Intellectual disability: genetic dissection promises clues to brain function
With a prevalence of about 2%, intellectual disability (ID) is one of the most important unsolved problems in health care. Mild forms of ID (intelligence quotient [IQ] 70 to 50) are thought to represent the lower end of the normal IQ distribution and to result from the interaction of many genes and non-genetic factors. In contrast, severe forms (IQ<50, incidence ~0.4%) may be due to catastrophic events such as perinatal hypoxia or, more often, specific genetic factors such as chromosomal aberrations and defects of specific genes.
Cytogenetically visible chromosomal aberrations are found in approximately 15% of all cases. The search for underlying gene defects has largely focused on the X-chromosome, because ID is significantly more frequent in males than in females. So far, roughly 60 different X-linked genes have been implicated in syndromic and non-syndromic forms of ID. However, recent data suggest that the role of X-linked gene defects in ID may be less important than previously thought.
Little is known about autosomal gene defects causing ID, because most of these cases are sporadic. Patients with autosomal dominant (AD) forms will seldomly reproduce, and in developed countries with small family sizes, autosomal recessive (AR) forms will be mostly sporadic, too. Functional considerations argue for AR-ID to be more common than AD-ID, and is has been speculated that up to 25% of all patients may carry AR gene defects.
We have employed various strategies to find gene defects underlying cognitive disorders, including breakpoint mapping in patients with balanced chromosome rearrangements, high-resolution array CGH, homozygosity mapping in large consanguineous families, and high-throughput mutation screening. Our results show that ID is an extremely heterogeneous disorder. Identification of the underlying genes provides unique opportunities for studying the function of the human brain and their possible role as genetic determinants of ‘normal’ intelligence.