RNA-based diagnostic studies in genetics: Review and guidance from a multidisciplinary French network

Abstract

The widespread use of high-throughput sequencing for genetic diagnosis has led to considerable advances in patient care, but interpretation of the variants identified remains a challenge and geneticists routinely face the question of variants of uncertain significance. The clinical interpretation of genomic variants requires a high level of expertise to ensure appropriate genetic counseling. Assessing the impact of variants on splicing is a key issue in order to determine their pathogenicity as each variant can impact pre-mRNA splicing by disruption of the splicing code. It is for this reason that a diverse group of French molecular and clinical genetics experts from different diagnostic laboratories nationwide was established to discuss splicing issues and elaborate diagnostic recommendations. We describe an update of these recommendations with the aim of highlighting the importance of transcript characterization for variant interpretation and facilitating the diagnostic implementation of transcript studies, an important source of new diagnostics in human genetics.