PDF(Pubmed)
Abstract：
Ellis-van Creveld syndrome (EvCS) is an autosomal recessive ciliopathy with a disproportionate short stature, polydactyly, dystrophic nails, oral defects, and cardiac anomalies. It is caused by pathogenic variants in the EVC or EVC2 genes. To obtain further insight into the genetics of EvCS, we identified the genetic defect for the EVC2 gene in two Mexican patients.
Two Mexican families were enrolled in this study. Exome sequencing was applied in the probands to screen potential genetic variant(s), and then Sanger sequencing was used to identify the variant in the parents. Finally, a prediction of the three-dimensional structure of the mutant proteins was made.
One patient has a compound heterozygous EVC2 mutation: a novel heterozygous variant c.519_519 + 1delinsT inherited from her mother, and a heterozygous variant c.2161delC (p.L721fs) inherited from her father. The second patient has a previously reported compound heterozygous EVC2 mutation: nonsense mutation c.645G > A (p.W215*) in exon 5 inherited from her mother, and c.273dup (p.K92fs) in exon 2 inherited from her father. In both cases, the diagnostic was Ellis-van Creveld syndrome. Three-dimensional modeling of the EVC2 protein showed that truncated proteins are produced in both patients due to the generation of premature stop codons.
The identified novel heterozygous EVC2 variants, c.2161delC and c.519_519 + 1delinsT, were responsible for the Ellis-van Creveld syndrome in one of the Mexican patients. In the second Mexican patient, we identified a compound heterozygous variant, c.645G > A and c.273dup, responsible for EvCS. The findings in this study extend the EVC2 mutation spectrum and may provide new insights into the EVC2 causation and diagnosis with implications for genetic counseling and clinical management.
Two Mexican families were enrolled in this study. Exome sequencing was applied in the probands to screen potential genetic variant(s), and then Sanger sequencing was used to identify the variant in the parents. Finally, a prediction of the three-dimensional structure of the mutant proteins was made.
One patient has a compound heterozygous EVC2 mutation: a novel heterozygous variant c.519_519 + 1delinsT inherited from her mother, and a heterozygous variant c.2161delC (p.L721fs) inherited from her father. The second patient has a previously reported compound heterozygous EVC2 mutation: nonsense mutation c.645G > A (p.W215*) in exon 5 inherited from her mother, and c.273dup (p.K92fs) in exon 2 inherited from her father. In both cases, the diagnostic was Ellis-van Creveld syndrome. Three-dimensional modeling of the EVC2 protein showed that truncated proteins are produced in both patients due to the generation of premature stop codons.
The identified novel heterozygous EVC2 variants, c.2161delC and c.519_519 + 1delinsT, were responsible for the Ellis-van Creveld syndrome in one of the Mexican patients. In the second Mexican patient, we identified a compound heterozygous variant, c.645G > A and c.273dup, responsible for EvCS. The findings in this study extend the EVC2 mutation spectrum and may provide new insights into the EVC2 causation and diagnosis with implications for genetic counseling and clinical management.
摘要：
背景：Ellis-vanCreveld综合征（EvCS）是一种常染色体隐性遗传性纤毛病，具有不成比例的身材矮小，多指,营养不良的指甲，口腔缺陷,和心脏异常.它是由EVC或EVC2基因中的致病变体引起的。为了进一步了解EvCS的遗传学，我们在两名墨西哥患者中发现了EVC2基因的遗传缺陷.
方法：两个墨西哥家庭被纳入本研究。在先证者中应用外显子组测序来筛选潜在的遗传变异，然后使用Sanger测序来鉴定亲本中的变体。最后,对突变蛋白的三维结构进行了预测。
结果：一名患者具有复合杂合EVC2突变：一种从母亲遗传的新型杂合变体c.519_5191delinsT，和杂合变体c.2161delC（p。L721fs）继承自父亲。第二名患者具有先前报道的复合杂合EVC2突变：无义突变c.645G>A（p。W215*）在外显子5中继承自母亲，和c.273dup（p。K92fs）在外显子2中继承自她的父亲。在这两种情况下，诊断结果是Ellis-vanCreveld综合征.EVC2蛋白的三维建模显示,由于过早终止密码子的产生,在两个患者中产生截短的蛋白。
结论：鉴定的新型杂合EVC2变体，c.2161delC和c.519_519+1delinsT，其中一名墨西哥患者的Ellis-vanCreveld综合征。第二个墨西哥病人,我们确定了一个复合杂合变体，c.645G>A和c.273dup，负责EvCS。这项研究的发现扩展了EVC2突变谱，并可能为EVC2因果关系和诊断提供新的见解，对遗传咨询和临床管理具有重要意义。
方法：两个墨西哥家庭被纳入本研究。在先证者中应用外显子组测序来筛选潜在的遗传变异，然后使用Sanger测序来鉴定亲本中的变体。最后,对突变蛋白的三维结构进行了预测。
结果：一名患者具有复合杂合EVC2突变：一种从母亲遗传的新型杂合变体c.519_5191delinsT，和杂合变体c.2161delC（p。L721fs）继承自父亲。第二名患者具有先前报道的复合杂合EVC2突变：无义突变c.645G>A（p。W215*）在外显子5中继承自母亲，和c.273dup（p。K92fs）在外显子2中继承自她的父亲。在这两种情况下，诊断结果是Ellis-vanCreveld综合征.EVC2蛋白的三维建模显示,由于过早终止密码子的产生,在两个患者中产生截短的蛋白。
结论：鉴定的新型杂合EVC2变体，c.2161delC和c.519_519+1delinsT，其中一名墨西哥患者的Ellis-vanCreveld综合征。第二个墨西哥病人,我们确定了一个复合杂合变体，c.645G>A和c.273dup，负责EvCS。这项研究的发现扩展了EVC2突变谱，并可能为EVC2因果关系和诊断提供新的见解，对遗传咨询和临床管理具有重要意义。
