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

Erwin Brosens, Elisabeth M. De Jong, Tahsin Stefan Barakat, Bert H. Eussen, Barbara D'Haene, Elfride De Baere, Hannah Verdin, Pino J. Poddighe, Robert Jan Galjaard, Joost Gribnau, Alice S. Brooks, Dick Tibboel, Annelies De Klein

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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.

Original languageEnglish
Pages (from-to)1077-1084
Number of pages8
JournalEuropean journal of human genetics
Issue number9
Publication statusPublished - Sept 2014


  • SHOX duplication
  • VACTERL association
  • esophageal atresia
  • tracheoesophageal fistula
  • triple X syndrome

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