Intelligence impairment, defined as an IQ of less than 70, has a prevalence of 1.5% to 2%; earlier data reported 2% to 3%. More severe forms with an IQ <50 have a prevalence of 0.3% to 0.4% (Leonhard H). Males are more commonly affected due to X-linked genes. The causes of intelligence impairment are diverse; however, genetic factors are involved in at least 50%. Comorbidities such as behavioral disorders and/or epilepsies are common. An accurate diagnosis is crucial for the patients and their families because knowing the cause of the disability usually allows to estimate the prognosis, to initiate more individualized support measures if necessary, to avoid further costly diagnostic measures to find the cause and to make statements about a possible risk of recurrence. If the cause of an intelligence impairment is not clear, an empirical risk of recurrence of approx. 8% must be assumed for further pregnancies. Despite increasing numbers of new genetic syndromes associated with intelligence impairment in recent years, the cause of intelligence impairment still remains unclear in some patients.
In syndromic forms of intelligence impairment, a characteristic combination of malformations, minor external abnormalities or characteristic behavior may suggest a tentative diagnosis, which can be clarified with a target diagnosis (e.g., fragile X, Rett syndrome, Angelman syndrome). However, many patients present with non-characteristic symptoms making the diagnosis impossible even for an experienced pediatrician or clinical geneticist. In those cases, a comprehensive diagnostic approach was chosen if a genetic cause is suspected, i.e. the whole genome of the patient has been investigated. Over time, the resolution was improved allowing identification of a multitude of “new” causes. The examinations start – even to date – with a chromosomal analysis, which can detect abnormal distributions of whole chromosomes, e.g. trisomies, or of smaller chromosomal parts, e.g. partial trisomies. Approximately 15% of developmental disorders are caused by chromosomal abnormalities that can be identified by light microscopy. However, even with a high resolution of 550 to 600 bands per haploid chromosome set, which can be achieved in routine diagnostics, changes that fall below 5-10 Mb cannot be detected. Therefore, a high-resolution chromosomal analysis using chromosomal microarray (CMA) is performed as a second diagnostic step. Large studies have shown that so-called Copy Number Variations (CNVs), i.e. submicroscopically small deletions or duplications, are responsible for approximately 10 to 15% of cases of intelligence impairment with inconspicuous chromosomal analysis. It has been shown that such CNVs are also frequently found in autism spectrum disorders, which occur both in isolation and in combination with a developmental disorder.
However, even with the mentioned investigations, about 60% of the causes of developmental disorders remain unexplained. Since developmental disorders often occur sporadically, i.e. as an isolated case in the family, it was assumed that new mutations occur in genes that are important for the development and interconnection of neurons, especially since humans have a high rate of new mutations.
In recent years, several studies investigating patients with intelligence impairment using new high-throughput techniques such as exome sequencing have confirmed that dominant new mutations seem to contribute to a large extent to the cause of severe (IQ< 50) intelligence impairment (e.g. Gillissen et al, Vissers et al, de Ligt et al, Rauch et al). While the risk of chromosomal trisomies increases with maternal age, the rate of dominant new mutations increases with paternal age (Veltman JA et al). Among the patients examined, variants were found in several genes. However, according to the study by de Ligt et al a causative mutation in a gene has already been described in connection with developmental disorders in 16% of the patients, and in 35% of the patients in Rauch et al. Based on these studies, it is thought that up to 50% of severe non-syndromic developmental disorders are caused by de novo point mutations and small indels with a large degree of genetic heterogeneity. Mutations in genes that are still unknown or not known to be associated with developmental disorders require immense effort including functional testing to prove causal association. Nevertheless, exome sequencing is increasingly used in routine diagnostics predominantly as a trio analysis while genome sequencing is still largely limited to research. Thus, using next generation sequencing (NGS) the underlying cause of approximately 30% of previously unexplained severe developmental disorders is expected to be determined.
Currently, the diagnosis of a non-syndromic developmental disorder is performed using a stepwise diagnostic approach starting with chromosomal analysis. If the findings are normal, a chromosomal microarray (CMA) is performed. If necessary, a molecular genetic examination can be conducted, e.g. to exclude a fragile X syndrome or Angelman syndrome.
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