Intellectual disability, defined as an IQ below 70, has a prevalence of 1.5 to 2%. Severe forms with an IQ of <50 have a prevalence of 0.3 to 0.4%. Males are more frequently affected due to X-linked genes. The causes of a reduction in intelligence are manifold; genetic factors, however, are involved in at least 50% of cases. With the examinations that have been possible so far, such as chromosome analysis, array CGH and targeted diagnostics (e.g., fragile X syndrome, Rett syndrome, Angelman syndrome), about 60% of the causes of developmental disorders remain unexplained. Several studies in recent years in which patients with severe intelligence impairment (IQ <50) were examined using new high-throughput sequencing (NGS) could confirm that dominant pathogenic de novo variants appear to contribute to a significant extent to the cause of severe intelligence impairment (e.g., Vissers L. et al, Nat Genet, 2010, de Ligt, J. et al, NEJM, 2012 and Rauch, A. et al, Lancet, 2012). According to these studies, it is assumed that up to about 30% of severe, non-syndromic developmental disorders are caused by de novo point mutations and small indels, with a large amount of genetic heterogeneity observed. In addition, autosomal recessive mutations also play a role in developmental disorders (approximately 13-24%), as well as mutations in X chromosomal genes (5-10% of male sufferers). As a further diagnostic tool, there is the possibility of using Next Generation Sequencing (NGS) for the simultaneous analysis of numerous genes related to neurological or developmental disorders that are already listed in databases.
In a number of developmental disorders, other symptoms are also at the forefront, such as autism spectrum disorders or conspicuous growth parameters, e.g., macrocephaly, microcephaly or macrosomia. In addition, there are syndromic forms of developmental disorders for which further syndromes and thus further pathological genes come into question for differential diagnosis (e.g., Rett and Rett-like syndromes). Finally, some better known, genetically heterogeneous syndromes are listed here, which can be effectively investigated by means of NGS (Cornelia de Lange syndrome, RASopathies, among others).
Alternatively, advanced diagnostics using clinical or whole exome analysis (CES/WES) is also possible.
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