️ Episode 10: Consensus Guidelines for Antisense Oligonucleotide Variant Eligibility
In this episode of Base by Base, we delve into the N1C VARIANT consensus guidelines presented by Cheerie et al. (2025) in The American Journal of Human Genetics, which establish a standardized framework for assessing which pathogenic DNA variants are suitable candidates for antisense oligonucleotide (ASO) therapies. This perspective walks geneticists and researchers through every step—from verifying variant annotations and inheritance patterns to selecting among ASO strategies such as splice correction, exon skipping, transcript knockdown, and emerging upregulation approaches—providing practical flowcharts, definitions, and decision points to guide eligibility assessments .
Study Highlights: The N1C VARIANT guidelines emerged from an iterative, multi-institutional process involving rounds of piloting with clinicians, genetic counselors, and translational researchers, culminating in version 1.0 that integrates directed acyclic graph–based flowcharts and a five-tier classification schema (eligible, likely eligible, unlikely eligible, not eligible, unable to assess). These guidelines are complemented by twelve training videos illustrating example variant assessments, detailed resources for database consultation, and an interactive online eligibility calculator that enforces comprehensive review at each decision point, ensuring reproducibility and facilitating adoption in diagnostic and research settings .
Conclusion: By combining consensus-driven criteria with user-friendly tools and educational materials, the N1C VARIANT guidelines represent a foundational advance for the rare-disease community, empowering professionals to systematically prioritize pathogenic variants for ASO treatment development and to update assessments as ASO technologies evolve .
Reference: Cheerie, D., Meserve, M. M., Beijer, D., Kaiwar, C., Newton, L., Taylor Tavares, A. L., … Lauffer, M. C. (2025). Consensus guidelines for assessing eligibility of pathogenic DNA variants for antisense oligonucleotide treatments. American Journal of Human Genetics, 112(5), 975–983. https://doi.org/10.1016/j.ajhg.2025.02.017
License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International license (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/