Genomic medicine and risk prediction across the disease spectrum

Referees: Prof Jeanine Marnewick, Cape Peninsula University of Technology, Health and Wellness Sciences, Cape Town, South Africa; Prof. Rafael Rangel-Aldao, Biotechnology, Simon Bolivar University, Venezuela

Abstract

Genomic medicine is based on the knowledge that virtually every medical condition, disease susceptibility or response to treatment is caused, regulated or influenced by genes. Genetic testing may therefore add value across the disease spectrum, ranging from single-gene disorders with a Mendelian inheritance pattern to complex multi-factorial diseases. The critical factors for genomic risk prediction are to determine: (1) where the genomic footprint of a particular susceptibility or dysfunction resides within this continuum, and (2) to what extent the genetic determinants are modified by environmental exposures. Regarding the small subset of highly penetrant monogenic disorders, a positive family history and early disease onset are mostly sufficient to determine the appropriateness of genetic testing in the index case and to inform pre-symptomatic diagnosis in at-risk family members. In more prevalent polygenic non-communicable diseases (NCDs), the use of appropriate eligibility criteria is required to ensure a balance between benefit and risk. An additional screening step may therefore be necessary to identify individuals most likely to benefit from genetic testing. This need provided the stimulus for the development of a pathology-supported genetic testing (PSGT) service as a new model for the translational implementation of genomic medicine in clinical practice. PSGT is linked to the establishment of a research database proven to be an invaluable resource for the validation of novel and previously described gene-disease associations replicated in the South African population for a broad range of NCDs associated with increased cardio-metabolic risk. The clinical importance of inquiry concerning family history in determining eligibility for personalized genotyping was supported beyond its current limited role in diagnosing or screening for monogenic subtypes of NCDs. With the recent introduction of advanced microarray-based breast cancer subtyping, genetic testing has extended beyond the genome of the host to also include tumor gene expression profiling for chemotherapy selection. The decreasing cost of next generation sequencing over recent years, together with improvement of both laboratory and computational protocols, enables the mapping of rare genetic disorders and discovery of shared genetic risk factors as novel therapeutic targets across diagnostic boundaries. This article reviews the challenges, successes, increasing inter-disciplinary integration and evolving strategies for extending PSGT towards exome and whole genome sequencing (WGS) within a dynamic framework. Specific points of overlap are highlighted between the application of PSGT and exome or WGS, as the next logical step in genetically uncharacterized patients for whom a particular disease pattern and/or therapeutic failure are not adequately accounted for during the PSGT pre-screen. Discrepancies between different next generation sequencing platforms and low concordance among variant-calling pipelines caution against offering exome or WGS as a stand-alone diagnostic approach. The public reference human genome sequence (hg19) contains minor alleles at more than 1 million loci and variant calling using an advanced major allele reference genome sequence is crucial to ensure data integrity. Understanding that genomic risk prediction is not deterministic but rather probabilistic provides the opportunity for disease prevention and targeted treatment in a way that is unique to each individual patient.

• Breast cancer
• database
• exome
• genome
• hg19
• major allele reference sequence
• metabolic syndrome
• multiple sclerosis

Acknowledgements

Dr Lynn Horn at Stellenbosch University is acknowledged for valuable advice related to the ethical aspects that had to be taken into account during development of a combined service and research platform. Dr Ruhan Slabbert and Carel van Heerden of the Central Analytical Facility, Stellenbosch University, are thanked for exome sequencing and variant calling using both the hg19 reference sequence and an advanced major allele reference sequence on the same samples. Family practitioner Dr Hein Badenhorst and registered dietitian Lindiwe Whati are thanked for their valuable contribution to the development of the questionnaire and nutrition scores used in the genomics-based chronic disease screening/wellness program. Roberta Rooney is thanked for her valuable contribution to the multiple sclerosis study over many years and Dieter Geiger for research co-ordination. Lujane Nutt, Theresa Brand and Janine Cronje are thanked for assistance with the informed consent process, literature review and administrative support. Dr Mike Urban is acknowledged for helpful discussions and clinical oversight.

Declaration of interest

Research reported in this publication was supported by the Strategic Health Innovation Partnerships (SHIP) Unit of the South African Medical Research Council (MRC) with funds received from the South African Department of Science and Technology (Research grant number S003665). The MRC is also acknowledged for an internship grant awarded to KE Moremi and a capacity development grant awarded to Y. Y. Yako towards development of the laboratory standard operating procedures in the Pathology Research Facility at Stellenbosch University. This work is also based on the research supported in part by the National Research Foundation (NRF) of South Africa (UID 83962). The Grantholder acknowledges that opinions, findings and conclusions or recommendations expressed in any publication generated by the NRF supported research are that of the authors and that the NRF accepts no liability whatsoever in this regard. The Cancer Association of South Africa is acknowledged for a travel grant awarded to doctoral student N van der Merwe. Financial support from Winetech and the Technology for Human Resources and Industry Program (THRIP) contributed to the development of a Short Course for clinician education registered at Stellenbosch University in October 2014. M. J. Kotze is a director and shareholder of Gknowmix (Pty) Ltd. that has developed a database tool for research translation under the auspices of the Innovation Centre of the South African Medical Research Council (MRC). The Support Program for Industry Innovation is gratefully acknowledged for financial support towards development of the Gknowmix™ Genetic Knowledge Integration System (2007–2009) and Clinical & Scientist Interface Model (2009–2012). In this context, the Technology Innovation Agency is also acknowledged for internship grants awarded to Leslie Fisher, Nicole van der Merwe and Jacobus Pretorius (2013–2014). M. J. Kotze, S. J. van Rensburg, F. J. Cronje and A. V. September are listed as inventors on patents filed by the MRC and the Universities of Stellenbosch and Cape Town. The remaining authors declared no declarations of interest and no writing assistance was obtained in the preparation of this manuscript.

Notes

Referees: Prof Jeanine Marnewick, Cape Peninsula University of Technology, Health and Wellness Sciences, Cape Town, South Africa; Prof. Rafael Rangel-Aldao, Biotechnology, Simon Bolivar University, Venezuela