How Do We Describe and Ascribe Clinical Significance to the Non-coding Genome?

Genomic sequencing has been used within the clinic for over a decade, yet our understanding of clinically significant genetic variation is largely limited to the protein-coding genome. Although international efforts are underway to systematically interrogate which non-coding genetic variants are clinically significant, translating these findings into clinical medicine remains a challenge. In this session, we will synthesize the literature on hundreds of clinically significant non-coding genetic variants that are known to cause Mendelian conditions via the disruption of gene regulatory elements. In addition, we will discuss the barriers that exist for describing these non-coding variants, as well as ascribing clinical significance to them. Specifically, we will go over challenges that are encountered when assigning nomenclature to regions outside of what is commonly defined as a “gene”. We will then explore challenges with annotating and summarizing the functional impact and clinical significance of non-coding variants within clinically-facing databases like ClinVar. Finally, we will provide examples of syndrome discovery in the Genomics England 100,000 Genomes Project using the recent ACMG/AMP guidelines for interpretation of non-coding variants. The session will end with a panel discussion that will explore how we can overcome these barriers to translate ongoing efforts to annotate the function of the non-coding genome into clinical medicine.

Learning Objectives:
1. Recognize our current knowledge of how non-coding variants contribute to Mendelian conditions
2. Summarize the current naming strategies for elements of the human genome
3. Evaluate how existing guidelines can be adapted for classifying non-coding variation
4. Identify critical data elements to describe functional effects of a variant in a database

Please note: This item is only available as part of the ASHG 2024 Annual Meeting Digital Pass.