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

(2015) CLINICAL GENETICS. 88(2). p.140-148
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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.
Keywords
genetic testing, exome sequencing, intellectual disability, mocaicism, DE-NOVO MUTATIONS, AUTISM SPECTRUM DISORDERS, MENTAL-RETARDATION, TM4SF2 GENE, SCHIZOPHRENIA, GENOME, PROTEIN, INVOLVEMENT, INDIVIDUALS, EXPRESSION

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MLA
Helsmoortel, C et al. “Challenges and Opportunities in the Investigation of Unexplained Intellectual Disability Using Family-based Whole-exome Sequencing.” CLINICAL GENETICS 88.2 (2015): 140–148. Print.
APA
Helsmoortel, C., Vandeweyer, G., Ordoukhanian, P., Van Nieuwerburgh, F., Van der Aa, N., & Kooy, R. (2015). Challenges and opportunities in the investigation of unexplained intellectual disability using family-based whole-exome sequencing. CLINICAL GENETICS, 88(2), 140–148.
Chicago author-date
Helsmoortel, C, G Vandeweyer, P Ordoukhanian, Filip Van Nieuwerburgh, N Van der Aa, and RF Kooy. 2015. “Challenges and Opportunities in the Investigation of Unexplained Intellectual Disability Using Family-based Whole-exome Sequencing.” Clinical Genetics 88 (2): 140–148.
Chicago author-date (all authors)
Helsmoortel, C, G Vandeweyer, P Ordoukhanian, Filip Van Nieuwerburgh, N Van der Aa, and RF Kooy. 2015. “Challenges and Opportunities in the Investigation of Unexplained Intellectual Disability Using Family-based Whole-exome Sequencing.” Clinical Genetics 88 (2): 140–148.
Vancouver
1.
Helsmoortel C, Vandeweyer G, Ordoukhanian P, Van Nieuwerburgh F, Van der Aa N, Kooy R. Challenges and opportunities in the investigation of unexplained intellectual disability using family-based whole-exome sequencing. CLINICAL GENETICS. 2015;88(2):140–8.
IEEE
[1]
C. Helsmoortel, G. Vandeweyer, P. Ordoukhanian, F. Van Nieuwerburgh, N. Van der Aa, and R. Kooy, “Challenges and opportunities in the investigation of unexplained intellectual disability using family-based whole-exome sequencing,” CLINICAL GENETICS, vol. 88, no. 2, pp. 140–148, 2015.
@article{7124754,
  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.},
  author       = {Helsmoortel, C and Vandeweyer, G and Ordoukhanian, P and Van Nieuwerburgh, Filip and Van der Aa, N and Kooy, RF},
  issn         = {0009-9163},
  journal      = {CLINICAL GENETICS},
  keywords     = {genetic testing,exome sequencing,intellectual disability,mocaicism,DE-NOVO MUTATIONS,AUTISM SPECTRUM DISORDERS,MENTAL-RETARDATION,TM4SF2 GENE,SCHIZOPHRENIA,GENOME,PROTEIN,INVOLVEMENT,INDIVIDUALS,EXPRESSION},
  language     = {eng},
  number       = {2},
  pages        = {140--148},
  title        = {Challenges and opportunities in the investigation of unexplained intellectual disability using family-based whole-exome sequencing},
  url          = {http://dx.doi.org/10.1111/cge.12470},
  volume       = {88},
  year         = {2015},
}

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