BRK1 – von Hippel-Lindau Disease

Recent multi‑patient studies have revealed that deletion of BRK1 (HGNC:23057) constitutes a genetic modifier in von Hippel-Lindau disease (MONDO_0008667). In cohorts comprising 123 patients from 55 families (PMID:14695531), 119 patients from 50 unrelated families (PMID:37080588), and 127 individuals (PMID:19764026), the presence of a BRK1 deletion was consistently correlated with a lower prevalence of renal cell carcinoma. This genotype‑phenotype correlation supports a strong association between BRK1 alterations and modulation of von Hippel-Lindau disease severity.

Although von Hippel-Lindau disease is primarily attributed to alterations in the VHL tumor suppressor gene and follows an autosomal dominant inheritance pattern, these studies indicate that deletions spanning BRK1 provide additional prognostic information. The observed association, noted by significant differences in renal tumor manifestation when a BRK1 deletion is present, reinforces the clinical relevance of comprehensive genomic evaluation in affected individuals.

The genetic evidence is bolstered by robust analyses from multiple independent cohorts, with extensive segregation across families and concordant findings across studies. In contrast, direct functional assessments linking BRK1 to VHL pathophysiology remain limited. While a functional study in non‑small cell lung cancer demonstrated that Sp1 directly regulates BRK1 expression (PMID:24680773), no specific experimental model has yet validated the modifier role of BRK1 in VHL disease.

Overall, the integration of multi‑cohort genetic data with a lack of direct functional data yields a strong ClinGen gene‑disease association classification for BRK1 in the context of von Hippel-Lindau disease. The clinical utility of assessing BRK1 deletion status may enhance diagnostic decision‑making and risk stratification in patients with VHL.

Key Take‑home: Evaluating BRK1 deletion status in VHL patients can provide critical prognostic insights, supporting tailored clinical management.

References

• Human Mutation • 2004 • Solid renal tumor severity in von Hippel Lindau disease is related to germline deletion length and location PMID:14695531
• Journal of Medical Genetics • 2023 • Genotype-phenotype correlations and clinical outcomes of patients with von Hippel-Lindau disease with large deletions PMID:37080588
• American Journal of Medical Genetics. Part A • 2009 • Genotype-phenotype correlations in VHL exon deletions PMID:19764026

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