Gene identification in female patients with intellectual disability and skewed X-inactivation.

Intellectual disability (ID), with a prevalence of 2 % in thegeneral population, is one of the leading socio-economical problems of the Western world today and yet in 40 to 60 % of cases the etiologyis still unknown. ID is often associated with aberrations on the X-chromosome (X-linked ID, XLID). Traditionally, XLID studies were focused on male patients from XLID families. Females can be carrier of a mutation but are generally not affected because of inactivation of the mutant X-chromosome in all their cells (skewing). Mutations in X-linked genes are therefore generally not searched for in female ID patients. My project however, will focus on the identification and characterization of (novel) female-specific ID genes in sporadic female ID patients, using skewing of X-inactivation as a first selection criterion for further research. This choice is based on our recent finding that the severe syndromic clinical phenotype of two females is due to unfavorable skewed X inactivation i.e. the genetic defect is located on the active X chromosome. Therefore, the masking effect caused by random X-inactivation no longer plays a role. We will first define the X-inactivation status in female ID patients. Next, DNA samples from females with skewing will be genetically analyzed with high-resolution X-oligo-array and X-exome sequencing to identify mutations that could have led to the ID. Potential causality of confirmed mutations will be subjected to functional analysis including genotype/phenotype correlation studies and tissue expression/endophenotype correlation studies.
 

Keywords:Skewing of X-inactivation, Array-CGH, Exome sequencing, Intellectual disability, Female patients

Disciplines:Genetics, Systems biology, Molecular and cell biology, Medical imaging and therapy, Other paramedical sciences

Project type:PhD project