P450 Oxidoreductase Deficiency via the POR Gene

Cytochrome P450 oxidoreductase (POR) deficiency (PORD) is a rare disorder of steroidogenesis with a wide range of clinical presentations. To date, approximate 100 diagnosed patients have been reported (Pandey and Flück 2013). Patients with PORD can be apparently healthy, but all have some degree of steroid deficiency, mainly due to combined indirect impairment of 21-hydroxylase, 17α-hydroxlyase, and aromatase in adrenal gland and gonads. Disordered sex development can occur in both males and females. Ambiguous genitalia is a common finding in affected neonates. Severely affected patients may also have congenital multiple malformations, including craniosynostosis, brachycephaly, severe midface hypoplasia, radiohumeral synostosis, and multiple joint contractures, which has been considered a recessive form of Antley-Bixler syndrome (ABS). Dominantly inherited ABS usually manifests with skeletal malformations with normal steroid metabolism, and is caused by gain-of-function mutations in FGFR2 (Huang et al. 2005; Cragun et al. 2009; Pandey and Flück 2013).

The POR gene encodes P450 oxidoreductase (POR), which is a ubiquitously expressed enzyme. POR acts as an obligatory electron donor to all cytochrome P450 enzymes, including CYP17A1, CYP21A2, CYP19A1, and CYP51A1. Therefore, clinical symptoms of PORD result from combined indirect impairment of cytochrome P450 enzymes secondary to mutations in the POR gene (Pandey and Flück 2013).

PORD is an autosomal recessive disorder. Over 40 disease-causing variants have been identified and are scattered throughout the gene, including missense, nonsense, splicing site mutations, small deletions/insertions, and large deletions/duplications (Krone et al. 2012; Huang et al. 2005). Nearly all severally affected patients carried a loss-of-function variant, whereas patients having two missense mutations usually present with milder skeletal malformations (Krone et al. 2012). The p.Ala287Pro variant (in exon 8) is the most common mutation found in patients with European ancestry, and the p.Arg457His variant (in exon 11) is most frequently reported in the Japanese population (Krone et al. 2012; Huang et al. 2005).

Reduced P450 oxidoreductase enzyme activity associated with non-disease causing polymorphisms has been reported and may contribute to some variation in drug metabolism. However, it is not well established (Pandey and Flück 2013) and is not the purpose of this test.

In a cohort of 30 patients with PORD, 28 patients (~93%) were identified to carry at least one causative POR variant (Krone et al. 2012).

To date, four gross deletions and one duplication have been reported to be causative for PORD (Krone et al. 2012; Soneda et al. 2011).

This test provides full coverage of all coding exons of the POR 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).