Authors
Anni Köhler, Alexandra A Baumann, Natasha Lewis, Anja Richter, Susan Richter, Doreen William, Andrés Cruz-García, Hanno Glimm, Stefan Fröhling, Diana Le Duc, Evelin Schröck, Arne Jahn
Published in
NPJ precision oncology. Volume 10. Issue 1. Sep 08, 2026. Epub Sep 08, 2026.
Abstract
Pathogenic germline variants in SDHB predispose to pheochromocytoma and paraganglioma, but limited functional evidence challenges clinical interpretation. To investigate splice-associated SDHB variants, we developed a minigene spanning exons 2-5 and assessed derived SDHB transcripts in HEK293T cells using targeted RNA sequencing. We evaluated 48 variants prioritized by SpliceAI (Δ≥0.42), two negative controls and endogenous SDHB, and compared findings with tumor data (n = 2). Nineteen variants (38%) showed ≥90% wildtype splicing, whereas 17 (34%) exhibited ≥90% aberrant splicing. Across all variants, 73 aberrant transcripts were observed (average of 2.3 per variant, 22 unique transcripts). Using a customized decision framework, RNA-based evidence strengths were assigned to 64 aberrant transcripts (88%). Among 26 classified variants, 10 received PVS1_Strong (RNA) (38%), including eight canonical splice-site variants, one missense variant and one stop-gain variant; two received PVS1_Moderate (RNA) and 14 received BP7_Strong (RNA). Integration of minigene RNA data changed ACMG scores by a mean of 2.7 points and led to reclassification of 13 variants (50%), including 12 downgrades from VUS to likely benign and one downgrade from likely pathogenic to VUS. These findings demonstrate that targeted sequencing of minigene-derived transcripts provides a scalable approach to evaluate splice-associated SDHB variants and improve variant classification.
PMID:
42711465
Bibliographic data and abstract were imported from PubMed on 09 Sep 2026.
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