Molecular cytogenetic analysis of a duplication Xp in a female with an abnormal phenotype and random X inactivation

Abstract

We describe a female infant with severe abnormal phenotype with a de novo partial duplication of the short arm of the X chromosome. Chromosome painting confirmed the origin of this X duplication. Molecular cytogenetic analysis with fluorescence in situ hybridization (FISH) was performed with YAC probes, further delineating the breakpoints. The karyotype was 46, X dup(X)(p11-p21.2). Cytogenetic replication studies showed that the normal and duplicated X chromosomes were randomly inactivated in lymphocytes. In most females with structurally abnormal X chromosomes, the abnormal chromosome is inactivated and they are phenotypically apparently normal relatives of phenotypically abnormal males having dupX. Therefore, in this case, there is functional disomy of Xp11-p21.2 in the cells with an active dup(X), most likely resulting in abnormal clinical findings in the patient.

Functional disomy of Xp including duplication of DAX1 gene with sex reversal due to t(X;Y)(p21.2;p11.3)

“…The replication pattern of the der (Y) chromosome indicates that the portion of Xp translocated is active. Reported cases with a partial duplication of the short arm of the X chromosome are uncommon [Portnoi et al, 2000], in particular for individuals with dup (Xp) and a normal Y chromosome [Baumstark et al, 1996;Telvi et al, 1996]. These individuals carry functional disomy of genes which are normally subject to X inactivation.…”

Two Patients with X Chromosome Duplication: dupXp and dupXq

“…Different inactivation patterns have also been reported in dup(X) patients [6,10,18]. In some cases there was full inactivation in all cells, in others a mosaic pattern of inactivation was observed [8,18,19]. Although selective X inactivation relatively diminishes phenotypic reflections, abnormal phenotypes could be observed in cases with pure dup(X) inactivation [9,19].…”

“…Abnormal X chromosomes that contain duplicated material can arise de novo or be of familial origin [2,[6][7][8]. Most reported cases of X chromosome duplications that are phenotypically normal are familial, whereas those with abnormal phenotypes arise as de novo mutations [9].…”

Autism in two females with duplications involving Xp11.22-p11.23

“…There have been 23 previously reported females with duplications of part of the p arm of the X chromosome. [1][2][3][4][5][6][7][8][9][10][11][12] Prominent phenotypic findings in affected females with Xp duplications are short stature, facial anomalies, and generalized muscular hypotonia. 2 Females with partial Xp duplications have been reported with moderate to severe intellectual disability and seizures, but the extent of neurological presentations has not always been fully described.…”

“…2 Females with partial Xp duplications have been reported with moderate to severe intellectual disability and seizures, but the extent of neurological presentations has not always been fully described. [5][6][7][8] A recent report described a recurrent duplication of Xp11.22-p11.23 associated with intellectual disability, electroencephalogram (EEG) abnormalities, and epilepsy. 12 There has only been one previous description of an autism spectrum disorder (ASD) in a female with a duplication of Xp.…”