Diagnostics and diagnosis oriented research of mental retardation of unknown cause

Mental retardation is definied as an IQ < 70, significant limitation in
adaptive functioning and onset before the age of 18 years. The prevalence is
estimated to be 2-3%. Severe MR has a prevalence of about 0,5%, while mild MR
(IQ 50-70) is more common. There is a male excess of about 40%, partially due
to monogeneic X-linked MR. The societal and psychosocial buden of MR is high.
The percentage health budget spent on MR is the highest among the different
disease categories. Causes of MR are multiple and very often genetic; well
known examples are Down syndrome and fragile X syndrome. However, in the
majority of cases the etiology is unknown. The importance of having an
etiological diagnosis is that it shed light on the prognosis and the related
comorbidity and is therefore contributing to the management plan. Also it is a
prerequisite for a reliable genetic counseling to healthy relatives of MR
patients.

The main objective of the study is to reach an etiological diagnosis in as many
cases of a selected group of MR patients. The aim is to do so in at least
15-20% of hitherto unexplained MR.
Also an objective is the establishment of a genetic-diagnostic protocol, to be
used in the MR sector by the physicians in the care of the mentally handicapped
(AVG).
Besides it is expected to find:
- one or more new MR syndromes
- one or more new MR genes
- genotype-phenotype correlations

In the 3 involved institutions about 8000 MR patients are known. Based on the
inclusion and exclusion criteria about 400 cases will be selected by the AVG in
consultation with the research team. These 400 cases will be physically
examined and will have their blood sampled. Also their parents will be sampled
in order to differentiate between polymorphisms and causal defects. The
physical examination is primarily meant to delineate carefully the
dysmorphological phenotype. The blood sample will be used for the
identification of genetic defects (chromosomal defects, monogenetic defects and
genomic defects).
A MR clinic will be held twice a month in the UMC St Radboud, in which the PhD
student, clinical geneticists and on a consultative basis also a child
neurologist and paediatrician for metabolic diseases are participating.

The burden of the study is having good preparation and selection, low. The same
holds true for risks.