Carriers of COL3A1 pathogenic variants in Denmark: Interfamilial variability in severity and outcome of elective surgical procedures.

The study describes all patients in Denmark with vascular Ehlers-Danlos syndrome (vEDS). Carriers of pathogenic or likely pathogenic COL3A1 variants were retrospectively identified through registries and specialized clinics. Medical records were reviewed for vascular- or organ ruptures and invasive procedures performed. Identified families were divided by variant type (null, splice, and missense) and familial phenotypes (severe or attenuated). Families in which at least one carrier has suffered a major event before the age of 30 were classified as severe, whereas families in which at least three carriers had reached the age of 40 without a major event were classified as attenuated. Eighty-seven persons (59 still alive) from 25 families were included with a mean observation time of 44 years. Sixty-seven percent of patients could be subclassified in a familial phenotype. Thirty-one major events were observed. Eleven complications in 172 invasive procedures were recorded. No fatal complications to elective surgery were observed. The type of COL3A1 variant did not reliably predict phenotype, but a pattern of intrafamilial consistency emerged with some families showing an attenuated form of vEDS. Elective medical procedures appear to be safer than previously thought, although data only allow for conclusions regarding individuals from families with the attenuated form of vEDS.

Exploring the hereditary background of renal cancer in Denmark.

BACKGROUND: Every year more than 800 patients in Denmark are diagnosed with renal cell carcinoma (RCC) of which 3-5% are expected to be part of a hereditary renal cancer syndrome. We performed genetic screening of causative and putative RCC-genes (VHL, FH, FLCN, MET, SDHB, BAP1, MITF, CDKN2B) in RCC-patients suspected of a genetic predisposition. METHODS: The cohort consisted of forty-eight Danish families or individuals with early onset RCC, a family history of RCC, a family history of RCC and melanoma or both RCC- and melanoma diagnosis in the same individual. DNA was extracted from peripheral blood samples or cancer-free formalin-fixed paraffin-embedded tissue. RESULTS: One start codon variant of unknown clinical significance (VUS) (c.3G>A, p.Met1Ile) and one missense VUS (c.631A>C, p.Met211Leu) was found in VHL in a patient with RCC-onset at twenty-eight years of age but without other manifestations or family history of von Hippel-Lindau (VHL). Furthermore, in three families we found three different variants in BAP1, one of which was a novel non-segregating missense variant (c.1502G>A, p.Ser501Asn) in a family with two brothers affected with RCC. Finally, we found the known E318K-substitution in MITF in a RCC-affected member of a family with multiple melanomas. No variants were detected in CDKN2B. CONCLUSION: Although we did find three VUS's in BAP1 in three families and a pathogenic variant in MITF in one family, pathogenic germline variants in BAP1, MITF or CDKN2B are not frequent causes of hereditary renal cancer in Denmark. It is possible that the high prevalence of risk factors such as male gender, smoking and obesity has influenced the development of cancer in the patients of the current study. Further investigations into putative predisposing genes and risk factors of RCC are necessary to enable better prediction of renal cancer risk or presymptomatic testing of relatives in hereditary renal cancer families.