Variability in a three-generation family with Pierre Robin sequence, acampomelic campomelic dysplasia, and intellectual disability due to a novel ∼1 Mb deletion upstream of SOX9, and including KCNJ2 and KCNJ16

Birth Defects Res A Clin Mol Teratol. 2016 Jan;106(1):61-8. doi: 10.1002/bdra.23463. Epub 2015 Dec 11.


Background: Campomelic dysplasia and acampomelic campomelic dysplasia (ACD) are allelic disorders due to heterozygous mutations in or around SOX9. Translocations and deletions involving the SOX9 5' regulatory region are rare causes of these disorders, as well as Pierre Robin sequence (PRS) and 46,XY gonadal dysgenesis. Genotype-phenotype correlations are not straightforward due to the complex epigenetic regulation of SOX9 expression during development.

Methods: We report a three-generation pedigree with a novel ∼1 Mb deletion upstream of SOX9 and including KCNJ2 and KCNJ16, and ascertained for dominant transmission of PRS.

Results: Further characterization of the family identified subtle appendicular anomalies and a variable constellation of axial skeletal features evocative of ACD in several members. Affected males showed learning disability.

Conclusion: The identified deletion was smaller than all other chromosome rearrangements associated with ACD. Comparison with other reported translocations and deletions involving this region allowed further refining of genotype-phenotype correlations and an update of the smallest regions of overlap associated with the different phenotypes. Intrafamilial variability in this pedigree suggests a phenotypic continuity between ACD and PRS in patients carrying mutations in the SOX9 5' regulatory region.

Keywords: Robin sequence; SOX9; acampomelic; deletion; genotype-phenotype correlations; variability.

MeSH terms

  • Adult
  • Base Sequence
  • Campomelic Dysplasia / diagnosis
  • Campomelic Dysplasia / genetics*
  • Campomelic Dysplasia / pathology
  • Female
  • Gene Expression
  • Genes, Dominant
  • Genetic Association Studies
  • Genetic Variation
  • Humans
  • Infant
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Pedigree
  • Pierre Robin Syndrome / diagnosis
  • Pierre Robin Syndrome / genetics*
  • Pierre Robin Syndrome / pathology
  • Potassium Channels, Inwardly Rectifying / deficiency
  • Potassium Channels, Inwardly Rectifying / genetics*
  • SOX9 Transcription Factor / genetics*
  • Sequence Deletion


  • KCNJ16 protein, human
  • KCNJ2 protein, human
  • Potassium Channels, Inwardly Rectifying
  • SOX9 Transcription Factor
  • SOX9 protein, human