In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This frameshift mutation was found in 2 VHL type 1 family of 8 and of 7 individuals (family ID 2956; 2693), using PCR and SSCP sequencing. The mutation of c.226_228delTTC was referred to in the paper by c.439delTTC due to a difference in transcript sequence. In the first, Family 2956, 2/8 members had a retinal angioma (hemangioma), 4 had RCC, and 5 members had CNS hemangioblastoma. In Family 2693 3/7 members had a retinal angioma (hemangioma), 3 had RCC, and 3 members had CNS hemangioblastoma. This is possibly previously published in PMID 9829911, as well as one member in a future publication: PMID: 32179488

Molecular and clinical analysis of 126 French VHL families tested for renal involvement revealed 92 different mutations. 90 of these families had renal involvement. The p.P71Lfs*61 (c.211_212insT) germline variant of the VHL gene was detected in a family (ID 96). Members 5997 and 5993 have unknown renal involvement. Member 5999 presented with mild renal disease. The paper states that this family is previously reported in PMID 12202531, where 1 patient with this mutation is reported and assumed to be part of this family.

Patients presenting with cerebellar hemangioblastomas at the Mexican National institute of Neurology and Neurosurgery to were prospectively enrolled alongside family members, resulting in 84 patients in 7 families with VHL mutations, and subjected to peripheral blood draw and PCR-based mutation screening, as well as full clinical screening for symptomatic individuals. 19 individuals across two families (Family B and Family C) presented with a c.298dupA mutation, leading to a frameshift (p.T100Nfs 32). Among these individuals, 2 in Family B and 6 in Family C were asymptomatic at the time of screening (ages 2, 7, 9, 12, 13, 17, 20, and 29). Of the 4 symptomatic individuals in Family B, one presented at 44 with cerebellar hemangioblastoma and bilateral retinal angiomas; one presented at 16 with 4 cerebellar hemangioblastomas, 1 bulbar hemangioblastoma, 1 spinal hemangioblastoma, bilateral retinal angiomas, pancreatic cysts, and kidney cysts; one presented at age 26 with cerebellar hemangioblastoma, bilateral retinal angiomas, pancreatic cysts, kidney cysts, and renal cell carcinoma; and one presented at 28 with 1 cerebellar hemangioblastoma. Of the 7 symptomatic individuals in Family C, one presented at 45 with cerebellar hemangioblastoma, pancreatic cysts, kidney cysts, and renal cell carcinoma; one presented at age 21 with epididymal cystadenoma; one presented at 36 with 2 cerebellar hemangioblastomas, pancreatic cysts, kidney cysts, hepatic cysts, adrenal cysts, and bilateral renal cell carcinomas; one presented at 20 with spinal hemangioblastoma, pancreatic cysts, and kidney cysts; one presented at 13 with 2 spinal hemangioblastomas, one presented at 13 with cerebellar hemangioblastoma, one presented at 30 with cerebellar hemangioblastoma, pancreatic cysts, and kidney cysts. They were previously published in PMID: 20064270, however with a reportedly different variant: p.G34Rfs98 (c.99_100insA).

Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors reported a nucleotide deletion (i.e. 476G>C) which coincides with legacy variant nomenclature (AF010238.1) and was mapped to c.263G>C (NM_000551.3). PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS Hb, RCC, and Pheo was available. Case 8 had p.Trp88Ser mutation. All 5 examined family members were affected with renal cell carcinoma. Other demographics of the members were not described.

Clinical case report of a 32-year-old male presenting with hematuria. Blood and tissue samples were isolated and samples were paired-end multiplex sequenced on the Illumina HiSeq platform to a median target depth of >100×.A germline de novo nonsense mutation, c.358A>T leading to an early stop codon, was confirmed on exon 3 of the VHL gene. The man also presented with multiple renal cysts; renal cell carcinoma; capillary retinal angiomas; brain hemangioma; and spinal hemangioma. Confirmation of paternity and maternity was not described, therefore assumed de novo.

Germline mutations were found in 20 Brazilian VHL probands and their families. The F76del (c.226_228del) germline mutation was found in a VHL type 1 family of 5 affected individuals (VHL family 1). Of the 5 affected family members four patients had hemangioblastomas of the central nervous system and 2 had renal carcinoma. In family 1 genetic testing was performed in a non-symptomatic boy, since no relatives were alive for testing. Although many members of this family had already presented with HB, the diagnosis of VHL was confirmed after necropsy of the proband’s father, who died at 37 years from complications following emergency surgery for cerebellar HB. The necropsy showed many occult lesions related to VHL, including RC, multiple pancreatic and renal cysts, and cystadenoma of the epididymis. This variant was not found in 120 alleles from normal subjects in the Brazilian population.