title: Structural and numerical changes of chromosome X in patients with esophageal atresia.
abstract: 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.
authors.affiliation: 1] Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands [2] Department of Paediatric Surgery, Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Erwin
authors.initials: E
authors.lastname: Brosens
authors.affiliation: 1] Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands [2] Department of Paediatric Surgery, Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: de Jong
authors.affiliation: Department of Reproduction and Development, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Tahsin Stefan
authors.initials: TS
authors.lastname: Barakat
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Bert H
authors.initials: BH
authors.lastname: Eussen
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Barbara
authors.initials: B
authors.lastname: D'haene
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Elfride
authors.initials: E
authors.lastname: De Baere
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Hannah
authors.initials: H
authors.lastname: Verdin
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Pino J
authors.initials: PJ
authors.lastname: Poddighe
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Robert-Jan
authors.initials: RJ
authors.lastname: Galjaard
authors.affiliation: Department of Reproduction and Development, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Gribnau
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Alice S
authors.initials: AS
authors.lastname: Brooks
authors.affiliation: Department of Paediatric Surgery, Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Annelies
authors.initials: A
authors.lastname: de Klein
mesh_terms: D000328:Adult; D001003:Anal Canal / Q000002:abnormalities*; D002869:Chromosome Aberrations; D041321:Chromosomes, Human, X / Q000235:genetics*; D004933:Esophageal Atresia / Q000175:diagnosis / Q000235:genetics*; D004947:Esophagus / Q000002:abnormalities*; D005260:Female; D056426:Genetic Loci; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D059785:Karyotype; D007668:Kidney / Q000002:abnormalities*; D017880:Limb Deformities, Congenital / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012729:Sex Chromosome Aberrations; D058533:Sex Chromosome Disorders of Sex Development / Q000175:diagnosis / Q000235:genetics*; D000074122:Short Stature Homeobox Protein; D013131:Spine / Q000002:abnormalities*; D014132:Trachea / Q000002:abnormalities*; D014157:Transcription Factors / Q000235:genetics; D014314:Trisomy / Q000175:diagnosis / Q000235:genetics*; D049951:X Chromosome Inactivation
chemical_list: D018398:Homeodomain Proteins; C104146:SALL1 protein, human; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein; D014157:Transcription Factors