Identification of Compound Heterozygous EVC2 Gene Variants in Two Mexican Families with Ellis–van Creveld Syndrome

Abstract

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Mexican patient with Ellis‐van Creveld syndrome and cleft palate: Importance of functional hemizygosity and phenotype expansion

“…This novel variant was originally reported as likely pathogenic by Negrete‐Torres et al. (2023) in accordance with PVS1 and PM2 criteria. The bioinformatic analysis they did of this variant allowed them to conclude that this variant alters the donor site of exon 4 and creates a premature stop codon, hypothetically generating a truncated protein of 173 amino acids.…”

“…The patient reported by Negrete‐Torres et al. (2023) shows an attenuated phenotype and a delayed diagnosis compared to our patient (Table 1). Although the variants are found in the same EVC2 gene, we could observe the absence of thoracic anomalies, congenital heart disease, and prenatal data in the previously reported patient.…”

“…One of the patients published by Negrete‐Torres et al. (2023) allowed us to make a comparison of this type with our patient because they shared the frameshift variant in EVC2 : c.2161delC p.[(Leu721Trpfs*19)] on one allele and differed in the variant of the second allele. In the patient described by Negrete, a splicing variant is observed in the other allele c.519_519+1delinsT, while our patient had a nonsense variant c.1195C>T p.[(Arg399*)].…”