Ellis-Van Creveld Syndrome: Clinical and Molecular Analysis of 50 Individuals

Area of Science:

• Genetics
• Molecular Biology
• Medical Genetics

Background:

• Ellis-Van Creveld (EVC) syndrome is a skeletal ciliopathy characterized by ectodermal dysplasia, short ribs, polydactyly, and congenital heart defects.
• The condition exhibits significant phenotypic variability, ranging from lethal to mild presentations.
• While EVC and EVC2 are the primary causative genes, other ciliopathy-associated genes (WDR35, GLI1, DYNC2LI1, PRKACA, PRKACB, SMO) are also implicated in EVC pathogenesis, particularly through Hedgehog pathway signaling in primary cilia.

Purpose of the Study:

• To further delineate the phenotype and molecular underpinnings of Ellis-Van Creveld syndrome.
• To analyze a cohort of 50 clinically diagnosed EVC cases from 45 distinct families.

Main Methods:

• Genetic analysis of 50 individuals with clinically diagnosed EVC.
• Variant detection in known EVC-associated genes and other ciliopathy genes.
• Analysis of genotype-phenotype correlations and identification of copy number variations (CNVs).

Main Results:

• A high diagnostic yield of 91.11% was achieved across 45 families.
• Mutations in EVC/EVC2 accounted for the majority of identified variants (77.8%).
• Other identified gene variants included DYNC2H1 (6.7%), DYNC2LI1 (2.2%), SMO (2.2%), and PRKACB (2.2%).
• A significant proportion of heterozygous deletions in EVC/EVC2 (26.92%), often maternally inherited and potentially arising from Alu sequence recombinations, were observed.
• No clear genotype-phenotype correlations were identified.

Conclusions:

• EVC and EVC2 are confirmed as the major genes responsible for Ellis-Van Creveld syndrome.
• The study highlights a high prevalence of previously unreported copy number variations (CNVs) in EVC/EVC2, emphasizing their importance in the syndrome's genetic landscape.