Mutation screening of fumarate hydratase by multiplex ligation-dependent probe amplification: Detection of exonic deletion in a patient with leiomyomatosis and renal cell cancer

Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, PO Box 63, FI-00014 Helsinki, Finland.
Cancer genetics and cytogenetics (Impact Factor: 1.93). 07/2008; 183(2):83-8. DOI: 10.1016/j.cancergencyto.2008.01.010
Source: PubMed


Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a syndrome predisposing to cutaneous and uterine leiomyomatosis as well as renal cell cancer and uterine leiomyosarcoma. Heterozygous germline mutations in the fumarate hydratase (FH, fumarase) gene are known to cause HLRCC. On occasion, no FH mutation is detected by direct sequencing, despite the evident HLRCC phenotype in a family. In the present study, to investigate whole gene or exonic deletions and amplifications in FH mutation-negative patients, we used multiplex ligation-dependent probe amplification technology. The study material comprised 7 FH mutation-negative HLRCC patients and 12 patients affected with HLRCC-associated phenotypes, including papillary RCC, early-onset RCC, uterine leiomyomas, or uterine leiomyosarcoma. A novel FH mutation, a deletion of FH exon 1 that encodes the mitochondrial signal peptide, was detected in one of the HLRCC patients (1/7). The patient with the FH mutation displayed numerous painful cutaneous leiomyomas and papillary type renal cell cancer. Our finding, together with the two patients with whole FH gene deletion who had been detected previously, suggests that exonic or whole-gene FH deletions are not a frequent cause of HLRCC syndrome.

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    • "Large intragenic rearrangements have been reported in the cancer predisposing genes von Hippel-Lindau (VHL[MIM608537]) (Franke et al., 2009; Hoebeeck et al., 2005; Hattori et al., 2006), succinate dehydrogenase subunit B (SDHB[MIM185470]) (McWhinney et al., 2004), fumarate hydratase (FH[MIM136850]) (Ahvenainen et al., 2008) and breast cancer 1 (BRCA1[MIM113705]) (Swensen et al., 1997). Recently Kunogi et al. (Kunogi et al., 2010) published the first report of large intragenic FLCN deletions in two unrelated BHDS patients. "
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