Structural and numerical changes of chromosome X in patients with esophageal atresia

Eur J Hum Genet. 2014 Sep;22(9):1077-84. doi: 10.1038/ejhg.2013.295. Epub 2014 Jan 8.


Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is a relatively common birth defect often associated with additional congenital anomalies such as vertebral, anal, cardiovascular, renal and limb defects, the so-called VACTERL association. Yet, little is known about the causal genetic factors. Rare case reports of gastrointestinal anomalies in children with triple X syndrome prompted us to survey the incidence of structural and numerical changes of chromosome X in patients with EA/TEF. All available (n=269) karyotypes of our large (321) EA/TEF patient cohort were evaluated for X-chromosome anomalies. If sufficient DNA material was available, we determined genome-wide copy number profiles with SNP array and identified subtelomeric aberrations on the difficult to profile PAR1 region using telomere-multiplex ligation-dependent probe amplification. In addition, we investigated X-chromosome inactivation (XCI) patterns and mode of inheritance of detected aberrations in selected patients. Three EA/TEF patients had an additional maternally inherited X chromosome. These three female patients had normal random XCI patterns. Two male EA/TEF patients had small inherited duplications of the XY-linked SHOX (Short stature HOmeoboX-containing) locus. Patients were small for gestational age at birth (<P5) and had additional, mostly VACTERL associated, anomalies. Triple X syndrome is rarely described in patients with EA/TEF and no duplications of the SHOX gene were reported so far in these patients. As normal patterns of XCI were seen, overexpression of X-linked genes that escape XCI, such as the SHOX gene, could be pathogenic by disturbing developmental pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anal Canal / abnormalities*
  • Chromosome Aberrations*
  • Chromosomes, Human, X / genetics*
  • Esophageal Atresia / diagnosis
  • Esophageal Atresia / genetics*
  • Esophagus / abnormalities*
  • Female
  • Genetic Loci
  • Heart Defects, Congenital / diagnosis
  • Heart Defects, Congenital / genetics*
  • Homeodomain Proteins / genetics
  • Humans
  • Karyotype
  • Kidney / abnormalities*
  • Limb Deformities, Congenital / diagnosis
  • Limb Deformities, Congenital / genetics*
  • Male
  • Polymorphism, Single Nucleotide
  • Sex Chromosome Aberrations
  • Sex Chromosome Disorders of Sex Development / diagnosis
  • Sex Chromosome Disorders of Sex Development / genetics*
  • Short Stature Homeobox Protein
  • Spine / abnormalities*
  • Trachea / abnormalities*
  • Transcription Factors / genetics
  • Trisomy / diagnosis
  • Trisomy / genetics*
  • X Chromosome Inactivation*


  • Homeodomain Proteins
  • SALL1 protein, human
  • SHOX protein, human
  • Short Stature Homeobox Protein
  • Transcription Factors

Supplementary concepts

  • Triple X syndrome
  • VACTERL association