Biallelic mutations in DYNC2LI1 are a rare cause of Ellis-van Creveld syndrome

Clin Genet. 2018 Mar;93(3):632-639. doi: 10.1111/cge.13128. Epub 2018 Jan 24.


Ellis-van Creveld syndrome (EvC) is a chondral and ectodermal dysplasia caused by biallelic mutations in the EVC, EVC2 and WDR35 genes. A proportion of cases with clinical diagnosis of EvC, however, do not carry mutations in these genes. To identify the genetic cause of EvC in a cohort of mutation-negative patients, exome sequencing was undertaken in a family with 3 affected members, and mutation scanning of a panel of clinically and functionally relevant genes was performed in 24 additional subjects with features fitting/overlapping EvC. Compound heterozygosity for the c.2T>C (p.Met1?) and c.662C>T (p.Thr221Ile) variants in DYNC2LI1, which encodes a component of the intraflagellar transport-related dynein-2 complex previously found mutated in other short-rib thoracic dysplasias, was identified in the 3 affected members of the first family. Targeted resequencing detected compound heterozygosity for the same missense variant and a truncating change (p.Val141*) in 2 siblings with EvC from a second family, while a newborn with a more severe phenotype carried 2 DYNC2LI1 truncating variants. Our findings indicate that DYNC2LI1 mutations are associated with a wider clinical spectrum than previously appreciated, including EvC, with the severity of the phenotype likely depending on the extent of defective DYNC2LI1 function.

Keywords: DYNC2LI1; Ellis-van Creveld syndrome; Jeune syndrome; genotype-phenotype correlations; short-rib thoracic dysplasia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles*
  • Child
  • Child, Preschool
  • Cytoplasmic Dyneins / genetics*
  • Ellis-Van Creveld Syndrome / diagnosis*
  • Ellis-Van Creveld Syndrome / genetics*
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Humans
  • Male
  • Mutation*
  • Odds Ratio
  • Pedigree
  • Phenotype
  • Radiography
  • Whole Exome Sequencing
  • Young Adult


  • Cytoplasmic Dyneins
  • DYNC2LI1 protein, human