A relatively mild skeletal ciliopathy phenotype consistent with cranioectodermal dysplasia is associated with a homozygous nonsynonymous mutation in WDR35

Am J Med Genet A. 2016 Mar;170(3):760-5. doi: 10.1002/ajmg.a.37514. Epub 2015 Dec 22.


Ciliopathies are a class of clinically and genetically heterogeneous disorders characterized by deficits of the primary cilium, an important organelle for cellular signaling and development. Here we report on a patient from a consanguineous family presenting with renal cysts, short stature, distinctive facial features, missing teeth, brachydactyly, narrow chest, and abnormal ribs. His phenotype resembled a skeletal ciliopathy and the initial clinical differential diagnosis included Jeune thoracic dystrophy and cranioectodermal dysplasia. Due to the presence of parental consanguinity, a homozygous recessive mutation was the suspected cause and homozygosity mapping was used to direct candidate gene sequencing. WDR35, an intraflagellar transport protein previously associated with cranioectodermal dysplasia, the more severe short rib polydactyly syndrome type V and recently Ellis van Creveld syndrome, is present within a region of homozygosity and sequencing of all coding exons identified a novel homozygous nonsynonymous variant, p.Trp1153Cys. This variant affects a highly conserved tryptophan residue, is predicted to be deleterious, and is the most distal mutation yet reported in WDR35. This case expands the spectrum of phenotypes caused by WDR35 mutations, which we review herein.

Keywords: Sensenbrenner syndrome; asphyxiating thoracic dystrophy; homozygosity mapping; polycystic kidney; short stature.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Bone and Bones / abnormalities*
  • Craniosynostoses / diagnosis*
  • Craniosynostoses / genetics*
  • Cytoskeletal Proteins
  • Ectodermal Dysplasia / diagnosis*
  • Ectodermal Dysplasia / genetics*
  • Ellis-Van Creveld Syndrome / diagnosis
  • Ellis-Van Creveld Syndrome / genetics
  • Hedgehog Proteins
  • Homozygote*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Mutation*
  • Phenotype*
  • Proteins / genetics*
  • Skeleton / diagnostic imaging
  • Skeleton / pathology


  • Cytoskeletal Proteins
  • Hedgehog Proteins
  • Intracellular Signaling Peptides and Proteins
  • Proteins
  • WDR35 protein, human

Supplementary concepts

  • Cranioectodermal Dysplasia
  • Jeune syndrome