Peripheral Blood Epi-Signature of Claes-Jensen Syndrome Enables Sensitive and Specific Identification of Patients and Healthy Carriers with Pathogenic Mutations in KDM5C.

Claes-Jensen syndrome is an X-linked inherited intellectual disabilitycaused by mutations in the KDM5C gene. Kdm5c is a histone lysine demethylaseinvolved in histone modifications and chromatin remodeling. Males with hemizygous mutations in KDM5C present with intellectual disabilityand facial dysmorphism, while most heterozygous female carriers are asymptomatic. We hypothesized that loss of Kdm5c function may influence other components of the epigenomicmachinery including DNA methylationin affected patients. Genome-wide DNA methylationanalysis of 7 male patients affected with Claes-Jensen syndrome and 56 age- and sex-matched controls identified a specific DNA methylationdefect (epi-signature) in the peripheral blood of these patients, including 1769 individual CpGs and 9 genomic regions. Six healthy female carriers showed less pronounced but distinctive changes in the same regions enabling their differentiation from both patients and controls. Highly specific computational model using the most significant methylation changes demonstrated 100% accuracy in differentiating patients, carriers, and controls in the training cohort, which was confirmed on a separate cohort of patients and carriers. The 100% specificity of this unique epi-signature was further confirmed on additional 500 unaffected controls and 600 patients with intellectual disabilityand developmental delay, including other patient cohorts with previously described epi-signatures. Peripheral blood epi-signature in Claes-Jensen syndrome can be used for molecular diagnosis and carrier identification and assist with interpretation of genetic variants of unknown clinical significance in the KDM5C gene.