Identification of Compound Heterozygous Gene Variants in Two Mexican Families with Ellis-van Creveld Syndrome.

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 or genes. To obtain further insight into the genetics of EvCS, we identified the genetic defect for the 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 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.

Conclusion: 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.