Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Clinical Exome

Dipl.-Bioinf. Sebastian Eck

In contrast to whole exome sequencing (WES), which involves the enrichment and sequencing of all protein-coding regions, clinical exome sequencing (CES) comprises enrichment of a subset of the exome. The focus of CES lies on disease-associated genes described in the Human Gene Mutation Database (HGMD). The enriched region currently comprises 4.813 genes and therefore almost 62.000 exons (additional information and complete gene list available at The advantage of CES lies in the pre-selection of relevant genes. This facilitates the interpretation of identified variants. CES can be used for a variety of indications e.g. unclear developmental disorders as well as diseases that may be caused by mutations in several different genes.

Since developmental disorders frequently occur sporadically, i.e. as single cases within one family, new mutations, for example, in genes which play a major part in the development and the neuronal interconnection, are suspected to cause the disorders, especially as humans exhibit a high rate of new mutations.

Several studies conducted during the last years confirmed that dominant new mutations seem to be involved in causing severe intellectual disability (e.g. Vissers L. et al, Nat Genet, 2010, de Ligt, J. et al, NEJM, 2012 und Rauch, A. et al, Lancet, 2012). These studies involved patients with severe intellectual disability (IQ < 50), who were examined using modern high throughput sequencing technologies such as exome sequencing. While the risk of developing chromosomal trisomy increases with the age of the mother, the rate of dominant new mutations rises according to the age of the father (Veltman JA et al, Nat Rev Genet, 2012). The examined patients exhibited variants in various genes; in the course of the study by Ligt et al, however, a causative mutation was found in a gene that had already been associated with developmental disorders in 16% of all patients, in the study by Rauch et al in 35% of all patients. It is therefore estimated that up to 50% of all severe, non-syndromal developmental disorders are caused by de novo point mutations and small indels; a high genetic heterogeneity has been observed. To prove association between the disorder and mutations in unknown genes or genes that have not been associated with developmental disorders is highly time-consuming and requires functional tests, which is why whole exome sequencing (whole genome sequencing even more so) is not yet suitable for routine diagnostics. However, simultaneous sequencing of genes which have been associated with neurological or developmental disorders and that have been listed in the databases using CES might become part of routine diagnostics. In order to detect inherited genetic variants in the course of the extensive analysis the affected child and its parents should be tested (trio analysis).

It is therefore likely that, with the use of next generation sequencing (NGS), the cause of approx. 30% of the previously unexplained severe developmental disorders will be identified. In the future, the diagnostic approach might take place like shown in the flowchart below. Prior to CES, genetic counseling has to be carried out. Part of the consultation will be the question, how additional information should be dealt with that may, aside from the indication, arise during the analysis. According to the German Genetic Diagnosis Act (GenDG), genes that may cause late-onset diseases would, for example, not be analyzed in minors.

In addition to the diagnosis of developmental disorders, CES can be used to complement current diagnostics. Regarding epilepsies, ciliopathies (Joubert syndrome) as well as other indications, sequencing of the relevant genes covered by the clinical exome is possible upon consultation. Only those genes that are associated with the respective disease will be included in the analysis.

Please note that CES generally requires priorauthorization by your insurance company in order to be covered.