Rare and prevalent neurological conditions such as Parkinson’s disease, motor neurone disease, and epilepsy affect millions of people globally and can be life-threatening, with many severely affecting an individual’s quality of life. These diseases may be caused by a combination of genetic and environmental factors. Many of these factors are not yet fully understood. Although some diseases can be highly heritable, some do not follow set paths of inheritance and are not often the result of a single mutation. Advanced NGS technologies are helping accelerate research into areas such as epigenetics to investigate the complex relationship between heritable and nonheritable mutations to increase our understanding of diseases, leading to novel innovations in the diagnosis, treatment, and prevention of these diseases.
Whole exome sequencing (WES) and whole genome sequencing (WGS) with broad coverage of the genome offer pathways to finding new mutations relevant to diseases. Targeted sequencing panels for exploring the roles of specific genes. Identification of underlying mutations in neurodegenerative diseases is of crucial importance to researchers, clinicians and patients due to the heterogeneous nature of the genome and different clinical manifestations. Selecting suitable cost-effectiveness genetic tests based on coverage area, and sequencing depth can improve diagnosis, treatments, and prevention.
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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).
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
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.