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

作者：Brosens Erwin^*; de Jong Elisabeth M; Barakat Tahsin Stefan; Eussen Bert H; D'haene Barbara; De Baere Elfride; Verdin Hannah; Poddighe Pino J; Galjaard Robert Jan; Gribnau Joost; Brooks Alice S; Tibboel Dick; de Klein Annelies

来源：European Journal of Human Genetics, 2014, 22(9): 1077-1084.

DOI：10.1038/ejhg.2013.295

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

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.

• 出版日期2014-9