Categories: Neoplasm , Integument (skin) phene , Renal / urinary system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 135150 (trait) , 607273 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2003

Species-specific name: Renal cancer syndrome, nodular dermatofibrosis and kidney disease

Species-specific symbol: RCND

Inheritance: A pedigree analysis by Lium and Moe (1985) implicated autosomal dominant inheritance, which was confirmed by Moe et al. (1998).

Mapping: Using a genome scan with mapped microsatellites, Jónasdóttir et al. (2000) mapped the RCND locus to "a small region of canine chromosome 5. The closest marker, C02608, is linked to RCND with a recombination fraction (θ) of 0.016, supported by a logarithm of odds score of 16.7". To the authors' knowledge, this was "the first localization of a mammalian cancer syndrome to be mapped in a species other than human and rat".

Molecular basis: The causal mutation was discovered via a comparative positional cloning approach. Building on the mapping results described in the Mapping section above, Lingaas et al. (2003) narrowed the candidate region homologous to human HSA17p, which includes the BHD gene, mutations in which cause Birt–Hogg–Dubé syndrome, which is very similar to the canine disorder. Sequencing of the canine BHD gene showed that this disorder in German Shepherd dogs is due to an A>G base substitution in exon 7 of the BHD (folliculin) gene, leading to a H255R amino-acid substitution in a highly conserved region. Using genetic variant nomenclature as of 2015, the causative variant would be denoted as c.764A>G or p.His255Arg.

Clinical features: As summarised by Lingaas et al. (2003), "The disease is characterized by bilateral, multifocal tumors in the kidneys, uterine leiomyomas and nodules in the skin consisting of dense collagen fibers". Ciccarelli et al. (2019) reported a case of "Unilateral renal cystadenocarcinoma and nodular dermatofibrosis in a mixed-breed dog carrying . . . [the p.His255Arg] FLCN gene mutation", concluding that "This case supports the hypothesis that nodular dermatofibrosis is not a paraneoplastic syndrome associated with cystadenocarcinoma. It may be instead an independent dermatological feature of the same genetic disease, linked to the mutation of FLCN given that the cutaneous nodules in this dog increased in size and number after removal of the adenocarcinoma."

Breeds: Beagle (Dog) (VBO_0200131), German Shepherd Dog (Dog) (VBO_0200577), Mixed Breed (Dog) (VBO_0200902).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: