Professor of Endocrine Genetics
Fast, accurate genetic testing for adrenal insufficiency has turned Queen Mary into a global referral centre for the condition.
Adrenal insufficiency (AI) happens when your adrenal glands don’t produce their normal output of hormones – in particular the main stress hormone, cortisol.
It can be a life-threatening condition, as it leaves sufferers unable to produce higher levels of cortisol when they face illness, pain or severe psychological stress. Without this increase in cortisol, the body can go into shock with low blood pressure, low levels of blood sugar and high potassium leading to convulsions, coma and, if untreated, death.
Patients also face uncertainty about whether they will pass their disorder on to any children they may have.
Getting a genetic diagnosis not only means that a tailored treatment and management plan can be put in place for each patient, it also helps clinicians to assess each individual’s inheritance risk, so that they can receive accurate genetic counselling – and greater certainty.
However, AI patients face significant delays in getting a diagnosis: fewer than 30 per cent of girls and 50 per cent of boys are diagnosed in the first six months after their first symptoms.
In fact, 20 per cent of patients endure the condition for more than five years before being diagnosed and approximately a third of patients lack a genetic diagnosis.
More than 25 genes are currently known to cause AI. In collaboration with clinician scientists from around the world, a research team based at Queen Mary’s Centre for Endocrinology and led by Professor Metherell is discovering more genes by whole exome sequencing in patients.
For some genes – MC2R, MRAP, NNT, TXNRD2, MCM4 and SGPL1 – the team at QM were the first to describe the defects causing AI, and their discovery led to further cases being identified. For other genes – STAR and CYP11A1 – the Queen Mary team recognised unusual ‘silent’ disease-causing mutations that cause AI milder versions of the disorders.
Genes thought to cause AI disorders are typically sequenced individually, a time-consuming and complicated process. However, Professor Metherell’s team has shown that ‘whole exome’ sequencing – which looks at the instructions given to the body by almost all 20,000 known genes – and targeted approaches to genomic sequencing can improve the cost-effectiveness of diagnosis, allowing more genes to be screened at the same time.
This work has enabled the development of a genetic diagnostic panel, now in clinical use, that allows patients to receive swift, effective treatment and genetic counselling for this potentially life-threatening disorder.
The panel has also greatly improved the diagnosis and understanding of AI by characterising recessive gene mutations, transforming the outlook for AI patients.
For many overseas samples, there is no financial support to cover genetic testing. In these cases, tests are run at no cost to the family.
Professor Metherell was the first to link several genes – including MC2R, MRAP, MCM4, NNT, TXNRD2 and SGPL1 – to AI and its associated syndromes.
Her team’s work led the European Society of Endocrinology and American Association for Clinical Chemistry to recommend in 2015 that AI should be diagnosed through genetic testing.
Professor Metherell and her team have also contributed significantly to professional and public understanding of AI.
Professor Metherell contributed to the International Classification of Paediatric Endocrine Diagnoses (ICPED) Consortium (Chapter 8, 2015) and has done much to bring understanding and clarity to patients seeking information about the condition. She has contributed to the US National Institutes of Health patient guide to understanding familial glucocorticoid deficiency (published in 2018) as well as the patient resource page Orphanet, where she is often contacted by worried parents looking for genetic tests for their children.
Understanding the precise genetic defects underlying each case of AI is crucial in deciding the right course of treatment.
It is standard practice when clinically diagnosing AI to begin a hydrocortisone and fludrocortisone treatment – but for certain gene defects, such as MC2R and MRAP, fludrocortisone may be unnecessary and can be stopped without the risk of developing further co-morbidities.
However, at the other extreme, standard practice can be insufficient. The genetic diagnosis of a SGPL1 defect, for instance, needs further discussion between clinicians and patients. Patients will need to be monitored to ensure that no other issues, such as kidney disease or neurological conditions, arise as a consequence of this type of AI.
In this way, determining the genetic cause(s) of AI is vital to helping AI patients lead healthy, active lives while avoiding unnecessary risk.
The pre-existing genetic test for the five most common genes of interest in AI costs £750 per person. However, this test can only diagnose half of all AI cases.
By contrast, Queen Mary’s approach costs £600 per person and can diagnose at least two-thirds of cases, using a regime of targeted and whole exome sequencing. This means families can receive fast and suitable treatment.
As a result, Queen Mary’s Centre of Endocrinology has become a major global referral centre for AI. It has tested samples from 33 countries to date and identified causal mutations for AI in 66 per cent of cases.
Approximately a third of all samples come from the UK, and the rest from overseas. For many overseas samples, there is no financial support to cover genetic testing. In these cases, tests are run at no cost to the family.
The Centre has also reduced the turnaround time for each test to under three months — a critical difference for many families trying to manage AI.
Professor Metherell’s gene discoveries have also been incorporated into a Haloplex targeted array designed at Great Ormond Street Hospital for the diagnosis of AI. The array was first used for a Turkish cohort study in 2016, the largest ever nationwide study of the molecular genetics of childhood AI. A molecular diagnosis was achieved for 80 per cent of these children.
The central importance of a definitive diagnosis for AI patients was confirmed by Professor Catherine Choong, consultant endocrinologist at Perth Children’s Hospital: “Given that these are rare conditions, identification of the genetic variants by Professor Metherell has allowed us to monitor the literature for emergent phenotypes thereby improving the clinical surveillance and management of these children and families”.
Moreover, Professor Metherell’s research has enabled clinicians to calculate levels of risk both during and after the birth of affected and unaffected children with “significant benefit to the health and safety of the parent and the neonate,” according to Professor Choong.
In this way, Professor Metherell and her team’s research improves the life chances of children with AI before they are born, bringing hope, understanding and support to countless families around the world.
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We place a high value upon training the next generation of researchers both non-clinical and clinical in a collaborative environment to deliver translational outcomes; however, we also place equal value on the patients and general public whose experience, talents and stories enrich the life of the Institute.
We are firmly embedded within our east London community, with an approach to education and research that is driven by the specific health needs of our diverse population.
A unique feature of endocrinology research at the William Harvey Research Institute is our focus on life-course consequences of endocrine and metabolic diseases from conception to old age and their biological bases.
The aim of A.D.R.E.N.A.L. is to identify genetic mutations that cause Primary Adrenal Insufficiency (PAI).