Clinical Bioinformatics

Marcus J Hinchcliffe, Marcus J. Hinchcliffe

Exome sequencing for research has become available for broadly based genomic studies as well as smaller targeted investigations. New exome research projects being considered will intentionally process a large amount of common and rare DNA variation for the purpose of finding specific links between genotype and phenotype. However, the risks of uncovering a clinically relevant incidental finding are not uniform across projects but are highly dependent on the question being asked and exactly how it is intended to be answered.Factors that influence the possibility of revealing a clinically relevant incidental DNA variation include the following: The overall design of the study and the number of participants involved, the mode of inheritance of the phenotype including whether the phenotype is likely to have a monogenic or a complex inheritance, whether the study is assessing a known list of genes or not, and whether the causative DNA variation is likely to be rare or common. Importantly, differing bioinformatics DNA variant filtering strategies strongly influence the odds of discovering an incidental finding. This chapter provides a framework for understanding and assessing the likelihood of discovering clinically relevant, incidental DNA variations that are not directly related to the question being addressed in a particular exome research project. It also outlines DNA variant filtering and functional informatics approaches that can investigate specific genomic questions while minimizing the risks of uncovering an incidental finding.