Xp21.2 Duplication

[Edilma Howard]

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Xp21.2 duplication syndrome is a rare genetic disorder of undetermined prevalence and clinical relevance. As the use of chromosomal microarray has become first line for the work-up of childhood developmental delay, more gene deletions and duplications have been recognized. To the best of our knowledge, the imaging findings of Xp21.2 duplication syndrome have not been reported. We report a case of a 33 month-old male referred for developmental delay that was found to have an Xp21.2 duplication containing IL1RAPL1 and multiple midline brain malformations.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

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Context: Testis development is a tightly regulated process that requires an efficient and coordinated spatiotemporal action of many factors, and it has been shown that several genes involved in gonadal development exert a dosage effect. Chromosomal imbalances have been reported in several patients presenting with gonadal dysgenesis as part of severe dysmorphic phenotypes.

Results: We screened for submicroscopic DNA copy number variations in two sisters with an apparent normal 46,XY karyotype and female external genitalia due to gonadal dysgenesis, and in which mutations in known candidate genes had been excluded. By high-resolution tiling bacterial artificial chromosome array comparative genome hybridization, a submicroscopic duplication at Xp21.2 containing DAX1 (NR0B1) was identified. Using fluorescence in situ hybridization, multiple ligation probe amplification, and PCR, the rearrangement was further characterized. This revealed a 637-kb tandem duplication that in addition to DAX1 includes the four MAGEB genes, the hypothetical gene CXorf21, GK, and part of the MAP3K7IP3 gene. Sequencing and analysis of the breakpoint boundaries and duplication junction suggest that the duplication originated through a coupled homologous and nonhomologous recombination process.

Conclusions: This represents the first duplication on Xp21.2 identified in patients with isolated gonadal dysgenesis because all previously described XY subjects with Xp21 duplications presented with gonadal dysgenesis as part of a more complex phenotype, including mental retardation and/or malformations. Thus, our data support DAX1 as a dosage sensitive gene responsible for gonadal dysgenesis and highlight the importance of considering DAX1 locus duplications in the evaluation of all cases of 46,XY gonadal dysgenesis.

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Abstract: A region of 160 kb at Xp21.2 has been defined as dosage-sensitive sex reversal (DSS) and includes the NR0B1 gene, considered to be the candidate gene involved in XY gonadal dysgenesis if overexpressed. We describe a girl with 46,XY partial gonadal dysgenesis carrying a 297 kb duplication at Xp21.2 upstream of NR0B1 initially detected by chromosomal microarray analysis. Fine mapping of the breakpoints by whole-genome sequencing showed a tandem duplication of TASL (CXorf21), GK and partially TAB3, upstream of NR0B1. This is the first description of an Xp21.2 duplication upstream of NR0B1 associated with 46,XY partial gonadal dysgenesis. Keywords: disorders of sex development; 46,XY partial gonadal dysgenesis; Xp21.2 duplication; NR0B1; chromosome microarray analysis; whole-genome sequencing

The existence of an X-specific gene involved in human sex determination was first postulated by German et al. (1978), on the basis of a family with an apparent X-linked mode of inheritance of 46,XY gonadal dysgenesis. A number of families with X-linked recessive (or sex-limited autosomal dominant) transmission of the disorder were reported thereafter (reviewed by Fechner et al., 1993).

Bardoni et al. (1994) studied 4 patients with 46,XY sex reversal, who were raised as girls due to their having either ambiguous or female external genitalia. Histologic examination of the internal genitalia was performed in 3 of the patients and confirmed partial gonadal dysgenesis. The authors noted that the patients exhibited a complex phenotype, including mental retardation and multiple minor malformation, but clinical details were not provided in that report.

Smyk et al. (2007) reported a 21-year-old 46,XY female who presented with primary amenorrhea, a small immature uterus, and gonadal dysgenesis without adrenal insufficiency, in whom they identified a submicroscopic 257-kb deletion with a distal breakpoint 11.3 kb upstream of the NR0B1 gene. The deletion was also present in the patient's mother, who had a history of ovarian cysts, but was not found in 1,184 controls. The authors suggested that loss of regulatory sequences may have resulted in position effect upregulation of NR0B1 expression.

Bardoni et al. (1994) studied 8 patients with duplications at chromosome Xp21, including 4 who had 46,XY sex reversal and 4 who were 46,XY phenotypic males. Breakpoint analysis identified an approximately 20-Mb region on Xp21.2-p22.1 that was duplicated only in the 46,XY females. Further analysis involving 1 additional 46,XY sex-reversed patient with a submicroscopic duplication on Xp defined a 160-kb critical region adjacent to the congenital adrenal hypoplasia locus (AHC; 300200) that was exclusively duplicated in the patients with male-to-female sex reversal; the authors designated the locus DSS for 'dosage sensitive sex reversal' (see 300473.0014). Identification of males deleted for DSS suggested that the locus is not required for testis differentiation. Bardoni et al. (1994) proposed that DSS has a role in ovarian development and/or functions as a link between ovary and testis formation.

Swain et al. (1998) created a transgenic mouse model for studying events in mammalian sex differentiation. The data showed that Dax1 functions as an anti-testis gene by acting antagonistically to Sry. This suggested that dosage-sensitive sex reversal can be caused by duplication of the DAX1 gene in humans.

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