title: De novo complex X chromosome rearrangement unmasking maternally inherited CSF2RA deletion in a girl with pulmonary alveolar proteinosis.
abstract: We report on a 3-year-old girl with a de novo complex X chromosome rearrangement associated with congenital pulmonary alveolar proteinosis (PAP) and short stature. Array comparative genome hybridization and FISH analyses contributed to characterize the complex rearrangement consisting of a 7.37 Mb terminal deletion of Xp22.33p22.2, a 17.3 Mb interstitial inverted duplication of Xp22.2p21.3, and a 10.14 Mb duplication of Xq27.3q28. PCR analysis of microsatellite markers supported a paternal origin of the X chromosome rearrangement. A pre-meiotic two-step mechanism may explain the occurrence of this complex X rearrangement: an inverted duplication deletion event on Xp, and duplication of the Xq27.3qter region through a telomere capture event stabilizing the broken chromosome Xp end. The girl has also inherited from her healthy mother an X chromosome with a colony stimulating factor 2 receptor, alpha (CSF2RA) gene deletion. Consistent with the recessive mode of inheritance, the de novo paternal Xp22.33p22.2 deletion combined to the maternally inherited CSF2RA gene deletion led to homozygous deletion of CSF2RA and PAP diagnosis in the girl. The Xp deletion encompasses the pseudoautosomal region 1 (PAR1) which contains genes that escape X inactivation. Short stature homeobox (SHOX) haploinsufficiency explains growth retardation. Absence of other symptoms in relation to the X deletion/amplification is most probably due to skewed X inactivation. Finally, inherited deletions may unmask rare pathogenic genomic rearrangement and contribute to clinical phenotypes by a recessive mode of gene action.
authors.affiliation: Laboratoire de Génétique Médicale, Centre Hospitalier Universitaire de Nancy, Vandoeuvre-les-Nancy, France; Service de Médecine Infantile 3 et Génétique Clinique, Centre Hospitalier Universitaire de Nancy, Vandoeuvre-les-Nancy, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Auger
authors.forename: Céline
authors.initials: C
authors.lastname: Bonnet
authors.forename: Mylène
authors.initials: M
authors.lastname: Valduga
authors.forename: Christophe
authors.initials: C
authors.lastname: Philippe
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bertolo-Houriez
authors.forename: Mylène
authors.initials: M
authors.lastname: Beri-Dexheimer
authors.forename: Cyril
authors.initials: C
authors.lastname: Schweitzer
authors.forename: Bruno
authors.initials: B
authors.lastname: Leheup
authors.forename: Philippe
authors.initials: P
authors.lastname: Jonveaux
mesh_terms: D000328:Adult; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D041321:Chromosomes, Human, X; D055028:Comparative Genomic Hybridization; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D011649:Pulmonary Alveolar Proteinosis / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D049951:X Chromosome Inactivation
chemical_list: C521678:CSF2RA protein, human; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
keywords: CSF2RA; array comparative genome hybridization; congenital pulmonary alveolar proteinosis; inv dup del Xp