Congenital heart defects in patients with deletions upstream of SOX9

Hum Mutat. 2013 Dec;34(12):1628-31. doi: 10.1002/humu.22449. Epub 2013 Oct 18.


Heterozygous loss-of-function coding-sequence mutations of the transcription factor SOX9 cause campomelic dysplasia, a rare skeletal dysplasia with congenital bowing of long bones (campomelia), hypoplastic scapulae, a missing pair of ribs, pelvic, and vertebral malformations, clubbed feet, Pierre Robin sequence (PRS), facial dysmorphia, and disorders of sex development. We report here two unrelated families that include patients with isolated PRS, isolated congenital heart defect (CHD), or both anomalies. Patients from both families carried a very similar ∼1 Mb deletion upstream of SOX9. Analysis of ChIP-Seq from mouse cardiac tissue for H3K27ac, a marker of active regulatory elements, led us to identify several putative cardiac enhancers within the deleted region. One of these elements is known to interact with Nkx2.5 and Gata4, two transcription factors responsible for CHDs. Altogether, these data suggest that disruption of cardiac enhancers located upstream of SOX9 may be responsible for CHDs in humans.

Keywords: CNV; SOX9; congenital heart defect; copy number variant; pierre robin sequence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Flanking Region*
  • Adult
  • Campomelic Dysplasia / diagnosis
  • Campomelic Dysplasia / genetics
  • Enhancer Elements, Genetic
  • Female
  • Gene Order
  • Heart Defects, Congenital / diagnosis
  • Heart Defects, Congenital / genetics*
  • Humans
  • Male
  • Pedigree
  • Pierre Robin Syndrome / diagnosis
  • Pierre Robin Syndrome / genetics
  • SOX9 Transcription Factor / genetics*
  • Sequence Deletion*
  • Young Adult


  • SOX9 Transcription Factor