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.

Characterization of CSF2RA mutation related juvenile pulmonary alveolar proteinosis

“…In addition, the clinical course is described as the initial presenting phenotype followed by the last documented condition. * [ 13 ], ** [ 14 ], *** [ 10 ], † [ 12 ], ‡ [ 11 ], § [ 16 ]. …”

“…Mutations in the genes encoding the GM-CSF receptor ( CSF2RA and CSF2RB ), in contrast, cause pure PAP without involvement of the interstitial space. In recent years, two cases due to CSF2RB mutations [ 4 , 9 ] and 13 cases caused by CSF2RA gene defects have been published, including one case series [ 10 ] and single case reports [ 11 - 16 ]. The protein encoded by the CSF2RA gene is the alpha subunit of the heterodimeric receptor for colony stimulating factor 2, a member of the cytokine family of receptors that controls production, differentiation, and function of granulocytes and macrophages [ 17 ].…”

Complex X-Chromosomal Rearrangements in Two Women with Ovarian Dysfunction: Implications of Chromothripsis/Chromoanasynthesis-Dependent and -Independent Origins of Complex Genomic Alterations

“…© 2017 S. Karger AG, Basel Complex chromosomal rearrangements are common in cancer genomes and can also appear in the germline [Liu et al, 2011;Kloosterman and Cuppen, 2013]. To date, germline complex rearrangements have been identified in a small number of individuals [Liu et al, 2011;Ochalski et al, 2011;Auger et al, 2013;Kloosterman and Cuppen, 2013;Plaisancié et al, 2014]. Of these, complex autosomal rearrangements were often associated with congenital malformations and mental retardation, which probably reflect dysfunction or dysregulation of multiple genes on the affected chromosome [Liu et al, 2011;Kloosterman and Cuppen, 2013;Plaisancié et al, 2014].…”

“…Of these, complex autosomal rearrangements were often associated with congenital malformations and mental retardation, which probably reflect dysfunction or dysregulation of multiple genes on the affected chromosome [Liu et al, 2011;Kloosterman and Cuppen, 2013;Plaisancié et al, 2014]. In contrast, complex X-chromosomal rearrangements were detected primarily in women with nonsyndromic ovarian dysfunction and were occasionally associated with other clinical features such as short stature, muscular hypotonia, and an unmasked X-linked recessive disorder [Ochalski et al, 2011;Auger et al, 2013]. The lack of severe developmental defects in women with complex X-chromosomal rearrangements is consistent with prior observations that structurally abnormal X chromosomes, except for X;autosome translocations, frequently undergo selective X inactivation [Heard et al, 1997].…”

Pulmonary Alveolar Proteinosis

“…The transmission is autosomal recessive. Very recently the mutation was described in a 3 year patient with PAP after a complex inactivation of the naïve gene in the other X chromosome [ 73 ]. Some mutations have varying and incomplete penetrance, and disease was found in three asymptomatic children between 5 and 8 years after the diagnosis of a familial index case [ 74 ].…”