Genomic profiling in mental retardation


General background
Mental retardation (MR) is defined by an IQ level below 70 and can be divided into mild (70-50), moderate (50-30) and severe (<30) level. It occurs in 2-3 % of newborns, and affects almost ½ million people in The Netherlands. Because of lifelong severity and poor curability the impact of MR is great, and there is great need for better basic knowledge. In clinical practice only ~50% of MR patients have received a proper diagnosis in The Netherlands. Any intervention or prevention in MR will require a much better insight into its underlying causes.

Patients with MR can be divided into non-syndromic and syndromic based upon the absence or presence of additional clinical features. Genetic anomalies especially chromosome aberrations are a major cause of MR. Microscopically detectable anomalies are mostly sporadic and usually cause MR in conjunction with physical malformations (=syndromic), because they lead to relatively large genetic imbalances (duplication/deletion of many genes). Three other genetic causes of MR exist. Single gene disorders can be transmitted through the germ line either as X-linked MR, which is largely limited to males, as dominant MR, which mostly occurs in a sporadic form, and recessive MR, which mostly affects sib-pairs. Despite significant progress, however, the genetic causes of MR remain largely unknown.

Objectives
This research project aims:
  1. to carefully phenotype a large cohort of patients with mental retardation
  2. to identify genomic disorders and genes causing dominant and recessive forms of mental retardation
  3. to unravel genetic networks underlying mental retardation

Approach
Within the current project phenotypically well-characterized patients are studied with three novel strategies in order to achieve a better understanding of the genetic networks underlying mental retardation.
  1. Clinical collection and phenotyping
  2. Different assay systems are used to identify the various genomic aberrations underlying mental retardation:
    1. Genome-wide deletion mapping: identification of dominant MR genes
    2. Genome-wide homozygosity mapping and expression profiling: identification of recessive MR genes
  3. Bioinformatics: towards genetic networks in mental retardation
  4. High throughput sequencing


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