Exome sequencing reveals germline gain-of-function mutation in an adult with Lhermitte-Duclos disease.

Lhermitte-Duclos disease (LDD) is a rare cerebellar disorder believed to be pathognomonic for Cowden syndrome. Presently, the only known etiology is germline mutation. We report a 41-yr-old white female diagnosed with LDD and wild-type for . Exome sequencing revealed a germline heterozygous mutation that breaks a disulfide bond in the receptor's extracellular domain, resulting in constitutive activation. Functional studies demonstrate activation of ERK/AKT signaling pathways, mimicking loss-of-function downstream effects. The identification of as a candidate LDD susceptibility gene contributes to advancement of molecular diagnosis and targeted therapy for this rare condition with limited treatment options.