Sha Youbao, Ortiz J Bryce, Bristow Sara L, Loranger Kate, Meng Linyan, Zhao Xiaonan, Xia Fan, Parmar Sheetal, ElNaggar Adam C, Xu Wenbo
Natera, Inc. Austin, TX.
Baylor Miraca Genetics Laboratories, LLC, Houston, TX.
Genet Med Open. 2024 Dec 10;3:101914. doi: 10.1016/j.gimo.2024.101914. eCollection 2025.
Although up to 25% of germline variants are predicted to affect splicing, most are classified as variants of uncertain significance (VUS) because of the limited understanding of their functional consequences. Here, we investigated the impact of RNA sequencing (RNA-seq) data on the ability to resolve splicing-related VUS.
Patients with VUS predicted to alter splicing identified through commercial hereditary cancer testing between October 2021 to July 2023 were included. RNA-seq was used to compare splicing patterns between patient blood samples and normal controls. VUS reclassification rates were calculated.
In total, 411 VUS in 52 genes predicted to affect splicing were included. RNA-seq results resolved 26.3% (108/411) of the VUS: 28 (6.8%) upgraded to pathogenic/likely pathogenic, and 80 (19.5%) downgraded to not reportable. Among the 28 upgraded, 17 (60.7%) were intronic, 9 (32.1%) were exonic missense variants, and 2 (7.1%) were exonic synonymous variants. Most of the VUS downgraded to not reportable were intronic (64/80, 80%). The remaining 16 (20%) of the downgraded VUS were synonymous variants.
This study underscores the utility of RNA-seq to detect variants that affect splicing and could have an impact on cancer risk assessment management and treatment.
尽管预计高达25%的种系变异会影响剪接，但由于对其功能后果的了解有限，大多数变异被归类为意义未明的变异（VUS）。在此，我们研究了RNA测序（RNA-seq）数据对解决剪接相关VUS能力的影响。
纳入2021年10月至2023年7月期间通过商业遗传性癌症检测鉴定出的预计会改变剪接的VUS患者。使用RNA-seq比较患者血液样本和正常对照之间的剪接模式。计算VUS的重新分类率。
总共纳入了52个预计影响剪接的基因中的411个VUS。RNA-seq结果解决了26.3%（108/411）的VUS：28个（6.8%）升级为致病性/可能致病性，80个（19.5%）降级为不可报告。在28个升级的变异中，17个（60.7%）是内含子变异，9个（32.1%）是外显子错义变异，2个（7.1%）是外显子同义变异。大多数降级为不可报告的VUS是内含子变异（64/80，80%）。其余16个（20%）降级的VUS是同义变异。
本研究强调了RNA-seq在检测影响剪接且可能对癌症风险评估管理和治疗产生影响的变异方面的实用性。
