Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies

Hum Mutat. 2018 Jan;39(1):152-166. doi: 10.1002/humu.23362. Epub 2017 Nov 6.


Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is distinguished by profound abnormalities of the skeleton that include a long narrow chest with markedly short ribs, extremely short limbs, and polydactyly. These include the perinatal lethal short-rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy (ATD), Ellis-van Creveld (EVC) syndrome, and cranioectodermal dysplasia (CED) phenotypes. To identify new genes and define the spectrum of mutations in the skeletal ciliopathies, we analyzed 152 unrelated families with SRPS, ATD, and EVC. Causal variants were discovered in 14 genes in 120 families, including one newly associated gene and two genes previously associated with other ciliopathies. These three genes encode components of three different ciliary complexes; FUZ, which encodes a planar cell polarity complex molecule; TRAF3IP1, which encodes an anterograde ciliary transport protein; and LBR, which encodes a nuclear membrane protein with sterol reductase activity. The results established the molecular basis of SRPS type IV, in which mutations were identified in four different ciliary genes. The data provide systematic insight regarding the genotypes associated with a large cohort of these genetically heterogeneous phenotypes and identified new ciliary components required for normal skeletal development.

Keywords: chondrocyte; cilia; ciliopathy; skeletal dysplasia.

MeSH terms

  • Ciliopathies / diagnosis*
  • Ciliopathies / genetics*
  • Cytoplasmic Dyneins / genetics
  • Exome Sequencing
  • Genetic Association Studies*
  • Genetic Markers
  • Genetic Variation*
  • Genotype
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Mutation
  • Phenotype*
  • Proteins / genetics
  • Radiography
  • Skeleton / abnormalities*


  • DYNC2H1 protein, human
  • EVC2 protein, human
  • Genetic Markers
  • Intercellular Signaling Peptides and Proteins
  • Proteins
  • Cytoplasmic Dyneins