DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III

Am J Hum Genet. 2009 May;84(5):706-11. doi: 10.1016/j.ajhg.2009.04.016.


Jeune asphyxiating thoracic dystrophy (ATD) is an autosomal-recessive chondrodysplasia characterized by short ribs and a narrow thorax, short long bones, inconstant polydactyly, and trident acetabular roof. ATD is closely related to the short rib polydactyly syndrome (SRP) type III, which is a more severe condition characterized by early prenatal expression and lethality and variable malformations. We first excluded IFT80 in a series of 26 fetuses and children belonging to 14 families diagnosed with either ATD or SRP type III. Studying a consanguineous family from Morocco, we mapped an ATD gene to chromosome 11q14.3-q23.1 in a 20.4 Mb region and identified homozygous mutations in the cytoplasmic dynein 2 heavy chain 1 (DYNC2H1) gene in the affected children. Compound heterozygosity for DYNC2H1 mutations was also identified in four additional families. Among the five families, 3/5 were diagnosed with ATD and 2/5 included pregnancies terminated for SRP type III. DYNC2H1 is a component of a cytoplasmic dynein complex and is directly involved in the generation and maintenance of cilia. From this study, we conclude that ATD and SRP type III are variants of a single disorder belonging to the ciliopathy group.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Chromosomes, Human, Pair 11 / genetics
  • Cytoplasmic Dyneins
  • Dyneins / chemistry
  • Dyneins / genetics*
  • Humans
  • Models, Molecular
  • Mutation
  • Pedigree
  • Respiratory Insufficiency / genetics*
  • Short Rib-Polydactyly Syndrome / genetics*


  • Carrier Proteins
  • DYNC2H1 protein, human
  • IFT80 protein, human
  • Cytoplasmic Dyneins
  • Dyneins