WHOLE GENOME SEQUENCING FOR THE DIAGNOSIS OF RARE GENETIC DISORDERS: DIAGNOSTIC YIELD AND CLINICAL VALUE

Abstract

Rare monogenic disorders collectively affect a substantial minority of the population, yet a large proportion of affected individuals remain without a confirmed molecular diagnosis even after exome sequencing, the current first-tier genetic test in most clinical settings. A landmark study sequencing the genomes of families with previously unexplained phenotypes, including both a large research cohort and an independent clinical replication cohort, reported an additional diagnostic yield of approximately eight percent among patients who had already undergone exome sequencing without a diagnosis, identifying pathogenic variation in regions and variant classes that exome sequencing systematically misses, including deep intronic, structural, and regulatory variants [1].