Genomics England Research Registry ID: 1107
Registered: 08/05/2024
Expert Summary
Congenital adrenal hyperplasia (CAH) refers to several disorders of biosynthesis of the steroid hormones cortisol and aldosterone. CAH is inherited in an autosomal recessive manner and although most cases are due to pathogenic variants within one gene, CYP21A2, the phenotypic spectrum is broad. Classic CAH is usually apparent early on, and presentation varies from ambiguous external genitalia in the simple-virilising form to life-threatening adrenal crisis in the salt-wasting form. Non-classic CAH (NCCAH) is one of the most common inherited conditions globally and is relatively milder, with symptoms largely due to shunting of precursor molecules towards androgenesis. NCCAH may be asymptomatic or may present in adolescence with early puberty, hirsutism and menstrual irregularities. In adults with CAH, infertility is a frequent initial presentation.
Despite advances in our understanding of the genetic basis of CAH, current diagnostic pathways for NCCAH primarily rely on clinical observations and testing for elevated levels of 17-hydroxyprogesterone (17OHP), the substrate for the 21-hydroxylase enzyme encoded by CYP21A2. Specifically, this testing is usually recommended before 8am to account for the expected rhythm of cortisol secretion. Recent studies have encouraged investigation into the regulatory sequences of CYP21A2 in the context of CAH, raising the possibility that some variants in regulatory regions may not only contribute to an overall phenotype but also evade diagnosis if their resulting expression pattern differs significantly from the wild type rhythm.
To investigate the pathogenic and diagnostic impacts of such variants, this study will compile a list of non-coding variants associated with CAH phenotypes using data from the 100,000 Genomes Project. Then, these regulatory sequences will be attached to luciferase reporter genes to monitor their expression. These results will hope to better our understanding of the pathogenesis of CAH and, more broadly, add to the burgeoning literature of chronomic medicine.
Lay Summary
Congenital adrenal hyperplasia (CAH) describes a group of inherited conditions that impair synthesis of cortisol and/or aldosterone with wide-ranging consequences. Classic CAH is usually diagnosed in infancy and can cause disordered sexual development, salt-wasting and death. Non-classic CAH may be asymptomatic or present with symptoms of hyperandrogenism, such as early puberty, excess body hair and menstrual irregularities. In adulthood, CAH can cause infertility in both men and women.
Usually, CAH is due to variants within the CYP21A2 gene. Currently however, clinical observations and biochemical tests remain the primary method of diagnosis before genotyping is considered. Biomarker testing is recommended before 8am in symptomatic individuals beyond infancy to account for the circadian rhythm of cortisol secretion. Recent research has implicated regulatory regions of the CYP21A2 gene in the context of CAH, raising the possibility that some pathogenic variants may produce false negatives due to aberrant gene expression.
This study will use data from the 100,000 Genomes Project to identify potential variants of this type. Regulatory DNA containing these variants will be attached to reporter genes to allow circadian expression monitoring. If these variants are found to cause markedly deviant expression, a review of clinical practice may be necessary.
Chronomic Medicine Group 