Molecular and Clinical Profiles of Patients with RASopathies: Targeted Next-Generation Sequencing Panel Results and Identification of 14 Novel Disease-Causing Variants

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dc.contributor.authorAtes, Kubra
dc.contributor.authorOzturk, Murat
dc.contributor.authorEsener, Zeynep
dc.contributor.authorDogan, Mustafa
dc.contributor.authorGezdirici, Alper
dc.contributor.authorSarac, Hatice
dc.contributor.authorYeninarcilar, Busra
dc.date.accessioned2026-04-04T13:33:16Z
dc.date.available2026-04-04T13:33:16Z
dc.date.issued2025
dc.departmentİnönü Üniversitesi
dc.description.abstractIntroduction: RASopathies are among the most prevalent genetic syndromes caused by variants in the Ras/MAPK signaling pathway, affecting various systems such as the heart, craniofacial features, skin, musculoskeletal system, hearing, and vision. They can also increase the risk of secondary malignancies. Despite clinical overlaps, distinguishing features are crucial for diagnosis, as different variants lead to distinct clinical implications. This study reviews the molecular and clinical characteristics of RASopathies, focusing on neurofibromatosis type 1 (NF1) and non-NF1 RASopathies. Methods: The study analyzed 76 patients referred to our outpatient clinic over a 6-year period, all of whom were clinically diagnosed with RASopathy and confirmed in most cases by molecular testing. Patient files, clinical photographs, and laboratory results were reviewed and analyzed. A targeted multigene next-generation sequencing panel test was performed, followed by Sanger sequencing for both confirmation and segregation analysis. Multiplex ligation-dependent probe amplification was conducted in a patient with normal sequence results but strong clinical suspicion, to identify potential deletions. Results: We identified 44 pathogenic, 25 likely pathogenic variants, and 6 variants of uncertain significance based on American College of Medical Genetics and Genomics (ACMG) criteria. Among these, 14 novel variants were found - 13 in the NF1 gene and one in SOS1. NF1 variants were present in 51 cases. Additional variants, likely to represent clinically significant findings, were identified in PTPN11 (n = 11), RAF1 (n = 4), SOS1 (n = 3), RIT1 (n = 3), KRAS (n = 1), NRAS (n = 1), SOS2 (n = 1), and BRAF (n = 1). Diagnoses included 49 patients with NF1, 21 with Noonan syndrome, 2 with neurofibromatosis-Noonan syndrome, 2 with Noonan syndrome with multiple lentigines, and 1 with cardiofaciocutaneous syndrome. Here, 12% of NF1 variants were located in exon 21, 36% of PTPN11 variants in exon 3, and 75% of RAF1 variants in exon 7. Conclusion: RASopathies have a broad molecular and clinical spectrum, complicating diagnosis and management. Accurate clinical correlation and molecular analysis are essential, as different RASopathy syndromes can result from variants in the same genes, while the same syndrome may arise from different genetic alterations. This study identifies novel variants and emphasizes the need for precise diagnostic approaches in these complex disorders.
dc.identifier.doi10.1159/000549593
dc.identifier.issn1661-8769
dc.identifier.issn1661-8777
dc.identifier.pmid41496802
dc.identifier.scopus2-s2.0-105027369445
dc.identifier.scopusqualityQ4
dc.identifier.urihttps://doi.org/10.1159/000549593
dc.identifier.urihttps://hdl.handle.net/11616/109047
dc.identifier.wosWOS:001656212000001
dc.identifier.wosqualityQ4
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherKarger
dc.relation.ispartofMolecular Syndromology
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_WOS_20250329
dc.subjectNeurofibromatosis type 1
dc.subjectNext-generation sequencing
dc.subjectNoonan syndrome
dc.subjectNovel variant
dc.subjectRASopathy
dc.titleMolecular and Clinical Profiles of Patients with RASopathies: Targeted Next-Generation Sequencing Panel Results and Identification of 14 Novel Disease-Causing Variants
dc.typeArticle

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