Genetic and clinical characterization of a novel FH founder mutation in families with hereditary leiomyomatosis and renal cell cancer syndrome.

BACKGROUND: Hereditary leiomyomatosis and renal cell cancer syndrome is a rare autosomal dominant hereditary syndrome. Previously, we published the largest cohort of FH mutation carriers in Spain and observed a highly recurrent missense heterozygous variant, FH(NM_000143.4):c.1118A > G p.(Asn373Ser), in 104 individuals from 31 apparently unrelated families. Here, we aimed to establish its founder effect and characterize the associated clinical phenotype. RESULTS: Haplotype analysis confirmed that families shared a common haplotype (32/38 markers) spanning 0.61-0.82 Mb, indicating this recurrent variant was inherited from a founder ancestor. Cutaneous and uterine leiomyomatosis were diagnosed in 64.6% (64/99) and 98% (50/51) of patients, respectively, and renal cell cancer was present in 10.4% (10/96). The pathogenic FH_c.1118A > G variant is a Spanish founder mutation that originated 12-26 generations ago. We estimate that the variant may have appeared between 1370 and 1720. Individuals carrying this founder mutation had similar frequency of renal cell cancer and a higher frequency of renal cysts and leiomyomas than those in other cohorts of this syndrome. CONCLUSIONS: In the Spanish province of Alicante there is a high prevalence of HLRCC because of the founder mutation FH c.1118A > G; p.(Asn373Ser). The characterization of founder mutations provides accurate and specific information regarding their penetrance and expressivity. In individuals with suspected HLRCC from the province of Alicante, genetic testing by direct analysis of the founder FH c.1118A > G; p.(Asn373Ser) mutation may be a faster and more efficient diagnostic tool compared with complete gene sequencing.

Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Spain: Clinical and Genetic Characterization.

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancers (RCCs). We aimed to describe the genetics, clinical features and potential genotype-phenotype associations in the largest cohort of fumarate hydratase enzyme mutation carriers known from Spain using a multicentre, retrospective study of individuals with a genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records, analysed genetic variants and looked for genotype-phenotype associations. Analyses were performed using R 3.6.0. software. We included 197 individuals: 74 index cases and 123 relatives. CLMs were diagnosed in 65% of patients, ULMs in 90% of women, RCys in 37% and RCC in 10.9%. Twenty-seven different pathogenic variants were detected, 12 (44%) of them not reported previously. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants (p = 0.0380, p = 0.0015 and p = 0.024, respectively). This is the first report of patients with HLRCC from Spain. The frequency of RCCs was lower than those reported in the previously published series. Individuals with missense pathogenic variants had higher frequencies of CLMs, ULMs and RCys.

Biallelic MYH germline mutations as cause of Muir-Torre syndrome.

Muir-Torre syndrome is a rare, inherited disease predisposing of gastrointestinal and cutaneous tumours, such as keratoacanthomas and sebaceous gland adenomas. Muir-Torre syndrome is usually inherited in an autosomal dominant fashion and associated with mutations in the mismatch repair genes, predominantly in MLH1 and MSH2 genes. This report describes a man who has multiple adenomatous colon polyps, a gastric cancer, multiple colorectal cancers and sebaceous adenomas caused by biallelic MYH germline mutations. This finding demonstrates that MYH gene analysis should be considered in Muir-Torre families where no mismatch repair gene mutations have been found. Furthermore, this report contributes to characterize the clinical phenotype caused by biallelic mutations in MYH gene, which may share with other hereditary colon cancer syndromes.