Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer

Background: Hereditary leiomyomatosis and renal cell cancer ( HLRCC; OMIM 605839) is the predisposition to develop smooth muscle tumours of the skin and uterus and/ or renal cancer and is associated with mutations in the fumarate hydratase gene ( FH). Here we characterise the clinical and genetic features of 21 new families and present the first report of two African- American families with HLRCC. Methods: Using direct sequencing analysis we identified FH germline mutations in 100% ( 21/ 21) of new families with HLRCC. Results: We identified 14 germline FH mutations ( 10 missense, one insertion, two nonsense, and one splice site) located along the entire length of the coding region. Nine of these were novel, with six missense ( L89S, R117G, R190C, A342D, S376P, Q396P), one nonsense ( S102X), one insertion ( 111insA), and one splice site ( 138+ 1G > C) mutation. Four unrelated families had the R58X mutation and five unrelated families the R190H mutation. Of families with HLRCC, 62% ( 13/ 21) had renal cancer and 76% ( 16/ 21) cutaneous leiomyomas. Of women FH mutation carriers from 16 families, 100% ( 22/ 22) had uterine fibroids. Our study shows that expression of cutaneous manifestations in HLRCC ranges from absent to mild to severe cutaneous leiomyomas. FH mutations were associated with a spectrum of renal tumours. No genotype- phenotype correlations were identified. Conclusions: In combination with our previous report, we identify 31 different germline FH mutations in 56 families with HLRCC ( 20 missense, eight frameshifts, two nonsense, and one splice site). Our FH mutation detection rate is 93% ( 52/ 56) in families suspected of HLRCC.