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Intellectual Disability, Developmental Disorder (Overview)

Dipl.-Biol. Uwe Heinrich, Dr. med. Imma Rost

Scientific Background

An intellectual disability, defined as the IQ being lower than 70, has a prevalence of 1.5 to 2%; earlier data suggested 2 to 3%. More severe forms with an IQ of < 50 exhibit a prevalence of 0.3 to 0.4% (Leonhard H). Due to X chromosomal genes, boys/men are more frequently affected. There is a wide range of causes for an intellectual disability; in 50% of all cases, genetic factors are involved. Comorbidities such as behavioural disorders and/or epilepsies are frequently observed.

A clear diagnosis is highly important for patients and their families, as by knowing the cause of the disability clearly, it is usually possible to estimate prognosis, take on individual support measures if needed, forgo further elaborate diagnostic testing to find the cause of the disability and predict a possible risk of recurrence. There is an empiric recurrence risk of 8% for future pregnacies if the cause of an intellectual disability is unknown.

Although within the last few years a growing number of newer genetic syndromes have been identified with intellectual disability as one of their symptoms, in at least half of all cases the cause of an intellectual disability remains unknown.

In syndromal forms of an intellectual disability, a characteristical combination of malformations, minor physical abnormalities or characteristical behaviour may allow to suspect a certain diagnosis, which can then be tested with target diagnostics (e.g. Fragile X syndrome, Rett syndrome, Angelman syndrome). Many patients, however, exhibit uncharacteristic signs and symptoms that make it difficult even for the experienced pediatrician or clinical geneticist to establish a diagnosis. In this situation, the diagnostic approach when genetic causes were suspected has always been a global one i.e. the entire genetic material of the patient was analyzed, but with time the resolution gradually enhanced so that a range of “new” causes could be defined. The first analysis was, and still is in our diagnostic procedure, chromosome analysis, in which incorrect distribution of entire chromosomes, such as trisomies, or smaller parts of chromosomes, such as partial trisomies, can be detected. Approx. 15% of all developmental disorders are caused by chromosomal abnormalities that can be detected under the light microscope. However, even with a good resolution of 550 to 600 bands per haploid set of chromosomes which can be achieved in routine diagnostics, abnormalities that fall below 5-10 mb cannot be detected. Therefore, the second diagnostic step is a high resolution chromosome analysis by array CGH. Major studies have shown that what is known as copy number variations (CNVs), small submicroscopic deletions or duplications, are responsible for approx. 10 to 15% of all cases of an intellectual disability with normal chromosome analysis. Such CNVs are also frequently found in autism spectrum disorders, which can occur isolated or in combination with a developmental disorder. However, with the above-mentioned analyses, 60% of all causes of developmental disorders remain unknown.

Since developmental disorders frequently occur sporadically, i.e. as a single case within one family, experts suspected de novo mutations as a frequent cause, for example, in genes that are important for the development and rewiring of neurons, particularly since humans exhibit a high de novo mutation rate.

Several studies from the last years in which patients with intellectual disability were examined applying new high-throughput technologies such as exome sequencing have confirmed that dominant new gene mutations seem to play a major role in causing severe (IQ < 50) intellectual disability (e.g. Vissers L. et al, de Ligt, J. et al, Rauch, A. et al). While the risk for chromosomal trisomies rises with the age of the mother, the rate of dominant de novo mutations increases with the age of the father (Veltman JA). The patients exhibited variants in different genes; in the study of de Ligt et al., however, a causative mutation in a gene that had already been associated with developmental disorders was found in 16% of all patients, in the study of Rauch et al. in 35%. After these studies, it has therefore been assumed that up to 50% of the severe, non-syndromal developmental disorders are caused by de novo point mutations and small indels with a high genetic heterogeneity being observed. Proving an association between developmental disorders and mutations in unknown genes or genes that have not yet been associated with developmental disorders is highly time-consuming and requires functional tests, which is why exome sequencing (as well as genome sequencing) are not part of routine diagnostics yet. However, analysis by means of next generation sequencing (NGS) of a large number of genes at the same time that have been associated with neurological or developmental disorders and have been listed in the databases may be possible for diagnostics. To recognize inherited genetic variants during the complex analysis, trios, i.e. the affected child and its parents, should always be tested.

With next generation sequencing, it can be assumed that it will be possible to define probably another 30% of the so far unexplained causes of severe developmental disorders. In the future, the diagnostic procedure could therefore be as follows: