Distinguishing Variant Pathogenicity From Genetic Diagnosis: How to Know Whether a Variant Causes a Condition

Genome sequencing (sequencing of nearly all DNA) and exome sequencing (sequencing of protein-coding DNA) allow broad assessment of a wide range of genetic variants for diagnostic purposes in conditions including epilepsy, autism, and intellectual disability.¹ Increasingly, genome and exome sequencing are being used in clinical settings when a genetic basis for disease is suspected, but the evaluation has not provided enough specificity to guide selection of a single gene test or a gene panel test. Sequencing is not currently indicated for healthy individuals for genetic risk screening,² but it is used for opportunistic screening through evaluation of secondary (ie, incidental) findings.³ Clinicians must understand how to interpret findings from sequencing in the context of multiple sources of information in order to make the best decisions regarding patient care.