A Small Supernumerary Xp Marker Chromosome Including Genes <b><i>NR0B1</i></b> and <b><i>MAGEB</i></b> Causing Partial Gonadal Dysgenesis and Gonadoblastoma

Abstract

Copy number variations of several genes involved in the process of gonadal determination have been identified as a cause of 46,XY differences of sex development. We report a non-syndromic 14-year-old female patient who was referred with primary amenorrhea, absence of breast development, and atypical genitalia. Her karyotype was 47,XY,+mar/46,XY, and FISH analysis revealed the X chromosome origin of the marker chromosome. Array-CGH data identified a pathogenic 2.0-Mb gain of an Xp21.2 segment containing &lt;i&gt;NR0B1/DAX1&lt;/i&gt; and a 1.9-Mb variant of unknown significance from the Xp11.21p11.1 region. This is the first report of a chromosomal microarray analysis to reveal the genetic content of a small supernumerary marker chromosome detected in a 47,XY,+der(X)/46,XY karyotype in a non-syndromic girl with partial gonadal dysgenesis and gonadoblastoma. Our findings indicate that the mosaic presence of the small supernumerary Xp marker, encompassing the &lt;i&gt;NR0B1/DAX1&lt;/i&gt; gene, may have been the main cause of dysgenetic testes development, although the role of &lt;i&gt;MAGEB&lt;/i&gt; and other genes mapped to the Xp21 segment could not be completely ruled out.

A Novel Look at Dosage-Sensitive Sex Locus Xp21.2 in a Case of 46,XY Partial Gonadal Dysgenesis without NR0B1 Duplication

“…Though current data support the hypothesis that NR0B1 is responsible for sex reversal if overexpressed, NR0B1 single duplication associated with 46,XY GD is still to be demonstrated as evidence of its direct involvement in this condition, and the role of other genes and regulatory regions mapped to the Xp21 may not be completely ruled out [6].…”

“…Mutations or deletions of NR0B1 cause X-linked congenital adrenal hypoplasia, characterized by primary adrenal insufficiency, hypogonadotropic hypogonadism and impaired fertility; however, boys have normal testicular development at birth [14], making NR0B1 dispensable for male external development. In turn, Xp duplications involving NR0B1 have been associated with both partial and complete 46,XY GD, the latter being characterized by streak gonads and normal internal and external female genitalia [5,6,15,16]. In normal XY individuals, NR5A1 interacts with SRY and later SOX9 to upregulate Sox9-driving SF1 +supporting cell precursors into the Sertoli cell line [17], allowing development of the male gonad.…”

“…Duplications in the short arm of the X chromosome involving NR0B1 (Nuclear Receptor Subfamily 0, Group B, Member 1) have been associated with 46,XY DSD. Initially detected by karyotyping [3], these duplications were further characterized by fluorescent in situ hybridization (FISH) [4] and chromosome microarray analysis (CMA) and/or multiplex ligation-dependent probe amplification (MLPA) [5,6]. A 160 kb region of Xp21.2 has been defined as the critical region responsible for sex reversal [3]; this area is known as dosage-sensitive sex reversal (DSS), and it is believed that the NR0B1 gene contained in that region causes sex reversal in a dosage-dependent manner [5,6].…”

Testicular differentiation in 46,XX DSD: an overview of genetic causes

“…If normal levels of NR0B1 are crucial for testicular development and spermatogenesis, an excessive dosage of NR0B1 has been suggested to act as an anti-testicular factor ( 164 ) Xp21.1 duplications, which include NR0B1 and testis-specific MAGEB genes, have been identified in some XY patients with gonadal dysgenesis. These duplications contribute to abnormalities in gonadal development and function ( 146 , 155 , 165 – 168 ).…”