Laboratorio de Genética y Oncología Molecular, Laboratorio 5, Edificio A4, Carrera de Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Mexico.
Laboratorio de Genética, Escuela Nacional de Ciencias Biológicas Zacatenco, Instituto Politécnico Nacional, Ciudad de México 07738, Mexico.
Genes (Basel). 2023 Apr 9;14(4):887. doi: 10.3390/genes14040887.
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 or genes. To obtain further insight into the genetics of EvCS, we identified the genetic defect for the 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 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 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 protein showed that truncated proteins are produced in both patients due to the generation of premature stop codons.
The identified novel heterozygous 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 mutation spectrum and may provide new insights into the causation and diagnosis with implications for genetic counseling and clinical management.
Ellis-van Creveld 综合征（EvCS）是一种常染色体隐性纤毛病，具有不成比例的身材矮小、多指（趾）畸形、营养不良性指甲、口腔缺陷和心脏异常。它是由 或 基因的致病性变异引起的。为了进一步了解 EvCS 的遗传学，我们在两名墨西哥患者中鉴定了 基因的遗传缺陷。
本研究纳入了两个墨西哥家庭。对先证者进行外显子组测序，以筛选潜在的遗传变异，然后用 Sanger 测序鉴定父母的变异。最后，对突变蛋白的三维结构进行预测。
一名患者为复合杂合 突变：从母亲遗传而来的新型杂合变异 c.519_519 + 1delinsT，以及从父亲遗传而来的杂合变异 c.2161delC（p.L721fs）。第二位患者携带先前报道的复合杂合 突变：从母亲遗传而来的exon5 中的无义突变 c.645G > A（p.W215*），以及从父亲遗传而来的exon2 中的 c.273dup（p.K92fs）。两种情况下的诊断均为 Ellis-van Creveld 综合征。对 蛋白的三维建模表明，由于产生了提前终止密码子，两位患者均产生截短蛋白。
在所鉴定的一名墨西哥患者中，新型杂合 变异 c.2161delC 和 c.519_519 + 1delinsT 负责 Ellis-van Creveld 综合征。在第二位墨西哥患者中，我们鉴定出一种复合杂合变异 c.645G > A 和 c.273dup，负责 EvCS。本研究中的发现扩展了 突变谱，可能为 致病原因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。
