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Dtsch Arztebl Int. 2019 Mar 22;116(12):197-204. doi: 10.3238/arztebl.2019.0197.

Exome Sequencing in Children.

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*Joint last authors; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf; Department of Pediatrics, University Medical Center Hamburg-Eppendorf; Institute of Human Genetics, Klinikum Rechts der Isar, TUM, Munich; Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen; Institute of Human Genetics, Helmholtz Center Munich; Undiagnosed Disease Program at the University Medical Center Hamburg-Eppendorf (UDP-UKE).



In developed countries, global developmental disorders are encounter- ed in approximately 1% of all children. The causes are manifold, and no exogenous cause can be identified in about half of the affected children. The parallel investi- gation of the coding sequences of all genes of the affected individual (whole exome sequencing, WES) has developed into a successful diagnostic method for identify- ing the cause of the problem. It is not yet clear, however, when WES should best be used in routine clinical practice in order to exploit the potential of this method to the fullest.


In an interdisciplinary study, we carried out standardized clinical pheno- typing and a systematic genetic analysis (WES of the index patient and his or her parents, so-called trio WES) in 50 children with developmental disturbances of unclear etiology and with nonspecific neurological manifestations.


In 21 children (42% of the collective), we were able to identify the cause of the disorder by demonstrating a mutation in a gene known to be associated with disease. Three of these children subsequently underwent specific treatment. In 22 other children (44%), we detected possibly etiological changes in candidate genes not currently known to be associated with human disease.


Our detection rate of at least 42% is high in comparison with the results obtained in other studies from Germany and other countries to date and implies that WES can be used to good effect as a differential diagnostic tool in pediatric neurol- ogy. WES should be carried out in both the index patient and his or her parents (trio- WES) and accompanied by close interdisciplinary collaboration of human geneti- cists and pediatricians, by comprehensive and targeted phenotyping (also after the diagnosis is established), and by the meticulous evaluation of all gene variants.

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