Gene identification in Intellectual Disability Disorders in the era of Next Generation Sequencing: personalized genomics, phenomics and functional characterization

General Background
Intellectual Disability (ID) is a leading medical and socio-economic problem with a strong genetic component affecting approximately 1% of the population. So far, no more than a handful of autosomal genes have been well established as ID genes for which we understand the pathogenic nature of the mutations. The main reasons for this are that (a) ID is a genetically heterogeneous disease, and (b) the unavailability of affected tissue from patients, complicating functional validation. As a consequence, the majority of patients remains undiagnosed and there are virtually no targets for therapy. Absence of accurate and timely molecular diagnostics and therapeutics for this large group of rare diseases has a strong negative effect on the health management and lives of patients and relatives.

The overall aims of this project are:
  • Extend an already existing database from 7,000 to 10,000 clinically well characterized ID patients.
  • Develop a universally applicable method that judges the likelihood of any conserved candidate gene to be an ID gene
  • Generate disease-relevant functional data on at least a 100 candidate genes
  • Validate 30-40 novel ID genes with specific ID phenotypes

Project description
Whole genome or exome sequencing approaches have recently emerged as excellent discovery tools. De novo mutations in candidate ID genes are readily detected using a patient-parent sequencing approach, but the clinical relevance of these candidate ID genes remains to be established. In this project we propose to move 100 candidate ID genes from the discovery to the clinical and functional validation phase. For this we will use a 4-step systematic approach:
  • Select 100 candidate ID genes from diagnostic exome sequencing studies and literature, and establish the clinical characteristics seen in each patient.
  • Interrogate phenotypically similar patients selected from large cohorts (n=10,000) of clinically well-characterised ID patients for recurrence of mutated genes.
  • Apply disease-relevant high-throughput phenotyping in a highly efficient animal model, Drosophila, and
  • Establish causality of ID genes by combining human and fly phenotype data
We expect to find recurrent mutations in 30 to 40 validated ID genes, for which detailed clinical studies in patients and functional studies in Drosophila will provide crucial insight into the underlying clinical, molecular and cellular (neuro)pathologies. This will improve clinical and molecular diagnostics. Our unconventional, interdisciplinary research aims to meet a major challenge in genome research and diagnostics, applied to one of the most frequent and complex class of disorders.

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