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Professor Karen Temple and Professor Deborah Mackay’s groundbreaking research in medical epigenetics defines the phenotypes and elucidates the molecular mechanisms of genomic imprinting disorders, which have grown from unknown or barely known entities in the 1990s to a spectrum of well-characterised congenital conditions affecting 1 in 3000 people worldwide.
Imprinting disorders (IDs) are congenital conditions involving imprinted genes whose expression is regulated by the parent from whom they are inherited. While some patients have genetic mutations in these genes, the majority have epigenetic mutations – those that change not their genetic sequence, but the way genes are expressed.
IDs affect approximately 1 in 3000 children worldwide, have a major impact on the way a child grows and develops; their metabolism, behaviour, cancer risk and overall quality of life. However, an early diagnosis can mitigate these problems through appropriate treatment and surveillance.
In 2000, the Wessex Imprinting Group, led at the University of BOB体育登录网址_欧宝体育官网平台-APP|下载 by Professor Mackay, discovered the mutations causing Transient Neonatal Diabetes Mellitus (TNDM), defining it as an imprinting disorder and developing effective diagnosis for patients.
In 2006, Professors Temple and Mackay established the?International Transient Neonatal Diabetes Register to learn about the history and long-term effects of TNDM and how best to manage it.
A study of the 90 TNDM patients on the Register showed that some had imprinting errors across different parts of the genome, known as multi-locus imprinting disorders (MLID).
By developing an international cohort of MLID patients, Professors Temple and Mackay identified an underlying single-gene cause of MLID, the ZFP57 mutation, defining a new category of genetic, epigenetic disease.
TNDM is now clinically well recognised and the research group remains in periodic contact with patients and families worldwide through the Register.
The Register provided patients for a landmark study which showed that 38% of all neonatal diabetics have the imprinting disorder TNDM. As a result, all patients with neonatal diabetes receive early testing, including TNDM testing, as standard.
Additionally, sequencing for the ZFP57 mutation is now included in genetic testing for neonatal diabetes in the UK, France, Germany, Italy, Spain and Switzerland, as well as in other centres around the world.
Professors Temple and Mackay have identified new clinical disorders, most notably Temple Syndrome (TS) associated with growth restriction, decreased muscle tone, obesity and early puberty.
TS is now recognised as a key differential diagnosis for Silver-Russell Syndrome (SRS). Children are now being diagnosed with TS much earlier and can benefit from early intervention to mitigate against its effects.
The positive impact was observed by Research Director at the MAGIC Foundation, USA – the global leader in endocrine health, advocacy, education, and support – who stated that the patients who were diagnosed at one to three years old “are far leaner, their parents are educated and, in many cases, the whole family exercises together.”
Genetic testing for TS was developed and made available to the NHS in 2008. From 2008 to 2013, only 1% of SRS referrals received TS testing, but it has grown in recognition, and in 2019, TS testing was performed in 62% of SRS referrals.
In 2017, Temple established a multidisciplinary clinic in BOB体育登录网址_欧宝体育官网平台-APP|下载 treating UK patients with TS, SRS and other IDs. The clinic enrols five to 10 new cases per year and sees over 50 cases regularly.
BOB体育登录网址_欧宝体育官网平台-APP|下载 research demonstrated the clinical need for ID testing and has driven development of diagnostic kits by biotechnology company MRC Holland.
ID testing has grown substantially, to the benefit of patients and MRC Holland. Two decades ago, TNDM, TS and MLID were undefined disorders. One decade ago, testing was limited to a handful of specialist research centres. Now, commercial tests are available for all known IDs, making diagnosis available to patients internationally. The sale of the MLID test has increased 40-fold since its introduction in 2017.
| Staff Member | Primary Position |
|---|---|
| Deborah Mackay | Professor of Medical Epigenetics |
| Karen Temple | Professor of Medical Genetics, Honorary Consultant in Clinical Genetics,Co-lead of the Wessex Genome Medicine Centre |