Pharmacogenomics & Precision Medicine

Pharmacological responses to drugs vary greatly across individuals. The importance of assessing the role of inherited variation in genes that affect pharmacokinetics (the absorption, distribution, metabolism and excretion [ADME] of a drug) and pharmacodynamics (the response of the organism to the drug) is now widely recognised (Schwarz, Gulilat and Kim, 2019). Genes involved in the encoding of drug-metabolising enzymes, drug transporters and drug targets are most commonly referred to as pharmacogenes.

Precision medicine or personalised medicine is an innovative approach to personalising disease prevention and treatment that takes into account differences in individuals’ genes, environments, and lifestyles. Advances in precision medicine have led to powerful discoveries that are tailored to specific characteristics of individuals, such as a person's genetic makeup, or the genetic profile of an individual's tumour.

Next-generation sequencing (NGS) represents an efficient and reliable method to evaluate the contribution of both common and rare polymorphisms to genetic variation in pharmacological research. Edinburgh Genetic’s comprehensive range of egSEQ NGS products provides researchers with the tools to conduct further research on rare variants to assess the functional and clinical significance and further clarify their effects and relevance. This enables a more precise prediction of drug phenotypes in patients and allows the implementation of genotype-based dose adjustments in clinical settings in the future (Schwarz, Gulilat and Kim, 2019). We offer a fully customisable solution with full bioinformatics solutions with reporting, enabling researchers and clinicians to realise the potential of personalised medicine for patients with rare diseases and cancer by helping to predict the future development of diseases, to make accurate diagnoses and to identify treatments.

Schwarz, U. I., Gulilat, M. and Kim, R. B. (2019) ‘The role of next-generation sequencing in pharmacogenetics and pharmacogenomics’, Cold Spring Harbor Perspectives in Medicine, 9(2), pp. 1–15. doi: 10.1101/cshperspect.a033027.

Maggo, S. D. S., Savage, R. L. and Kennedy, M. A. (2016) ‘Impact of New Genomic Technologies on Understanding Adverse Drug Reactions’, Clinical pharmacokinetics. Springer International Publishing, 55(4), pp. 419–436. doi: 10.1007/s40262-015-0324-9.

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Pre-Conception Screening

Whole genome mate-pair sequencing, which includes the whole genome sequencing of both parents and in the case of IVF, the embryo as well offers parents accurate screening for fetal aneuploidy and monogenetic diseases. In the case of IVF, preimplantation genetic testing for aneuploidy is a powerful and practical method in the setting of assisted reproduction for couples with recurrent miscarriages due to chromosomal abnormalities. The incidence of spontaneous abortions and abnormal pregnancy outcomes in couples with complex chromosomal rearrangements (CCRs) was estimated to be 48.3 and 53.7%, respectively but with the help of WGS testing on both the parents and the embryo before artificial implantation, this risk has shown to be greatly reduced (Ou et al., 2020).

Pre-Clinical Screening

The use of NGS offers safer and more accurate screening in early pregnancies, as early as 7 weeks. NGS results offer parents and clinicians valuable risk-based analyses to help make decisions about traditional clinical invasive testing that may carry a risk of miscarriage, including amniocentesis and chorionic villus sampling (CVS).

NGS can be utilised to verify the health of the fetus indirectly by assessing the health of the placenta. As cell-free DNA originating from the pregnancy is specifically derived from the trophoblast layer of the placenta, this offers unprecedented insight into the health of the placenta, an organ of great importance during pregnancy and one for which a noninvasive method of assessing its chromosomal health has never before existed. It is well established that chromosome aneuploidy, even when isolated to the placenta and not present in the fetus itself, can have devastating impacts on pregnancy health, resulting in serious placental insufficiency and perinatal morbidity and mortality as a result of severe

Post-Clinical Diagnosis

Following a positive prenatal ultrasound scan for fetal abnormalities after 11 weeks of gestation, the option for invasive testing (e.g. chorionic villus sampling or amniocentesis) becomes available. In foetuses that exhibit multiple multi-system major structural and selected other abnormalities, NGS technology enables the analysis of fetal genetic material obtained from the invasive procedure to allow for the further screening of multiple genes in one test (Mellis, Chandler and Chitty, 2018).

Read more about the role of NGS in prenatal testing.

 

Hancock, S., Johansen Taber, K., & Goldberg, J. D. (2021). Fetal screening and whole genome sequencing: where are the limits?. Expert Review of Molecular Diagnostics, 21(5), 433-435

 

Kilby, M. D. (2021) ‘The role of next-generation sequencing in the investigation of ultrasound-identified fetal structural anomalies’, BJOG: An International Journal of Obstetrics and Gynaecology, 128(2), pp. 420–429. doi: 10.1111/1471-0528.16533.

 

Lord, J. et al. (2019) ‘Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study’, The Lancet, 393(10173), pp. 747–757. doi: 10.1016/S0140-6736(18)31940-8.

 

Mellis, R., Chandler, N. and Chitty, L. S. (2018) ‘Next-generation sequencing and the impact on prenatal diagnosis’, Expert Review of Molecular Diagnostics. Taylor & Francis, 18(8), pp. 689–699. doi: 10.1080/14737159.2018.1493924.

 

Ou, J., Yang, C., Cui, X., Chen, C., Ye, S., Zhang, C., ... & Zhang, W. (2020). Successful pregnancy after prenatal diagnosis by NGS for a carrier of complex chromosome rearrangements. Reproductive Biology and Endocrinology, 18(1), 1-7.

 

Shum, B. O., Bennett, G., Navilebasappa, A., & Kumar, R. K. (2021). Racially equitable diagnosis of cystic fibrosis using next-generation DNA sequencing: a case report. BMC pediatrics, 21(1), 1-5.

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