Multiplex Ligation-Dependent Probe Amplification Analysis of the <i>NR0B1</i><i>(DAX1)</i> Locus Enables Explanation of Phenotypic Differences in Patients with X-Linked Congenital Adrenal Hypoplasia

Abstract

Background/Aim:X-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency and hypogonadic hypogonadism. It is caused by deletions or point mutations of the NR0B1 gene, on Xp21. AHC can be associated with glycerol kinase deficiency, Duchenne muscular dystrophy and mental retardation (MR), as part of a contiguous gene deletion syndrome. A synthetic probe set for multiplex ligation-dependent probe amplification analysis was developed to confirm and characterize NR0B1 deletions in patients with AHC and to correlate their genotypes with their divergent phenotypes. Results:In 2 patients, isolated AHC was confirmed, while a patient at risk for metabolic crisis was revealed as the deletion extends to the GK gene. A deletion extending to IL1RAPL1 was confirmed in both patients showing MR. Thus, a good genotype-phenotype correlation was confirmed. Conclusions:Multiplex ligation-dependent probe amplification analysis is a valuable tool to detect NR0B1 and contiguous gene deletions in patients with AHC. It is especially helpful for IL1RAPL1 deletion detection as no clinical markers for MR are available. Furthermore, multiplex ligation-dependent probe amplification has the advantage to identify female carriers that, depending on the deletion extension, have a high risk of giving birth to children with MR, AHC, glycerol kinase deficiency and Duchenne muscular dystrophy.

X‐linked congenital adrenal hypoplasia: Report of long clinical follow‐up and description of a new complex variant in the NR0B1 gene

“…However, attempts to amplify and sequence these regions were unsuccessful. The use of different molecular techniques to study NR0B1 has been described previously (Barbaro et al, 2012; Rojek et al, 2016; SIKL, 1948).…”

Disruption of the topologically associated domain at Xp21.2 is related to 46,XY gonadal dysgenesis

“…No effects of reproductive development and function were reported so far. NR0B1 duplications do not seem to impair ovarian function 5 6 40 41…”

Female-to-male sex reversal associated with unique Xp21.2 deletion disrupting genomic regulatory architecture of the dosage-sensitive sex reversal region

“…Red bars represent the extent of the genomic deletion previously identified in the unaffected fertile mothers of male patients with AHC or DSD. M1, M2, M3 and M5 are mothers of patients Pt4, Pt5, Pt1 and Pt3, respectively, described previously 15. M4 and M6 deletions were reported in the mothers of male children with AHC16 and an XY female individual 17.…”