Publication Date:
2014-06-05
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gilissen, Christian -- Hehir-Kwa, Jayne Y -- Thung, Djie Tjwan -- van de Vorst, Maartje -- van Bon, Bregje W M -- Willemsen, Marjolein H -- Kwint, Michael -- Janssen, Irene M -- Hoischen, Alexander -- Schenck, Annette -- Leach, Richard -- Klein, Robert -- Tearle, Rick -- Bo, Tan -- Pfundt, Rolph -- Yntema, Helger G -- de Vries, Bert B A -- Kleefstra, Tjitske -- Brunner, Han G -- Vissers, Lisenka E L M -- Veltman, Joris A -- England -- Nature. 2014 Jul 17;511(7509):344-7. doi: 10.1038/nature13394. Epub 2014 Jun 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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 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. ; Complete Genomics Inc. 2071 Stierlin Court, Mountain View, California 94043, USA. ; 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. ; 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].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24896178" target="_blank"〉PubMed〈/a〉
Keywords:
Chromosomes, Human, Pair 4/genetics
;
Chromosomes, Human, X/genetics
;
Cohort Studies
;
DNA Copy Number Variations/*genetics
;
Gene Duplication/genetics
;
Genome, Human/*genetics
;
Guanine Nucleotide Exchange Factors/genetics
;
Humans
;
Intellectual Disability/*genetics
;
Male
;
Mutation/*genetics
;
Polymorphism, Single Nucleotide/*genetics
;
*Sequence Analysis, DNA
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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