Prioritizing de novo potential non-canonical splicing variants in neurodevelopmental disorders
Authors: Li K, Xiao J, Ling Z, Luo T, Xiong J, Chen Q, Dong L, Wang Y, Wang X, Jiang Z, Xia L, Yu Z, Hua R, Guo R, Tang D, Lv M, Lian A, Li B, Zhao G, He X, Xia K, Cao Y, Li J.
Source：EBioMedicine. 2023 Dec 18;99:104928.
Doi: 10.1016/j.ebiom.2023.104928
Background
Genomic variants outside of the canonical splicing site (±2) may generate abnormal mRNA splicing, which are defined as non-canonical splicing variants (NCSVs). However, the clinical interpretation of NCSVs in neurodevelopmental disorders (NDDs) is largely unknown.
Methods
We investigated the contribution of NCSVs to NDDs from 345,787 de novo variants (DNVs) in 47,574 patients with NDDs. We performed functional enrichment and protein–protein interaction analysis to assess the association between genes carrying prioritised NCSVs and NDDs. Minigene was used to validate the impact of NCSVs on mRNA splicing.
Findings
We observed significantly more NCSVs (p = 0.02, odds ratio [OR] = 2.05) among patients with NDD than in controls. Both canonical splicing variants (CSVs) and NCSVs contributed to an equal proportion of patients with NDD (0.76% vs. 0.82%). The candidate genes carrying NCSVs were associated with glutamatergic synapse and chromatin remodelling. Minigene successfully validated 59 of 79 (74.68%) NCSVs that led to abnormal splicing in 40 candidate genes, and 9 of the genes (ARID1B, KAT6B, TCF4, SMARCA2, SHANK3, PDHA1, WDR45, SCN2A, SYNGAP1) harboured recurrent NCSVs with the same variant present in more than two unrelated patients with NDD. Moreover, 36 of 59 (61.02%) NCSVs are novel clinically relevant variants, including 34 unreported and 2 clinically conflicting interpretations or of uncertain significance NCSVs in the ClinVar database.
Interpretation
This study highlights the common pathology and clinical importance of NCSVs in unsolved patients with NDD.
背景
典型剪接位点 （±2） 之外的基因组变异可能会产生异常的 mRNA 剪接，这被定义为非典型剪接变异 （NCSV）。然而，神经发育障碍 （NDD） 中 NCSV 的临床解释在很大程度上是未知的。
方法
我们调查了 47,574 名 NDD 患者的 345,787 个新发变异 （DNV） 中 NCSV 对 NDD 的贡献。我们进行了功能富集和蛋白质-蛋白质相互作用分析，以评估携带优先NCSV和NDDs的基因之间的关联。 Minigene用于验证NCSVs对mRNA剪接的影响。
发现
我们观察到NDD患者中的NCSVs（p = 0.02，比值比[OR] = 2.05）明显多于对照组。典型剪接变异 （CSV） 和 NCSV 对 NDD 患者的贡献比例相同（0.76% vs. 0.82%）。携带NCSV的候选基因与谷氨酸能突触和染色质重塑有关。Minigene成功验证了79个NCSV中的59个（74.68%），这些NCSV导致40个候选基因的异常剪接，其中9个基因（ARID1B、KAT6B、TCF4、SMARCA2、SHANK3、PDHA1、WDR45、SCN2A、SYNGAP1）携带复发性NCSVs，在两个以上的无关NDD患者中存在相同的变异。此外，59 例 NCSV 中有 36 例 （61.02%） 是新的临床相关变异，包括 34 例未报告和 2 例临床冲突解释或 ClinVar 数据库中意义不明的 NCSV。
解释
本研究强调了 NCSV 在未解决的 NDD 患者中的常见病理学和临床重要性。
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