Erdheim-Chester disease associated with a novel, complex BRAF p.Thr599-Val600delinsArgGlu mutation

Document Type

Journal Article


B M J Group

Place of Publication

United Kingdom


School of Medical and Health Sciences


Originally published as: Bentel, J. M., Thomas, M. A., Rodgers, J. J., Arooj, M., Gray, E., Allcock, R., ... & Parry, J. (2017). Erdheim–Chester disease associated with a novel, complex BRAF p. Thr599_Val600delinsArgGlu mutation. BMJ Case Reports, 2017, bcr-2017. Available here.


BRAF mutation testing to determine eligibility for treatment with vemurafenib was performed on archival skin lesions of a 54-year-old patient diagnosed with Erdheim-Chester disease (ECD) in 1999. Sanger sequencing of DNA extracted from a 2008 skin lesion identified two non-contiguous base substitutions in BRAF, which were shown by next-generation sequencing (NGS) to be located in the same allele. Due to its long-standing duration, molecular evolution of disease was possible; however, both Sanger and NGS of a 2000 skin lesion were unsuccessful due to the poor quality of DNA. Finally, droplet digital PCR using a probe specific for this novel mutation detected the complex BRAF mutation in both the 2000 and 2008 lesions, indicating this case to be ECD with a novel underlying BRAF p.Thr599-Val600delinsArgGlu mutation. Although well at present, molecular modelling of the mutant BRAF suggests suboptimal binding of vemurafenib and hence reduced therapeutic effectiveness.