Clinical genomics and precision medicine.

Area of Science:

• Genomics
• Precision Medicine
• Medical Genetics

Background:

• Precision Medicine relies on understanding individual genetic makeup for health and disease.
• Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) are key genomic analysis tools.
• WGS offers comprehensive variant detection, including single nucleotide and copy number variants, without exon capture.

Purpose of the Study:

• To evaluate the utility of Whole Genome Sequencing (WGS) for healthy individuals in the context of Precision Medicine.
• To address the challenges of variant penetrance and polygenic risk prediction in genomic health assessments.
• To determine if current WGS capabilities support reliable risk predictions for hereditary diseases in the general population.

Main Methods:

• Analysis of Whole Genome Sequencing (WGS) data.
• Examination of monogenic and polygenic disease architectures.
• Assessment of variant penetrance and its impact on disease prediction.
• Incorporation of ancestry data and Polygenic Risk Scores (PRS) development.

Main Results:

• WGS can identify both monogenic disease-causing variants and susceptibility variants for polygenic diseases.
• The major challenge of variant penetrance complicates direct disease risk prediction in healthy individuals.
• While Polygenic Risk Scores can be generated, current WGS analysis is not sufficiently developed for reliable hereditary disease risk prediction.

Conclusions:

• The genetic architecture of diseases is complex and often polygenic, with ancestry adding further complexity.
• Current evidence does not support the widespread use of WGS for predicting hereditary disease risks in healthy individuals.
• Whole Genome Sequencing (WGS) remains most valuable for diagnosing pathogenic variants in Mendelian diseases.