| Title: |
Intronic branchpoint-to-acceptor variants underlying inborn errors of immunity |
| Authors: |
Alioua, Najiba; Lambert, Nathalie; Puel, Mathilde; Hanein, Sylvain; Bastard, Paul; Fusaro, Mathieu; Jaffray, Marie; Medel, Bernardita; Khellaf, Lydia; Seeleuthner, Yoann; Perin, Mélodie; Jacques, Corinne; Pasquet, Marlène; Olivier, Laura; Sepulveda, Fernando; Le Voyer, Tom; Cobat, Aurélie; Nitschké, Patrick; Galicier, Lionel; Schleinitz, Nicolas; Oksenhendler, Eric; Malphettes, Marion; Neven, Bénédicte; Moshous, Despina; Suarez, Felipe; Fieschi, Claire; Casanova, Jean-Laurent; de Saint Basile, Geneviève; Dorval, Guillaume; Picard, Capucine; Bustamante, Jacinta; Zhang, Peng; Rosain, Jérémie |
| Contributors: |
Howard Hughes Medical Institute; The Rockefeller University; St. Giles Foundation; French National Research Agency; Square Foundation; Grandir - Fonds de solidarité pour l’enfance; General Atlantic Foundation; Institut National de la Santé et de la Recherche Médicale; University of Paris Cité; French Foundation for Medical Research; Imagine Institute; Fondation Bettencourt-Schueller |
| Source: |
Journal of Human Immunity ; volume 1, issue 3 ; ISSN 3065-8993 |
| Publisher Information: |
Rockefeller University Press |
| Publication Year: |
2025 |
| Description: |
Clinical laboratories searching for pathogenic variants focus mostly on the protein-coding region and corresponding essential splicing sites. Screening for variants in intronic regions requires dedicated bioinformatics tools and detailed experimental studies to confirm deleteriousness and pathogenicity. We report intronic variants in a cohort of eight patients from seven kindreds with unexplained inborn errors of immunity (IEI). Using ad hoc bioinformatics tools, we identified seven kindreds carrying three branchpoint variants at three loci (BTK, SH2D1A, and WAS) and four AG-gain acceptor site variants at another four loci (DOCK8, NFKB1, STXBP2, and UNC13D). The variants were located between positions −9 and −49 relative to the wild-type acceptor site. The deleteriousness and, thus, pathogenicity of these variants were confirmed by exon-captured transcriptome studies and flow cytometry analyses of protein production or function. Our findings indicate that intronic variants should be systematically screened and investigated, even in clinical laboratory settings. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.70962/jhi.20250041 |
| DOI: |
10.70962/jhi.20250041/1947414/jhi_20250041.pdf |
| Availability: |
https://doi.org/10.70962/jhi.20250041; https://rupress.org/jhi/article-pdf/doi/10.70962/jhi.20250041/1947414/jhi_20250041.pdf |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.61CB38A8 |
| Database: |
BASE |