Multiplex ligation-dependent probe amplification analysis of the NR0B1(DAX1) locus enables explanation of phenotypic differences in patients with X-linked congenital adrenal hypoplasia.

Background/Aim:X-linked adrenal hypoplasiacongenita (AHC) is a rare disorder characterized by primary adrenal insufficiencyand 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 dystrophyand mental retardation (MR), as part of a contiguousgene deletion syndrome. A synthetic probe set for multiplex ligation-dependent probe amplificationanalysis 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, isolatedAHC 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 contiguousgene 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 amplificationhas 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 deficiencyand Duchenne muscular dystrophy.