A homozygous EVC mutation in a prenatal fetus with Ellis-van Creveld syndrome.

Background: Ellis-van Creveld (EvC) syndrome, caused by variants in EVC, is a rare genetic skeletal dysplasia. Its clinical phenotype is highly diverse. EvC syndrome is rarely reported in prenatal stages because its presentation overlaps with other diseases.

Methods: A Chinese pedigree diagnosed with EvC syndrome was enrolled in this study. Whole-exome sequencing (WES) was applied in the proband to screen potential genetic variant(s), and then Sanger sequencing was used to identify the variant in family members. Minigene experiments were applied.

Results: WES identified a homozygous variant (NM_153717.3:c.153_174 + 42del) in EVC which was inherited from the heterozygous parents and confirmed by Sanger sequencing. Further experiments demonstrated that this variant disrupts the canonical splicing site and produces a new splicing site at NM_153717.3: c.-164_174del, which ultimately leads to a 337 bp deletion at the 3' end of exon 1 and loss of the start codon.

Conclusion: This is the first reported case of EvC syndrome based on a splicing variant and detailed delineation of the aberrant splicing effect in the fetus. Our study demonstrates the pathogenesis of this new variant, expands the spectrum of EVC mutations, and demonstrates that WES is a powerful tool in the clinical diagnosis of diseases with genetic heterogeneity.