SUFU: A potential novel gene responsible for Lhermitte Duclos disease

Abstract Lhermitte-Duclos disease (LDD) is a rare dysplastic gangliocytoma of the cerebellum, typically presenting as a hamartomatous lesion in the posterior fossa. PTEN and the PI3K/AKT/mTOR pathway are involved in the pathogenesis of LDD. We present a case of a patient who incidentally was detected with LDD. A novel, pathogenic, heterozygous, de novo, splice site variant c.183-2A > G (NM_016169.4) in the SUFU gene was identified with targeted next-generation sequencing from genomic DNA. SUFU, a tumor suppressor gene, negatively regulates the hedgehog (Hh) signaling pathway. SUFU also influences WNT and PTEN/AKT/mTOR signaling pathways. While SUFU pathogenic variants are associated with various central nervous system (CNS) tumors, this is the first reported link between SUFU and LDD. The study delves into the role of SUFU in LDD development, establishing the novel SUFU variant as a potential genetic marker for the disease. Sanger sequencing and gel electrophoresis were applied to RNA isolated from blood to show that the variant disrupts splicing. DNA extracted from tumor tissue underwent NGS with the TWIST Exome 2.0 Panel. Results unveiled the de novo pathogenic SUFU (c.183-2A > G) and PTEN (c.389G > A) variants. In conclusion, this study establishes the first reported association between LDD and a germline, de novo SUFU variant, and sheds light on the crucial role of SUFU in LDD pathogenesis. It contributes to the broader understanding of genetic factors influencing this rare cerebellar disorder.