Investigating the contribution of non-coding genetic variation to rare disorders

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Genetic testing is rapidly emerging as a cornerstone of medicine, enabling targeted therapies for patients with both common and rare disorders, and empowering patients, families and communities with knowledge about their condition. However, despite significant advances over the past decade, including the introduction of clinical whole genome sequencing, clinical genetics remains largely limited to the study of less than 1% of the genome, the exome. This limitation is thought to underlie the fact that clinical genomic sequencing is unsuccessful in elucidating the culprit pathogenic variant(s) for the majority of patients with presumed monogenic disorders who undergo testing. It is hypothesized that a significant percentage of these patients harbor pathogenic non-coding variants that disrupt the gene regulatory architecture of known Mendelian genes, a class of variants poorly illuminated using current sequencing approaches. Directly addressing this limitation requires a wholesale revision of how genetic testing is performed and interpreted, as is outlined in this proposal. Specifically, this proposal aims to overcome this fundamental limitation of human genetics by leveraging a novel approach we recently developed for simultaneously mapping the genetic and epigenetic landscape of a sample, thereby illuminating the functional impact of non-coding genetic variants that disrupt local chromatin architecture and gene regulatory patterns – Whole Epi-Genome Sequencing (WEGS). Using this approach, we plan to directly test the hypothesis that rare non-coding genetic alterations contribute to monogenic disorders. In Aim 1, we will use the WEGS approach to characterize the gene regulatory impact of non-coding sequence, structural and epigenetic alterations in healthy individuals as well as patients with known imprinting disorders. The goal of this aim is to establish the sensitivity and power of WEGS for identifying genetic variants that disrupt local chromatin architecture and gene regulatory patterns and improve our understanding of the functional impact of non-coding genetic variation. In Aim 2, we will directly evaluate the contribution of rare non-coding genetic alterations to monogenic disorders by applying WEGS to patients with suspected monogenic disorders for whom whole exome or genome sequencing has previously been non- diagnostic. Overall, this proposal has the potential to dramatically change how we approach genomic testing and our understanding of the impact of non-coding sequence and structural variation on gene regulatory patterns and human disease.