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Abstract：
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.
RESULTS: 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.
CONCLUSIONS: This study highlights the common pathology and clinical importance of NCSVs in unsolved patients with NDD.
BACKGROUND: The present study was funded by grants from the National Natural Science Foundation of China, China Postdoctoral Science Foundation, the Hunan Youth Science and Technology Innovation Talent Project, the Provincial Natural Science Foundation of Hunan, The Scientific Research Program of FuRong laboratory, and the Natural Science Project of the University of Anhui Province.
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.
RESULTS: 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.
CONCLUSIONS: This study highlights the common pathology and clinical importance of NCSVs in unsolved patients with NDD.
BACKGROUND: The present study was funded by grants from the National Natural Science Foundation of China, China Postdoctoral Science Foundation, the Hunan Youth Science and Technology Innovation Talent Project, the Provincial Natural Science Foundation of Hunan, The Scientific Research Program of FuRong laboratory, and the Natural Science Project of the University of Anhui Province.
摘要：
背景：规范剪接位点（±2）之外的基因组变体可能会产生异常的mRNA剪接，其被定义为非规范剪接变体(NCSV)。然而,NCSV在神经发育障碍(NDD)中的临床解释在很大程度上是未知的.
方法：我们在47,574例NDD患者中调查了来自345,787个从头变异体（DNV）的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NDD的基因之间的关联。Minigene用于验证NCSV对mRNA剪接的影响。
结果：我们观察到NDD患者的NCSV明显多于对照组（p=0.02，比值比[OR]=2.05）。规范剪接变体（CSV）和NCSV对NDD患者的贡献比例相等（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％），导致40个候选基因的异常剪接，和9个基因(ARID1B，KAT6B,TCF4,SMARCA2,SHANK3,PDHA1,WDR45,SCN2A,SYNGAP1）在两个以上无关的NDD患者中存在具有相同变体的复发性NCSV。此外，59个NCSV中有36个（61.02%）是新的临床相关变体，包括ClinVar数据库中34个未报告和2个临床上相互矛盾或意义不确定的NCSV。
结论：本研究强调了未解决的NDD患者中NCSV的共同病理和临床重要性。
背景：本研究由国家自然科学基金资助，中国博士后科学基金,湖南省青年科技创新人才工程，湖南省自然科学基金,福荣实验室科研计划,和安徽省大学自然科学项目。
方法：我们在47,574例NDD患者中调查了来自345,787个从头变异体（DNV）的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NDD的基因之间的关联。Minigene用于验证NCSV对mRNA剪接的影响。
结果：我们观察到NDD患者的NCSV明显多于对照组（p=0.02，比值比[OR]=2.05）。规范剪接变体（CSV）和NCSV对NDD患者的贡献比例相等（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％），导致40个候选基因的异常剪接，和9个基因(ARID1B，KAT6B,TCF4,SMARCA2,SHANK3,PDHA1,WDR45,SCN2A,SYNGAP1）在两个以上无关的NDD患者中存在具有相同变体的复发性NCSV。此外，59个NCSV中有36个（61.02%）是新的临床相关变体，包括ClinVar数据库中34个未报告和2个临床上相互矛盾或意义不确定的NCSV。
结论：本研究强调了未解决的NDD患者中NCSV的共同病理和临床重要性。
背景：本研究由国家自然科学基金资助，中国博士后科学基金,湖南省青年科技创新人才工程，湖南省自然科学基金,福荣实验室科研计划,和安徽省大学自然科学项目。
