Clinical genomics and precision medicine

Abstract

Precision Medicine emerges from the genomic paradigm of health and disease. For precise molecular diagnoses of genetic diseases, we must analyze the Whole Exome (WES) or the Whole Genome (WGS). By not needing exon capture, WGS is more powerful to detect single nucleotide variants and copy number variants. In healthy individuals, we can observe monogenic highly penetrant variants, which may be causally responsible for diseases, and also susceptibility variants, associated with common polygenic diseases. But there is the major problem of penetrance. Thus, there is the question of whether it is worthwhile to perform WGS in all healthy individuals as a step towards Precision Medicine. The genetic architecture of disease is consistent with the fact that they are all polygenic. Moreover, ancestry adds another layer of complexity. We are now capable of obtaining Polygenic Risk Scores for all complex diseases using only data from new generation sequencing. Yet, review of available evidence does not at present favor the idea that WGS analyses are sufficiently developed to allow reliable predictions of the risk components for monogenic and polygenic hereditary diseases in healthy individuals. Probably, it is still better for WGS to remain reserved for the diagnosis of pathogenic variants of Mendelian diseases.

Whole Genome Sequencing in Era of Newborn Screening

“…Limitations of phenotypic driven panels can include missing diagnoses because the panel is not updated as rapidly as disorders are discovered or because of atypical presentations of conditions that were not included on the panel. Although the rate varies depending on the standards for diagnosing rare disease regionally, approximately 50% of individuals with a rare disease do not receive a diagnosis overall [14].…”

“…Comparing the genomes of affected and unaffected individuals identifies highly penetrant variants and susceptibility variants for disease. Such diseases are polygenic and the genotypes across associated loci can be used to calculate Polygenic Risk Scores (PRS) [14]. Understanding the complexities of the genetic interactions with disease can allow medical providers and the patient and their families to make decisions to help lower the risk of disease through lifestyle changes and improve surveillance.…”

“…In summary, understanding and diagnosing rare disease have many positive clinical outcomes. Besides diagnostic closure, these can include improved management, treatment/surveillance, understanding of disease progression, and recurrence counseling [14]. In addition to these direct clinical benefits, genomics studies contribute to the understanding the underlying pathophysiology of disease by defining variation associated with disease phenotypes [7].…”

Integrating oculomics with genomics reveals imaging biomarkers for preventive and personalized prediction of arterial aneurysms

“…Exploring biomarkers associated with aneurysms identified from routinely collected electronic health records might suffer from misclassification bias due to the asymptomatic nature of the disease. Genomics can provide unique data about an individual’s unique risk of disease [ 13 , 14 ] and genetic risks of aneurysms were stable and precise, which might assist in identifying robust biomarkers [ 15 , 16 ]. There have been several large-scale genome-wide association studies (GWAS) that report a potential shared genetic aetiology among the main types of aneurysms [ 17 – 21 ], including AAA, thoracic aortic aneurysm (TAA), intracranial aneurysm (ICA) and Marfan syndrome (MFS) in which the main complication is TAA [ 22 , 23 ].…”