Reference:
90700365
Abstract:
Intellectual disability (ID) affects 2% of our population, but still most ID patients remain undiagnosed mainly due to the huge genetic heterogeneity. It has recently become clear that the complexity of ID genes can be understood in terms of ﾓmodulesﾔ of several genes acting together in a single biological pathway or complex. ID is a particularly rich resource for the identification of biological modules because many genes are involved, and on the other hand there are numerous different clinically defined syndromes, which in turn can be grouped into phenotypically related syndrome families. Within few years, the genetic causes of ID will be discovered especially by next generation sequencing (NGS). In order to make sense of all this genetic information, I propose a modular approach to ID. It appears that mutations in genes that disturb epigenetic gene regulation contribute significantly to the prevalence of ID. Therefore the general aim of this study is to identify novel genetic causes responsible for ID that are active in similar genetic and epigenetic pathways and thereby reconstruct a ﾑchromatin modification moduleﾒ based on interconnective genotypes and phenotypes. The basis of my study population will be a unique homogeneous cohort of 150 patients with a phenotype reminiscent of Kleefstra syndrome. I have recently demonstrated that haploinsufficiency of Eu-chromatin Histone Methyl Transferase 1 (EHMT1) is the cause of this syndrome comprising ID and various associated features. The corresponding protein functions as an epigenetic modulator through mono- and dimethylation of lysine 9 histone 3 in euchromatic regions. Interestingly, in part of the cases from my cohort, no EHMT1 mutations have been detected, suggesting the involvement other genes in the module. The aim of this study is to identify such novel ID genes. My protocol consists of three complementary subprojects: 1.Building the phenotype network. I will select 50 patients with a phenotype reminiscent of Kleefstra syndrome but without an EHMT1 aberration. I have already collected clinical data and DNA of thepatients and their parents. I will re-evaluate and follow-up patients diagnosed with a causative genetic defect in order to establish genotype-phenotype relations and to provide accurate information for monitoring of co-morbidity to medical professionals and counseling of patients and families. Furthermore I aim to set up a digital clinical consultancies service (ﾑHealthbridgeﾒ) for families and medical specialists living and working on a distance both within and outside the Netherlands to disseminate the clinical and genetic knowledge of Kleefstra syndrome and related disorders in close collaboration with the department of “Geneeskunde voor mensen met verstandelijke beperkingen”. Finally, novel ID genes will be implemented for testing in the DNA diagnostic department which is of great importance for further genetic counseling of the patients and families. 2.Building the gene network. I will apply NGS to identify mutations by whole ﾓexomeﾔ sequencing of all 18.000 protein-coding genes. I will simultaneously anayse the patients and their parents “trio-study’. We are one of the few groups world-wide who already found several disease genes by this technology. I envisage an autosomal dominant model of inheritance, similar as for EHMT1 mutations. Therefore I shall test candidate changes for de novo occurrence. I have recently obtained strong support for my hypothesis by the identification of a de novo nonsense mutation in a gene encoding a modulator of chromatin structure in a patient with the typical Kleefstra syndrome phenotype. 3.Building the chromatin modification module of ID The challenge will be to put the novel identified genes into a relevant biological context. I will do this by identification of the genes that are normally regulated by the chromatin modification module and whose expression is disrupted in fibroblasts of patients with mutations in EHMT1 and other ID genes from the chromatin modification module.Determination of the gene expression patterns will be established by RNA-seq analysis.I have already personal experience with these technique by conducting such experiments with material from hippocampi derived from Ehmt+/- mouse mutants. Through collaborations, I will determine the histone methylation patterns (as H3K9me2) and extend my functional studies to model organisms and induced pluripotent stem cells generated from patient fibroblasts and re-differentiated into neural lineages. The identification of novel genetic causes and initiation of translational research will considerably increase specific knowledge on the clinical conditions within the module and are essential for studies on fundamental and neurobiological aspects of (epigenetic) processes disrupted in ID. This is a prerequisite for the development of new diagnostic and therapeutic approaches in ID and other related human disorders of the brain.
PROJECT DETAILS
beginning: 2011.
end: 2016.
Country of research: Netherlands
Counry of funding source: Netherlands
Funding organization: Netherlands Organisation for Health Research and Development
Financing: NATIONAL FUNDINGS – 160 000 €