Abstract
BackgroundClaes-Jensen syndrome is an X-linked inherited intellectual disability caused by mutations in the KDM5C gene. Kdm5c is a histone lysine demethylase involved in histone modifications and chromatin remodeling. Males with hemizygous mutations in KDM5C present with intellectual disability and facial dysmorphism, while most heterozygous female carriers are asymptomatic. We hypothesized that loss of Kdm5c function may influence other components of the epigenomic machinery including DNA methylation in affected patients.ResultsGenome-wide DNA methylation analysis of 7 male patients affected with Claes-Jensen syndrome and 56 age- and sex-matched controls identified a specific DNA methylation defect (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 disability and developmental delay, including other patient cohorts with previously described epi-signatures.ConclusionPeripheral 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.
Highlights
Claes-Jensen syndrome is an X-linked inherited intellectual disability caused by mutations in the Lysine-specific demethylase 5C (KDM5C) gene
We demonstrate that the DNA methylation signature of Claes-Jensen syndrome has the potential to be used as a diagnostic tool for detection of both patients and healthy carriers with KDM5C mutations
We further show that this episignature is highly specific to KDM5C mutations, but not to the broad range of other Mendelian diseases resulting from the disruption of genes in the epigenomic machinery or other forms of developmental delay and intellectual disabilities (DD/ID)
Summary
Claes-Jensen syndrome is an X-linked inherited intellectual disability caused by mutations in the KDM5C gene. Males with hemizygous mutations in KDM5C present with intellectual disability and facial dysmorphism, while most heterozygous female carriers are asymptomatic. Mutations in the genes involved in the modification of histones cause a broad spectrum of Mendelian disorders [2]. Among these are mutations in the X-linked gene KDM5C, which encodes the histone H3 lysine 4 (H3K4) demethylase protein and causes Claes-Jensen syndrome [2]. The clinical manifestations in affected males carrying hemizygous KDM5C mutations include intellectual disability, impairments in adaptive behavior, slowly progressive spastic paraplegia, seizures, and facial dysmorphism [3, 4]. KDM5C is among the genes that escape Xchromosome inactivation; female mutation carriers usually remain unaffected but can demonstrate mild learning deficits [5]
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