Heterozygous variants in the fumarate hydratase (FH) gene are associated with the autosomal dominant disorder hereditary leiomyomatosis and renal cell cancer (HLRCC). This was first proposed by Tomlinson et al in 2002 (PMID: 11865300). Numerous genetic studies have reported familial segregation of FH variants in families with leiomyomatosis or renal cell cancer. Affected individuals with heterozygous mutations had decreased fumarate hydratase enzyme activity in their lymphoblastoid cell lines although penetrance varies among individuals with similar decreases in FH activity. Tumors from HLRCC patients with a FH germline heterozygous mutations presented markedly reduced enzyme activity due to a second hit on FH, compared with tumors with similar histology from non HLRCC patients. There are substantial other functional assays demonstrating deficiency of FH activity and abnormality in smooth muscle differentiation. In summary, FH is definitively associated with HLRCC. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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