Neurology. Genetics · 2026
Variant Resolution Through RNA Testing and Affected Tissue Analysis in the Neurofibromatoses: A Case Series.
СтатьяНазвание и аннотация: Перевод в очереди
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Schatz Krista S, Applegate Carolyn D, Belzberg Allan J, Chen Yunjia, Romo Carlos G, Slobogean Bronwyn, Blakeley Jaishri, Dimachkie Mazen M
Аннотация
OBJECTIVES: This series reports 3 unrelated individuals with features of neurofibromatosis type 1 (NF1) and/or schwannomatosis (SWN) in whom variants of uncertain significance (VUSs) were resolved through RNA testing and tissue analysis, highlighting the clinical impact of these tests.
METHODS: Each patient's genetic testing identified a VUS that could have explained their clinical presentation. Because diagnostic criteria were not met, we performed VUS resolution. For patient 1, we conducted tissue analysis and RNA-based Sanger sequencing. For patients 2 and 3, RNA-based Sanger sequencing was pursued.
RESULTS: Tissue analysis and RNA testing reclassified the NF1 c.8050 + 93A>T VUS in patient 1 as pathogenic, confirming diagnosis of NF1. RNA testing of the NF2 c.448-5T>C VUS in patient 2 reclassified the variant as likely benign, ruling out diagnosis of germline neurofibromatosis type 2 (NF2). RNA testing of the SPRED1 c.377-13T>A VUS in patient 3 reclassified the variant as likely benign, ruling out diagnosis of germline Legius syndrome.
DISCUSSION: Because diagnostic criteria for NF1 and SWN include genetic testing, resolving VUSs in those who do not meet criteria is crucial for clinical care. In this article, we report 3 cases in which RNA testing and tissue analysis clarified pathogenicity of VUSs, thereby affecting clinical care, and in one case providing a definitive diagnosis.
METHODS: Each patient's genetic testing identified a VUS that could have explained their clinical presentation. Because diagnostic criteria were not met, we performed VUS resolution. For patient 1, we conducted tissue analysis and RNA-based Sanger sequencing. For patients 2 and 3, RNA-based Sanger sequencing was pursued.
RESULTS: Tissue analysis and RNA testing reclassified the NF1 c.8050 + 93A>T VUS in patient 1 as pathogenic, confirming diagnosis of NF1. RNA testing of the NF2 c.448-5T>C VUS in patient 2 reclassified the variant as likely benign, ruling out diagnosis of germline neurofibromatosis type 2 (NF2). RNA testing of the SPRED1 c.377-13T>A VUS in patient 3 reclassified the variant as likely benign, ruling out diagnosis of germline Legius syndrome.
DISCUSSION: Because diagnostic criteria for NF1 and SWN include genetic testing, resolving VUSs in those who do not meet criteria is crucial for clinical care. In this article, we report 3 cases in which RNA testing and tissue analysis clarified pathogenicity of VUSs, thereby affecting clinical care, and in one case providing a definitive diagnosis.