title: Challenges and opportunities in the investigation of unexplained intellectual disability using family-based whole-exome sequencing.
abstract: 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.
authors: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors: C
authors: http://orcid.org/0000-0001-7180-7707
authors: C
authors: Helsmoortel
authors: 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.
authors: G
authors: G
authors: Vandeweyer
authors: Next Generation Sequencing Core, The Scripps Research Institute, La Jolla, CA, USA.
authors: P
authors: P
authors: Ordoukhanian
authors: Laboratory of Pharmaceutical Biotechnology, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
authors: F
authors: F
authors: Van Nieuwerburgh
authors: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.|Department of Medical Genetics, University Hospital Antwerp, Antwerp, Belgium.
authors: N
authors: N
authors: Van der Aa
authors: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors: R F
authors: RF
authors: Kooy
mesh_terms: D001483:Base Sequence; D056915:DNA Copy Number Variations; D059472:Exome / Q000235:genetics*; D005190:Family / Q000523:psychology; D005260:Female; D005820:Genetic Testing; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008607:Intellectual Disability / Q000453:epidemiology / Q000235:genetics* / Q000523:psychology; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA
keywords: exome sequencing; genetic testing; intellectual disability; mocaicism