Impact case study database

Queen Mary’s Centre for Endocrinology has greatly improved diagnosis and understanding of AI by characterising recessive gene mutations and developing a novel and cost-effective genetic screening panel that is helping patients to receive swift, appropriate, effective treatment and genetic counselling for this potentially life-threatening disorder.

Influencing international clinical guidelines and developing patient resources

Metherell was the first to link several genes – including CYP11A1, STAR, MC2R, MRAP, MCM4, NNT, TXNRD2 and SGPL1 – with AI and associated syndromes. This work led the European Society of Endocrinology and American Association for Clinical Chemistry to recommend that AI is diagnosed through genetic testing in 2015 [5.1].

Metherell has also contributed to:

• The International Classification of Paediatric Endocrine Diagnoses (ICPED) Consortium (Chapter 8, 2015) [5.2]

• The US National Institutes of Health patient guide [5.3] to understanding familial glucocorticoid deficiency, published in 2018 [3.2-3.5]

• The patient resource page Orphanet, through which she has been contacted by concerned parents seeking genetic testing for their children [5.4].

Changing clinical practice to ensure efficacy of treatment

As a result of these guidelines, genetic testing is now offered via the United Kingdom Genetic Testing Network (UKGTN) at Exeter [5.5], with approximately 10 tests offered per year. Understanding the precise genetic defects underlying an expression of AI is crucial to ascertain the correct course of treatment and ensure that it is neither excessive nor insufficient. Standard practice upon clinically diagnosing AI is 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 risk of developing further co-morbidities.

At the other extreme, standard practice may be insufficient. Genetic diagnosis of a SGPL1 defect, for instance, requires discussion between clinicians and patients, and patients must be monitored to ensure that no other features arise as a consequence of their AI (with kidney disease and neurological conditions being of particular concern). In this way, determining the genetic cause(s) of AI is essential in helping AI patients achieve optimal health and quality of life while avoiding unnecessary risk.

Developing a fast, accurate, cost-effective genetic testing panel, which has turned Queen Mary into a global referral centre

Metherell’s team has become a major global referral centre for AI [5.5], and has developed genetic screening strategies for AI to a) increase the accuracy of mutation detection, and b) reduce testing turnaround time to under three months — critical for clinical management for many AI families.

Figure 1: World map representing countries from which Queen Mary’s Centre for Endocrinology has tested patient samples.

The pre-existing genetic test for the five most common genes of interest in AI costs GBP750 per individual, but is only able to diagnose half of cases. By contrast, Queen Mary’s approach costs GBP600 per individual and diagnoses at least two-thirds of cases using targeted and whole exome high-throughput sequencing. This ensures timely and suitable treatment, while preventing costly further investigations when diagnosis cannot be made on phenotyping alone. Around 20 families a year from all over the world now send samples to Queen Mary for genetic analysis and diagnosis, and causal mutations have been identified in 66% of cases. To date, samples from 33 countries (represented in Figure 1) have been tested [5.6]. Approximately one-third of 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.

Metherell’s gene discoveries have also been incorporated into a Haloplex targeted array designed at GOSH for diagnosis of AI. The array was first used for a Turkish cohort study in 2016 [5.7], in which 95 patients from 85 families and their unaffected siblings and parents were recruited from 19 tertiary paediatric endocrinology clinics in Turkey – the largest ever nationwide study of the molecular genetics of childhood AI. A molecular diagnosis was achieved for 80% of the children.

Improving management of AI and reassuring worried families

AI patients require a definitive formal diagnosis to begin timely, appropriate treatment and genetic counselling, access support and relevant clinical trials, and understand how their disease will progress. The importance of diagnosis was confirmed by Prof. Catherine Choong, consultant endocrinologist at Perth Children’s Hospital who said, “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” [5.8]. Additionally, Metherell’s research has enabled clinicians to stratify levels of risk both during and after delivery of affected and unaffected children with “significant benefit to the health and safety of the parent and the neonate,” according to Prof. Choong [5.8].