Genome sequencing identifies major causes of severe intellectual disability

@article{Gilissen2014GenomeSI,
  title={Genome sequencing identifies major causes of severe intellectual disability},
  author={Christian Gilissen and Jayne Y. Hehir-Kwa and D. T. Thung and Maartje van de Vorst and Bregje W.M. van Bon and Marjolein H Willemsen and Michael P. Kwint and Irene M. Janssen and Alexander Hoischen and Annette Schenck and Richard A Leach and Robert Klein and Rick Tearle and Tan Bo and Rolph Pfundt and Helger G Yntema and Bert B. A. de Vries and Tjitske Kleefstra and Han G. Brunner and Lisenka E.L.M. Vissers and Joris A. Veltman},
  journal={Nature},
  year={2014},
  volume={511},
  pages={344-347}
}
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… 
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Genome-wide investigation of an ID cohort reveals de novo 3′UTR variants affecting gene expression
TLDR
The identification and characterization of de novo non-coding variation in 3′UTR regulatory regions within an ID cohort of 50 patients is described and two variants interfered with miRNA-mediated regulation of their target genes, AMD1 and FAIM.
The diagnostic yield of intellectual disability: combined whole genome low-coverage sequencing and medical exome sequencing
TLDR
There were differences in the diagnostic yields of different variation types among the three ID subgroups, and the single-nucleotide variations showed a higher occurrence rate in the other IDs subgroup.
Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield
TLDR
The results expand the morbid genome of ID and support the adoption of genomics as a first-tier test for individuals with ID.
Whole genome sequencing of 45 Japanese patients with intellectual disability
TLDR
This is the first report of WGS analysis in Japanese patients with ID, and results would provide insight into the correlation between novel variants and expanded phenotypes of the disease.
Novel clinical and genetic insight into CXorf56-associated intellectual disability
TLDR
The causative role of variants in CXorf56 for an X-linked form of intellectual disability with additional neurological features is confirmed and the gene should be considered for molecular diagnostics of patients with ID, specifically when family history is suggestive of X- linked inheritance.
Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA.
High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing
TLDR
Next-generation sequencing has the potential for high-throughput identification of genetic variations, although the challenges of an adequate clinical interpretation of these variants and the knowledge on further unknown genes causing intellectual disability remain to be solved.
Targeted Next‐Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability
TLDR
To diagnose patients with ID in the absence of parental DNA, it is recommended that investigation of all LoF variants in known genes that cause ID and assessment of a limited list of proven pathogenic missense variants in these genes are investigated.
De Novo Mutations in Moderate or Severe Intellectual Disability
TLDR
It is concluded that DNMs represent a major cause of moderate or severe ID.
Challenges in molecular diagnosis of X-linked Intellectual disability.
TLDR
To improve variant interpretation, there is need to refine in silico predictions with specific criteria for each gene, and to develop cost-effective functional tools, which can be easily transferred to diagnostics.
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References

SHOWING 1-10 OF 31 REFERENCES
Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.
Whole-Genome Sequencing in Autism Identifies Hot Spots for De Novo Germline Mutation
De novo mutations revealed by whole-exome sequencing are strongly associated with autism
TLDR
It is shown, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects.
Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study
Clinical Significance of De Novo and Inherited Copy‐Number Variation
TLDR
Patients with multiple CNVs presented with a more severe phenotype than patients with a single CNV, pointing to a combinatorial effect of the additional CNVs, and 20 de novo single‐gene CNVs that directly indicate novel genes for ID/MCA are identified.
Patterns and rates of exonic de novo mutations in autism spectrum disorders
TLDR
Results from de novo events and a large parallel case–control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors and support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold.
Exome sequencing supports a de novo mutational paradigm for schizophrenia
TLDR
A comparison to rare inherited variants indicated that the identified de novo mutations show a large excess of non-synonymous changes in schizophrenia cases, as well as a greater potential to affect protein structure and function.
Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy.
TLDR
As shown in this study of a family with Charcot-Marie-Tooth disease, whole-genome sequencing can identify clinically relevant variants and provide diagnostic information to inform the care of patients.
Pathogenic or not? Assessing the clinical relevance of copy number variants
TLDR
CNV interpretation within the context of these different genetic disease models is discussed and common pitfalls that can occur when searching for supportive evidence that a CNV is clinically relevant are discussed.
Genomics, intellectual disability, and autism.
TLDR
Technological advances — which include array comparative genomic hy bridization (CGH), single-nucleotide-polymorphism (SNP) genotyping arrays, and massively parallel sequencing — have transformed the approach to the identification of etiologic genes and genomic rearrangements in the research laboratory and are now being applied in the clinical diagnostic arena.
...
1
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4
...