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HLRCC is caused by germline inactivating pathogenic variants in the fumarate hydratase (FH) gene, which encodes the enzyme that catalyzes the interconversion of fumarate and L-malate. We utilized enzyme and protein mobility assays to evaluate the FH enzyme in a cohort of patients who showed clinical manifestations of HLRCC but were negative for known pathogenic FH gene variants. FH enzyme activity and protein levels were decreased by 50% or greater in three family members, despite normal FH mRNA expression levels as measured by quantitative PCR. Direct Nanopore RNA sequencing demonstrated 57 base pairs of retained intron sequence between exons 9 and 10 of polyadenylated FH mRNA in these patients, resulting in a truncated FH protein. Genomic sequencing revealed a heterozygous intronic alteration of the FH gene (chr1: 241498239\u00a0T\/C) resulting in formation of a splice acceptor site near a polypyrimidine tract, and a uterine fibroid obtained from a patient showed loss of heterozygosity at this site. The same intronic FH variant was identified in an unrelated patient who also showed a clinical phenotype of HLRCC. These data demonstrate that careful clinical assessment as well as biochemical characterization of FH enzyme activity, protein expression, direct RNA sequencing, and genomic DNA sequencing of patient-derived cells can identify pathogenic variants outside of the protein coding regions of the FH gene.<\/jats:p>","DOI":"10.1093\/hmg\/ddad131","type":"journal-article","created":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T15:27:22Z","timestamp":1691681242000},"page":"3135-3145","source":"Crossref","is-referenced-by-count":5,"title":["Cryptic splice mutation in the fumarate hydratase gene in patients with clinical manifestations of Hereditary Leiomyomatosis and Renal Cell Cancer"],"prefix":"10.1093","volume":"32","author":[{"given":"Daniel R","family":"Crooks","sequence":"first","affiliation":[{"name":"Urologic Oncology Branch , Center for Cancer Research, , 10 Center Drive, Bethesda, MD 20892 , United States"},{"name":"National Cancer Institute , Center for Cancer Research, , 10 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Laboratory for Cancer Research, , 1050 Boyles St., Frederick, MD 21072 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria J","family":"Merino","sequence":"additional","affiliation":[{"name":"Translational Surgical Pathology , Laboratory of Pathology Center for Cancer Research, , 10 Center Drive, Bethesda, MD 20892 , United States"},{"name":"National Cancer Institute, National Institutes of Health , Laboratory of Pathology Center for Cancer Research, , 10 Center Drive, Bethesda, MD 20892 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark W","family":"Ball","sequence":"additional","affiliation":[{"name":"Urologic Oncology Branch , Center for Cancer Research, , 10 Center Drive, Bethesda, MD 20892 , United States"},{"name":"National Cancer Institute , Center for Cancer Research, , 10 Center Drive, Bethesda, MD 20892 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan 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