Renal cell carcinoma (RCC) occurs in a number of cancer predisposition syndromes, but the genetic architecture of susceptibility to RCC is not well defined. We investigated the frequency of pathogenic and likely pathogenic (P/LP) germline variants in cancer susceptibility genes (CSGs) within a large series of unselected RCC participants. Whole-genome sequencing data on 1336 RCC participants and 5834 controls recruited to the UK 100 000 Genomes Project, a nationwide multicentre study, was analyzed to identify rare P/LP short variants (single nucleotide variants and insertions/deletions ranging from 1 to 50 base pairs) and structural variants in 121 CSGs. Among 1336 RCC participants [mean: 61.3 years (±12 SD), range: 13–88 years; 64% male], 85 participants [6.4%; 95% CI (5.1, 7.8)] had one or more P/LP germline variant in a wider range of CSGs than previously recognized. A further 64 intragenic variants in CSGs previously associated with RCC were classified as a variant of uncertain significance (VUS) (24 ‘hot VUSs’) and were considered to be of potential clinical relevance as further evaluation might results in their reclassification. Most patients with P variants in well-established CSGs known to predispose to renal cell carcinoma (RCC-CSGs) were aged <50 years. Burden test analysis for filtered variants in CSGs demonstrated a significant excess of CHEK2 variants in European RCC participants compared with the healthy European controls (P = 0.0019). Approximately, 6% of the patients with RCC unselected for family history have a germline variant requiring additional follow-up analysis. To improve diagnostic yield, we suggest expanding the panel of RCC-CSGs tested to include CHEK2 and all SDHx subunits and raising the eligibility criteria for age-based testing.

Background: Germline pathogenic variants in NSD1 cause Sotos syndrome, a developmental disorder characterised by overgrowth, intellectual disability, macrocephaly, developmental anomalies, and, in some cases, tumour development. Familial cases of Sotos syndrome are rare and genotype–phenotype correlations are not well described. NSD1, a lysine-specific histone methyltransferase, is an important epigenetic regulator and pathogenic variants in NSD1 are associated with a distinctive blood DNA methylation pattern (episignature). We described a family with an NSD1 exon 3 deletion and an atypical clinical phenotype. Methods: DNA episignature profiling was undertaken with a next generation sequencing-based approach. Results: Within the family, the three affected individuals showed clinical variability with the proband being most severely affected, although none showed unequivocal macrocephaly or the characteristic facial features of Sotos syndrome. DNA methylation profiling was performed in the three affected family members, eight individuals with Sotos syndrome, and compared to control samples. The eight individuals with Sotos syndrome displayed genome-wide hypomethylation as previously described. DNA hypomethylation was also apparent in the three family members with the NSD1 exon 3 deletion with the proband being most similar to the episignature observed in confirmed Sotos syndrome patients. The two more mildly affected relatives had less pronounced DNA hypomethylation. Conclusions: A familial germline exon 3 NSD1 deletion was associated with mild Sotos syndrome phenotype with variable expressivity and a DNA methylation episignature that was less marked in milder cases than in individuals with classical Sotos syndrome. These findings support the use of methylation episignature analysis to explore intrafamilial variability in chromatin disorders.