and its molecular basis in diverse populations.