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Challenges and opportunities in the investigation of unexplained intellectual disability using family‐based whole‐exome sequencing
Author(s) -
Helsmoortel C.,
Vandeweyer G.,
Ordoukhanian P.,
Van Nieuwerburgh F.,
Van der Aa N.,
Kooy R.F.
Publication year - 2015
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.12470
Subject(s) - exome sequencing , intellectual disability , sanger sequencing , exome , medical diagnosis , medicine , cohort , genetic diagnosis , medical genetics , genetics , bioinformatics , pediatrics , mutation , biology , psychiatry , pathology , gene
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.