{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T11:19:24Z","timestamp":1769426364948,"version":"3.49.0"},"reference-count":84,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ulsan City Research Fund","award":["1.200047.01"],"award-info":[{"award-number":["1.200047.01"]}]},{"name":"Korea Government","award":["RS-2023-00263429"],"award-info":[{"award-number":["RS-2023-00263429"]}]},{"name":"Alchemist Project of the Korea Evaluation Institute of Industrial Technology","award":["KEIT 20018560"],"award-info":[{"award-number":["KEIT 20018560"]}]},{"name":"Korea Planning & Evaluation Institute of Industrial Technology with support from the Ministry of Trade, Industry and Energy","award":["RS-2024-00435468"],"award-info":[{"award-number":["RS-2024-00435468"]}]},{"name":"Korea Health Technology R&D Project through the Korea Health Industry Development Institute","award":["RS-2025-25463093"],"award-info":[{"award-number":["RS-2025-25463093"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The neurofibromin 1 (NF1) splice-site mutation c.61-2A&gt;G (rs1131691100) is a rare, pathogenic, autosomal dominant variant that disrupts NF1 tumor-suppressor function, causing neurofibromatosis type 1 (NF1). Its pathogenic mechanism is poorly understood, and the potential for personalized therapeutic genome editing remains unknown due to the absence of a standard framework for investigating splicing disorders. Here, we performed a comprehensive multi-omics analysis of a de novo c.61-2A&gt;G case from South Korea, integrating short- and long-read whole genome sequencing, whole transcriptome sequencing, and methylation profiling. We confirm that c.61-2A&gt;G abolishes the canonical splice acceptor site, activating a cryptic splice acceptor 16 nucleotides downstream in exon 2. This splicing shift generates a 16-nucleotide deletion, causing a frameshift and premature stop codon that truncates the protein\u2019s N-terminal region. Long-read sequencing further reveals that the mutation creates a novel CpG dinucleotide, which is methylated in the majority of reads. Finally, we assessed therapeutic correction strategies, revealing that CRISPR-Cas9 prime editing is the only viable approach for in vivo correction. This study provides the first comprehensive multi-omics characterization of the NF1 c.61-2A&gt;G mutation and establishes a minimal framework for precision therapeutic development in silico in monogenic splicing disorders.<\/jats:p>","DOI":"10.3390\/ijms27031177","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T17:52:38Z","timestamp":1769190758000},"page":"1177","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neurofibromin 1 (NF1) Splicing Mutation c.61-2A&gt;G: From Aberrant mRNA Processing to Therapeutic Implications In Silico"],"prefix":"10.3390","volume":"27","author":[{"given":"Asta","family":"Blazyte","sequence":"first","affiliation":[{"name":"Korean Genomics Center (KOGIC), Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea"},{"name":"Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), College of Information and Biotechnology, Ulsan 44919, Republic of Korea"},{"name":"School of Medicine, Gachon University, Incheon 21565, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1291-2846","authenticated-orcid":false,"given":"Hojun","family":"Lee","sequence":"additional","affiliation":[{"name":"Korean Genomics Center (KOGIC), Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea"},{"name":"Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), College of Information and Biotechnology, Ulsan 44919, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changhan","family":"Yoon","sequence":"additional","affiliation":[{"name":"Korean Genomics Center (KOGIC), Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea"},{"name":"Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), College of Information and Biotechnology, Ulsan 44919, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sungwon","family":"Jeon","sequence":"additional","affiliation":[{"name":"AgingLab, Ulsan 44919, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaesuk","family":"Lee","sequence":"additional","affiliation":[{"name":"nSAGE, Incheon 21999, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Delger","family":"Bayarsaikhan","sequence":"additional","affiliation":[{"name":"nSAGE, Incheon 21999, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jungeun","family":"Kim","sequence":"additional","affiliation":[{"name":"Personal Genomics Institute (PGI), Genome Research Foundation (GRF), Osong 28160, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sangsoo","family":"Park","sequence":"additional","affiliation":[{"name":"Korean Genomics Center (KOGIC), Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juok","family":"Cho","sequence":"additional","affiliation":[{"name":"Korean Genomics Center (KOGIC), Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sun Ah","family":"Baek","sequence":"additional","affiliation":[{"name":"Korean Genomics Center (KOGIC), Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabin","family":"Byun","sequence":"additional","affiliation":[{"name":"Korean Genomics Center (KOGIC), Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bonghee","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Medicine, Gachon University, Incheon 21565, Republic of Korea"},{"name":"nSAGE, Incheon 21999, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4228-1299","authenticated-orcid":false,"given":"Jong","family":"Bhak","sequence":"additional","affiliation":[{"name":"Korean Genomics Center (KOGIC), Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea"},{"name":"Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), College of Information and Biotechnology, Ulsan 44919, Republic of Korea"},{"name":"AgingLab, Ulsan 44919, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"ref_1","first-page":"483","article-title":"Neurofibromatosis type I (von Recklinghausen\u2019s disease): A family case report and literature review","volume":"9","author":"Ghalayani","year":"2012","journal-title":"Dent. 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