Abstract:

Objective: The combined sequencing techniques were used in a case of Ellis-van Creveld syndrome (EVC syndrome) to test the genetic variants, so as to provide a basis for genetic consulting. Methods: Ultrasound examination of a fetus at 24 weeks of gestation showed the fetal six fingers behind hands′ axis, short limb of long bone, heart malformation, aortic arch constriction and other malformations. The amniotic fluid and parental peripheral bloods were collected and genomic DNAs were extracted. The high-throughput sequencing platform was used to perform Trio-whole exome sequencing (Trio-WES) and low-depth whole genome copy number variation sequencing (CNV-seq). Positive variants were verified by Sanger sequencing and real-time quantitative polymerase chain reaction. Results: The Trio-WES showed that there were compound heterozygous variants of EVC2 gene in fetus: c.682G>C(p.A228P) homozygous variation and loss1(Exon:2-22)all heterozygous loss. Two EVC2 gene variants were inherited from parents. According to the American College of Medical Genetics and Genomics (ACMG): c.682G>C(p.A228P) and loss1(Exon:2-22)all caused likely pathogenic variations: PM1+PM2_Supporting+PM3+PP4 and PVS1+PM2_Supporting. Conclusions: The compound heterozygous c.682G>C(p.A228P) and loss1(Exon:2-22)all variants of the EVC2 gene probably underlay the EVC syndrome in this fetus. Above two variations were new mutations, which enriched the mutational spectrum of the EVC2 gene. At the same time, it provided the theoretical basis for the prenatal genetic consultation.

Key words: Ellis-van Creveld syndrome, Whole exome sequencing, Genetic counseling, Mutation, EVC2 gene