title: Genome sequencing identifies major causes of severe intellectual disability.
abstract: Severe intellectual disability (ID) occurs in 0.5% of newborns and is thought to be largely genetic in origin. The extensive genetic heterogeneity of this disorder requires a genome-wide detection of all types of genetic variation. Microarray studies and, more recently, exome sequencing have demonstrated the importance of de novo copy number variations (CNVs) and single-nucleotide variations (SNVs) in ID, but the majority of cases remain undiagnosed. Here we applied whole-genome sequencing to 50 patients with severe ID and their unaffected parents. All patients included had not received a molecular diagnosis after extensive genetic prescreening, including microarray-based CNV studies and exome sequencing. Notwithstanding this prescreening, 84 de novo SNVs affecting the coding region were identified, which showed a statistically significant enrichment of loss-of-function mutations as well as an enrichment for genes previously implicated in ID-related disorders. In addition, we identified eight de novo CNVs, including single-exon and intra-exonic deletions, as well as interchromosomal duplications. These CNVs affected known ID genes more frequently than expected. On the basis of diagnostic interpretation of all de novo variants, a conclusive genetic diagnosis was reached in 20 patients. Together with one compound heterozygous CNV causing disease in a recessive mode, this results in a diagnostic yield of 42% in this extensively studied cohort, and 62% as a cumulative estimate in an unselected cohort. These results suggest that de novo SNVs and CNVs affecting the coding region are a major cause of severe ID. Genome sequencing can be applied as a single genetic test to reliably identify and characterize the comprehensive spectrum of genetic variation, providing a genetic diagnosis in the majority of patients with severe ID.
authors.affiliation: 1] Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands [2].
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.affiliation: 1] Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands [2].
authors.forename: Jayne Y
authors.initials: JY
authors.lastname: Hehir-Kwa
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Djie Tjwan
authors.initials: DT
authors.lastname: Thung
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Maartje
authors.initials: M
authors.lastname: van de Vorst
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Bregje W M
authors.initials: BW
authors.lastname: van Bon
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Marjolein H
authors.initials: MH
authors.lastname: Willemsen
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: Kwint
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Janssen
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Annette
authors.initials: A
authors.lastname: Schenck
authors.affiliation: Complete Genomics Inc. 2071 Stierlin Court, Mountain View, California 94043, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Leach
authors.affiliation: Complete Genomics Inc. 2071 Stierlin Court, Mountain View, California 94043, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Klein
authors.affiliation: Complete Genomics Inc. 2071 Stierlin Court, Mountain View, California 94043, USA.
authors.forename: Rick
authors.initials: R
authors.lastname: Tearle
authors.affiliation: 1] Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands [2] State Key Laboratory of Medical Genetics, Central South University. 110 Xiangya Road, Changsha, Hunan 410078, China.
authors.forename: Tan
authors.initials: T
authors.lastname: Bo
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Helger G
authors.initials: HG
authors.lastname: Yntema
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: 1] Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands [2] Department of Clinical Genetics, Maastricht University Medical Centre. Universiteitssingel 50, 6229 ER Maastricht, the Netherlands [3].
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.affiliation: 1] Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands [2].
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.affiliation: 1] Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands [2] Department of Clinical Genetics, Maastricht University Medical Centre. Universiteitssingel 50, 6229 ER Maastricht, the Netherlands [3].
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
mesh_terms: D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D020440:Gene Duplication / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C550083:IQSEC2 protein, human