Mosaicism in von Hippel–Lindau Disease: Lessons from Kindreds with Germline Mutations Identified in Offspring with Mosaic Parents

Abstract

von Hippel-Lindau disease (VHL [MIM 193300]) is a heritable autosomal dominant multiple-neoplastic disorder with high penetrance. It is characterized by brain and spinal-cord hemangioblastomas, retinal angiomas, clear-cell renal carcinoma, neuroendocrine tumors and cysts of the pancreas, pheochromocytomas, endolymphatic-sac tumors, and papillary cystadenomas of the epididymis and broad ligament. Although most index cases have a positive family history of VHL, some do not and may represent de novo cases. Cases without a family history of VHL may or may not have a germline mutation in their VHL tumor-suppressor gene. We present two cases of VHL mosaicism. In each of two families, standard testing methods (Southern blot analysis and direct sequencing) identified the germline mutation in the VHL gene of the offspring, but not in their clinically affected parent. Additional methods of analysis of the affected parents' blood detected the VHL-gene mutation in a portion of their peripheral blood lymphocytes. In one case, detection of the deleted allele was by FISH, and, in the second case, the 3-bp deletion was detected by conformational sensitive gel electrophoresis and DNA sequencing of cloned genomic DNA. Mosaicism in VHL is important to search for and recognize when an individual without a family history of VHL has VHL. Patients diagnosed without family histories of the disease have been reported in as many as 23% of kindreds with VHL. Identification of individuals potentially mosaic for VHL will affect counseling of families, and these individuals should themselves be included in clinical screening programs for occult disease.

Genetic analysis of von Hippel-Lindau disease

“…De novo germline and mosaic mutations have been documented in VHL patients [Martin et al, 1996;Murgia et al, 2000;Sgambati et al, 2000]. Our consolidated data (Supp .…”

“…Mosaic patients can have variable expression of VHL disease, from clinically silent to the full spectrum of disease, depending on the degree of mosaicism [Murgia et al, 1999;Sgambati et al, 2000]. In the case of suspected mosaicism, it is critical to determine the heritability of the disease for adequate counseling.…”

VHL mosaicism can be detected by clinical next-generation sequencing and is not restricted to patients with a mild phenotype

“…The prevalence of mosaicism in VHL, that is largely under-explored owing to the difficulty of its detection, is currently estimated to be around 5%. 3,4 However, the identification of mosaicism is important since it will influence both patient monitoring and genetic counseling in the relatives.…”

Family history of von Hippel–Lindau disease was uncommon in Chinese patients: suggesting the higher frequency of de novo mutations in VHL gene in these patients

“…16,17 Approximately 20% of VHL disease patients do not have a family history and carry a 'de novo mutation' . 18,19 Actually, these 'de novo mutations' may be inherited from their germline mosaic parents who are phenotypically normal and may have no mutations in their somatic cells. 4 Here, we used the methods of PCR-direct sequencing and UPQFM-PCR to investigate germline mutations in VHL in 16 probands diagnosed with VHL disease by clinical diagnosis criteria.…”