Multigeneration Inheritance through Fertile XX Carriers of an NR0B1 (DAX1) Locus Duplication in a Kindred of Females with Isolated XY Gonadal Dysgenesis

Abstract

A 160 kb minimal common region in Xp21 has been determined as the cause of XY gonadal dysgenesis, if duplicated. The region contains the MAGEB genes and the NR0B1 gene; this is the candidate for gonadal dysgenesis if overexpressed. Most patients present gonadal dysgenesis within a more complex phenotype. However, few independent cases have recently been described presenting with isolated XY gonadal dysgenesis caused by relatively small NR0B1 locus duplications. We have identified another NR0B1 duplication in two sisters with isolated XY gonadal dysgenesis with an X-linked inheritance pattern. We performed X-inactivation studies in three fertile female carriers of three different small NR0B1 locus duplications identified by our group. The carrier mothers did not show obvious skewing of X-chromosome inactivation, suggesting that NR0B1 overexpression does not impair ovarian function. We furthermore emphasize the importance to investigate the NR0B1 locus also in patients with isolated XY gonadal dysgenesis.

Figure 1

Family pedigree. Pedigree of a family with two sisters with 46,XY gonadal dysgenesis. +DAX1 indicates the subjects that carry the X chromosome containing the NR0B1 locus duplication. XX and XY have been added underneath some subjects indicating a 46,XX or 46,XY karyotype, respectively. Mandatory female carriers and potential carriers are marked.

Figure 2

Comparison of NR0B1 locus duplications. Representation from the UCSC genome browser (NCBI36/hg18) of the NR0B1 locus on Xp21.2. The probes that delineate the breakpoints in the three independent families identified by our group are represented by red vertical lines. The horizontal blue line represents the extension of the duplication in the family here described, the green lines represent the duplicated regions previously described by our group, and the orange lines represent the two duplications identified by array CGH in patients with isolate 46,XY GD by other groups. The C and P at the right ends of the lines indicate if the GD was complete or partial, respectively.