With 1 in 50 people in European countries affected by inherited monogenic disease Genomic Medicine is a priority area for health systems globally.

Our Genomic Medicine theme drives the translation of experimental medicine studies into patient benefit through development of genetic diagnostic tools for disease identification, approaches for identification of genetic contribution to common disorders, as well as predicting responses to therapy, and effective therapeutic target validation.

Through identification of genetic contribution to common genetic disorders, predicting responses to therapy, and effective therapeutic target validation our Genomic Medicine theme aims to deliver deep human phenotyping of human gene knockouts, enable therapeutic target identification, validation and off-target prediction, to the Advanced Therapeutic platform, through Cluster 1, for cardio-metabolic, inflammatory, autoimmune disorders, malignancy and rare inherited diseases.

The Genomic medicine theme also aims to develop Genomic Biomarkers and Co-Diagnostics, to deliver identification of disease genes, genomic signatures for therapeutic and disease risk scores and gene-environment (microbiome) profiles, each delivered through Cluster 2 (Precision Medicine, for rare human diseases and autoimmune/inflammatory disorders and cancer.

Our BRC’s Genomic Medicine theme will deliver its aims through a series of programmes

  • Programme 1.  From Genomes to Mechanisms of Human Disease
    Focusing on rare mutations in the population, diagnostics in rare inherited diseases, and phenotype variations, this programme will enable target identification and validation for multiple non-coding signals, for both rare disease and hits from genome wide association studies.
  • Programme 2. Genomic interactions, a pipeline for risk analysis and therapeutic stratification
    This programme will develop a pipeline to define the architecture of genetic variants underlying a range of phenotypes,  and provide deep and single cell analysis for genomic stratification and prognostic biomarkers of disease.
  • Programme 3. Genome Classification and Therapeutic Analysis
    Through the application of human genetics (Programme 1) and integration of large-scale genomics with additional datasets (Programme 2) this programme will develop therapeutic target validation studies.


Discovery leading to new diagnostics in rare diseases.

The translational genetics theme within our BRC partnership established a pipeline for disease gene discovery, using targeted and whole exome (gene coding regions) DNA sequencing, across a broad and diverse range of rare inherited diseases. This has included cholestatic liver disease (Sambrotta, Nat Genet 2014), Ectodermal Dysplasia, (Petrof, AJHG 2014), Vici syndrome, Cullup, Nat Genet 2013, and Wiedemann-Steiner syndrome (Jones, AJHG 2012) but represents more than 10 previously unidentified genes underlying monogenic disorders. Whilst individually rare, resolution of the causal basis of what are diseases, typically conditions with life-long health related requirements, has a profound impact for the individuals, the immediate and in many cases the extended family.

Moreover, these discoveries have immediately been translated as diagnostic tools, through the addition to gene panels of the NHS UK Genetic Testing Network (UKGTN) and delivered through the regional Molecular Genetics Service at Guy’s. The discoveries have not only provided tools for confirmation/definition (molecular diagnosis) of a disease, but have enabled development of pre-symptomatic (before the onset of disease) tests, with important implications for patient decision-making. This may be the result of cascade testing when there is a family history of the condition by genetic testing of relatives at risk of disease development.

Disease monitoring through molecular genomics

In acute myeloid leukemia (AML), Grimwade and colleagues have created translational impact, through targeted sequencing to detect minimal residual disease

(Ivey, NEJM 2016). Despite recognized molecular heterogeneity, standard-risk treatment decisions in AML are based on a limited number of molecular genetic markers and the morphology-based assessment of remission. They hypothesised that sensitive detection of a leukemia-specific marker (e.g. a mutation in the gene encoding nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic disease during remission. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle and was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs. 30%; hazard ratio, 4.80; 95% confidence interval [CI], 2.95 to 7.80; P<0.001) and a lower rate of survival (24% vs. 75%; hazard ratio for death, 4.38; 95% CI, 2.57 to 7.47; P<0.001). Hence, they were able to track preleukaemic clones, and demonstrate that quantitation of NPM1-mutated transcripts, provides powerful prognostic information independent of other risk factors. These findings have been adopted into treatment assessment protocols, as evidence that quantitative monitoring of NPM1-mutated transcripts will improve patient outcomes in AML therapy.

Adoption of a novel method that provides accurate analysis of genetic defects in human embryos

We have developed a generic test now being used to provide a cost effective format and easily detect a large number of single-gene disorders and chromosomal abnormalities in in vitro fertilised embryos, a highly significant impact. The test resulted from King’s research to develop new strategies for pre-implantation genetic diagnosis (PGD), which involved developing a small number of DNA probes targeted around a known area of genetic risk to identify mutations as well as methods to detect chromosomal translocations (Renwick, Reprod Biomed Online 2006). Because the approach is of low cost and easy to apply, it is being used by IVF clinics worldwide as well as by the NHS. Specifically, the Guy’s Centre for PGD (licensed by the UK Human Fertilisation and Embryo Authority in 2008) has analysed over 50 genetic conditions affecting single genes and performed more than half of all the UK’s PGD testing. Embryos can now be tested using these techniques for any characterised inherited genetic disease prior to implantation with a 98% success rate. This approach has reduced the need for later prenatal diagnosis and termination of an affected foetus. At Guy’s alone, PGD has been used to identify the presence of high-risk genes for multiple inherited diseases in embryos from at-risk couples, including cystic fibrosis, Duchenne and Becker muscular dystophy, trisomy, Alport syndrome, Haemophilia A, Huntington’s disease and sickle-cell disease. Ultimately, King’s/Guy’s partnered research has helped couples avoid the risk of bearing children with inherited diseases or the distress of terminating pregnancies. In 2011, our Centre celebrated the birth of over 300 babies following PGD analysis.


Richard Trembath FMedSci

Professor of Medical Genetics and clinician scientist (clinically active); present Executive Dean, Faculty of Life Science and Medicine, KCL, past Vice-Principal for Health, Queen Mary University of London (2011-15), former Guy’s/King’s Comprehensive BRC Director (2007-2011), Board Executive, UK BioCentre (NIHR National Bio-sample Centre), Co-Director of East London Genes and Health, Board of the Hefce Catalyst Centre for Precision Medicine.