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Clin Genet. 2015 Aug;88(2):140-8. doi: 10.1111/cge.12470. Epub 2014 Oct 13.

Challenges and opportunities in the investigation of unexplained intellectual disability using family-based whole-exome sequencing.

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Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Biomedical Informatics Research Center Antwerpen (Biomina), Department of Mathematics and Computer Science, University of Antwerp, Antwerp, Belgium.
Next Generation Sequencing Core, The Scripps Research Institute, La Jolla, CA, USA.
Laboratory of Pharmaceutical Biotechnology, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Department of Medical Genetics, University Hospital Antwerp, Antwerp, Belgium.


Intellectual disability (ID), characterized by an intellectual performance of at least 2 SD (standard deviations) below average is a frequent, lifelong disorder with a prevalence of 2-3%. Today, only for at most half of patients a diagnosis is made. Knowing the cause of the ID is important for patients and their relatives, as it allows for appropriate medical care, prognosis on further development of the disorder, familial counselling or access to support groups. Whole-exome sequencing (WES) now offers the possibility to identify the genetic cause for patients for which all previously available genetic tests, including karyotyping, specific gene analysis, or microarray analysis did not reveal causative abnormalities. However, data analysis of WES experiments is challenging. Here we present an analysis workflow implementable in any laboratory, requiring no bioinformatics knowledge. We demonstrated its feasibility on a cohort of 10 patients, in which we found a conclusive diagnosis in 3 and a likely diagnosis in 2 more patients. Of the three conclusive diagnoses, one was a clinically suspected mutation missed by Sanger sequencing, and one was an atypical presentation of a known monogenic disorder, highlighting two essential strengths of WES-based diagnostics.


exome sequencing; genetic testing; intellectual disability; mocaicism

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