AI Article Synopsis
- The study investigates non-canonical splicing variants (NCSVs) and their potential role in neurodevelopmental disorders (NDDs) using a large dataset of de novo variants from patients.
- Researchers found a significant presence of NCSVs in NDD patients compared to controls and confirmed their impact on mRNA splicing through experiments.
- The findings suggest that NCSVs are clinically relevant, with many being novel variants, and highlight the need for further investigation into their role in the pathology of NDDs.
Article 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.
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.
Funding: 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10767160 | PMC |
| http://dx.doi.org/10.1016/j.ebiom.2023.104928 | DOI Listing |
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Article Synopsis
- The study investigates non-canonical splicing variants (NCSVs) and their potential role in neurodevelopmental disorders (NDDs) using a large dataset of de novo variants from patients.
- Researchers found a significant presence of NCSVs in NDD patients compared to controls and confirmed their impact on mRNA splicing through experiments.
- The findings suggest that NCSVs are clinically relevant, with many being novel variants, and highlight the need for further investigation into their role in the pathology of NDDs.
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