NR0B1-Related Disorders via the NR0B1 Gene

The majority of documented NR0B1 (previously known as DAX1) mutations cause X-linked congenital adrenal hypoplasia (AHC), which is characterized by adrenal insufficiency and hypogonadotropic hypogonadism in males (Muscatelli et al. 1994). The primary adrenocortical failure in X-linked AHC is lack of the permanent adult cortical zone in the adrenal glands. The majority of X-linked AHC patients have disease onset at the neonatal stage while some patients can present in childhood. Significant clinical variability exists. In rare cases, carrier females have symptoms of adrenal insufficiency or hypogonadotropic hypogonadism due to skewed X-chromosome inactivation (Achermann et al. 2013).

The other important NR0B1-related disease is the gene-dosage-sensitive type of 46, XY sex reversal, which is a disorder of human sex determination (Bardoni et al. 1994). Some of these affected 46, XY individuals have female or ambiguous external genitalia while some have impaired testis formation. Isolated 46, XY gonadal dysgenesis has been associated with an interstitial duplication containing the NR0B1 gene (Barbaro et al. 2007).

The NR0B1 gene has 2 coding exons that encode an orphan nuclear hormone receptor, which plays a key role in the development of the adrenal gland and the hypothalamic-pituitary-gonadal axis.

X-linked congenital adrenal hypoplasia is caused by loss-of-function (partial or complete) mutations in the NR0B1 gene in a recessive manner (Muscatelli et al. 1994). These mutations can be de novo or transmitted within family. In this X-linked disease, genetic defects located throughout the NR0B1 gene include missense, nonsense, splicing mutations and small deletion/insertions (Human Gene Mutation Database). In addition, gross deletions involving the NR0B1 gene are common. In particular, deletion of the entire NR0B1 gene and even the neighboring genes has been repeatedly reported (Human Gene Mutation Database).

NR0B1-related 46, XY sex development disorders are caused by increased amount of its encoded protein secondary to gene duplication (Bardoni et al. 1994; Barbaro et al. 2007).

In a study of 31 unrelated patients with X-linked congenital adrenal hypoplasia, 12 (~39%) were found to have NR0B1 mutations via DNA sequencing (Muscatelli et al. 1994). In another study of 17 families with X-linked congenital adrenal hypoplasia, NR0B1 mutations were found in all families via DNA sequencing (Zhang et al. 1998).

Gene copy number testing should be performed for patients with NR0B1-related 46, XY sex development disorders due to a gene dosage effect.

This test provides full coverage of all coding exons of the NR0B1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).