Department of Obstetrics and Gynecology, School of Medicine, Sabzevar University of Medical Sciences, Sabzevar, Iran.
Department of Genetics, Faculty of Biological sciences, Tarbiat Modares University, Tehran, Iran.
J Gene Med. 2020 Jun;22(6):e3175. doi: 10.1002/jgm.3175. Epub 2020 Mar 17.
Ellis-van Creveld syndrome (EvCS) is a rare autosomal recessive skeletal dysplasia that is characterized by short stature, short limbs, short ribs, polydactyly and structural heart defect. Despite locus heterogeneity, in the majority of the cases, the disorder segregates with mutations in the EVC and EVC2 genes, notably mutations with truncating protein as a final sequence. In the present study, we report the prenatal findings and genetic analysis of a terminated pregnancy affected by severe thoracic and skeletal dysplasia.
After detailed physical and clinical examination, whole exome sequencing (WES) was performed and the variant was confirmed by Sanger sequencing.
One homozygote variant in EVC2 gene was identified in the fetus (NM_147127, c.942G>A, p.W314X). The EVC2 gene is strongly associated with EvCS, which is consistent with the sonographic findings of the fetus.
The homozygous p.W314X mutation found in this family was recently reported to be segregated in a consanguineous family originating from Pakistan. The occurrence of the p.W314X mutation in two unrelated families (Iranian and Pakistani) may be the result of an old founder effect or arose because of a mutational hotspot and is supporting evidence for the pathogenicity of this variant. Because skeletal dysplasia belongs to a broad spectrum of syndromes and therefore exhibits considerable background locus and allelic heterogeneity, our report highlights the need for appropriate genetic counseling and supports the feasibility of WES to determine an accurate diagnosis, as well as precise recurrence risk prediction.
Ellis-van Creveld 综合征（EvCS）是一种罕见的常染色体隐性骨骼发育不良，其特征为身材矮小、四肢短小、肋骨短、多趾和结构性心脏缺陷。尽管存在基因座异质性，但在大多数情况下，该疾病与 EVC 和 EVC2 基因突变相关，尤其是具有截断蛋白的突变。在本研究中，我们报告了一例因严重胸骨骼发育不良而终止妊娠的产前发现和遗传分析。
在进行详细的体格检查和临床检查后，对胎儿进行全外显子组测序（WES），并通过 Sanger 测序确认变异。
在胎儿中发现 EVC2 基因中的一个纯合变异（NM_147127，c.942G>A，p.W314X）。EVC2 基因与 EvCS 密切相关，这与胎儿的超声表现一致。
在本家族中发现的纯合 p.W314X 突变最近在一个来自巴基斯坦的近亲家庭中被报道。该 p.W314X 突变在两个无血缘关系的家庭（伊朗和巴基斯坦）中的发生可能是由于一个古老的起始效应，或者是由于突变热点而发生的，这为该变异的致病性提供了支持证据。由于骨骼发育不良属于广泛的综合征谱，因此具有相当大的背景基因座和等位基因异质性，我们的报告强调了进行适当遗传咨询的必要性，并支持 WES 用于确定准确诊断和精确复发风险预测的可行性。
