Diagnostic Genetics at a Distance: Von Hippel-Lindau Disease and a Novel Mutation

Genetic testing at a distance is commonplace where members of a family with a segregating germline mutation are geographically separated. For the most part, this challenge is addressed through the intervention of health professionals in taking and/or processing blood samples for subsequent couriering of DNA to a referral laboratory. In some circumstances, however, the collecting of pivotal clinical material may involve direct patient involvement. We describe such a situation where noninvasive saliva samples were provided by members of a family manifesting Von Hippel-Lindau (VHL) disease. The analysis identified a novel mutation in the VHL gene that was used to exclude other family members as being at risk of VHL disease. 1. Introduction Von Hippel-Lindau (VHL) disease is an autosomal dominant familial cancer syndrome with a prevalence of approximately 1/39,000 births [1]. The most common tumours in VHL disease are renal cell carcinomas (RCCs), retinal and central nervous system haemangioblastomas, phaeochromocytomas, pancreatic islet tumours, and endolymphatic sac tumours (ELSTs) [2]. In patients with a family history of VHL, a diagnosis can be made with the finding of a single retinal or cerebellar haemangioblastoma, a phaeochromocytoma, or an RCC [3]. In the absence of a family history, a diagnosis can be made with two or more retinal or cerebellar haemangioblastomas or one haemangioblastoma and one visceral tumour [3]. Families can be characterised by the absence (type 1) or presence (type 2) of phaeochromocytomas [4]. VHL disease is due to germline mutation in the VHL tumour suppressor gene, which is located on the short arm of chromosome 3 [5]. The gene comprises three exons and encodes for two proteins: 30？kD (pVHL30, NP_000542.1 expressed from NM_000551.3; transcript variant 1) and 18？kD (pVHL18, NP_937799.1 expressed from NM_198156.2; transcript variant 2) [6]. The shorter pVHL18 protein is generated from alternative translation that starts from an internal methionine at codon 54 [6]. In nude mouse xenograft assays, both the pVHL30 (wildtype) and pVHL18 proteins function as tumour suppressors when introduced into clear-cell RCC cell lines lacking functioning VHL genes [6]. Over 1000 somatic and germline VHL gene mutations have been documented [7], although the web-accessible database at http://databases.lovd.nl/genomed/home.php?select_db=VHL, updated January 14, 2013, shows 430 unique variants with 18 of these identified using tumour samples. Nordstrom-O’Brien et al. report a mutation spectrum of 43.2% in exon 1, 17% in exon 2, and 39.8% in exon