Abstract

Fetal genetic skeletal disorders are common congenital anomalies with notable genetic and phenotypic heterogeneity. Genetic analysis plays an important role in the definitive diagnosis of these skeletal conditions. In the present study, we aimed to determine the causative genetic factors underlying fetal skeletal disorders with shortened limbs (femoral lengths <−2.0 standard deviations) detected by routine second-trimester prenatal ultrasonography in a Chinese family. Whole exome sequencing (WES) analysis identified in trans heterozygous variants in EVC in the affected fetus, including a previously unreported frameshift variant (NM_153717.2: c.130del) and a previously reported variant (NM_153717.2: c.1099_1563del). Combined genetic and clinical information indicated a diagnosis of Ellis-van Creveld (EVC, OMIM 225500) syndrome in the affected fetus. The functional impact of this previously unreported variant on mRNA and protein expression was assessed in vitro using quantitative reverse transcription PCR (RT-qPCR) and Western blot analysis. In vitro RT-qPCR analysis revealed that the c.130del variant did not affect the transcriptional expression of the EVC gene, suggesting the likely absence of nonsense-mediated mRNA decay (NMD). In contrast, Western blot analysis demonstrated the accumulation of truncated protein isoforms, indicating a potential role in the pathogenic mechanism. Preimplantation genetic testing (PGT) was performed on this family for a baby not affected by EVC syndrome or chromosomal aneuploidies. The present study identified and characterized a previously unreported variant in the EVC gene, which has broadened the established mutational spectrum and held notable implications for the clinical management and genetic counseling of families affected by EVC syndrome.