Exome sequencing: Dual role as a discovery and diagnostic tool

@article{Ku2012ExomeSD,
  title={Exome sequencing: Dual role as a discovery and diagnostic tool},
  author={C S Ku and David N. Cooper and Constantin Polychronakos and Nasheen Naidoo and Mengchu Wu and Richie Soong},
  journal={Annals of Neurology},
  year={2012},
  volume={71}
}
Recent developments in high‐throughput sequence capture methods and next‐generation sequencing technologies have now made exome sequencing a viable approach to elucidate the genetic basis of Mendelian disorders with hitherto unknown etiology. In addition, exome sequencing is increasingly being employed as a diagnostic tool for specific genetic diseases, particularly in the context of those disorders characterized by significant genetic and phenotypic heterogeneity, for example, Charcot‐Marie… 
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176 Citations
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176 Citations

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Concordance between whole‐exome sequencing and clinical Sanger sequencing: implications for patient care
TLDR
High concordance for well‐covered coding variants is reported, supporting the use of WES as a screening tool for heterogeneous disorders, and recommend the useof supplementary Sanger sequencing for poorly‐covered genes when the clinical suspicion is high.
The Rise and Rise of Exome Sequencing
TLDR
Progress has been made in heritable germline and de novo mutations and somatic driver mutations for rare Mendelian disorders with hitherto unknown genetic aetiologies and the application of exome sequencing as a diagnostic tool is discussed.
Next generation diagnostics of heritable connective tissue disorders.
What we have learned from the next-generation sequencing: Contributions to the genetic diagnoses and understanding of pathomechanisms of neurodegenerative diseases
TLDR
Establishment of consensus guidelines and development of public genomic/phenotypic databases are vital to facilitate data sharing and validation of the pathogenic roles of the variants identified by NGS.
Characterisation and Validation of Insertions and Deletions in 173 Patient Exomes
TLDR
A strong enrichment of very low-frequency insertion/deletion variants, so far under-investigated, are indicated, which might be difficult to capture with low coverage and imputation approaches and for which most of study designs would be under-powered.
Identifying disease mutations in genomic medicine settings: current challenges and how to accelerate progress
TLDR
The need for clinical-grade sample collection, high-quality sequencing data acquisition, digitalized phenotyping, rigorous generation of variant calls, and comprehensive functional annotation of variants is urged and a 'networking of science' model that encourages much more collaboration and online sharing of medical history, genomic data and biological knowledge is suggested.
Whole-exome sequencing: opportunities in pediatric endocrinology.
TLDR
The view is that protocols involving next-generation sequencing should now be considered as an appropriate component of routine clinical diagnosis for relevant patients.
Next-generation sequencing for research and diagnostics in kidney disease
TLDR
The development of next-generation sequencing in basic and clinical research is described and the implementation of this novel technology in routine patient management is discussed, including use of high-throughput disease modelling as a tool to support the clinical diagnosis of kidney diseases.
Exome Sequencing as a Diagnostic Tool for Pediatric-Onset Ataxia
TLDR
The data suggest that exome sequencing is an effective first line test for pediatric patients with ataxia where a specific single gene is not immediately suspected to be causative.
Clinical exome sequencing in neurologic disease.
TLDR
CES can be cost-effective due to its high diagnostic yield in comparison to other genetic tests in current use and should be utilized as a routine diagnostic test in patients with heterogeneous neurologic phenotypes facing a broad genetic differential diagnosis.
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References

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TLDR
An overview of the current and future use of next generation sequencing as it relates to whole exome sequencing in human disease by focusing on the technical capabilities, limitations and ethical issues associated with this technology in the field of genetics and human disease is provided.
Revisiting Mendelian disorders through exome sequencing
TLDR
Although exome sequencing has been proven to be a promising approach to study Mendelian disorders, several shortcomings of this method must be noted, such as the inability to capture regulatory or evolutionary conserved sequences in non-coding regions and the incomplete capturing of all exons.
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
The exomes of four members of a family presenting with spondylo‐epiphyseal dysplasia and retinitis pigmentosa were sequenced and a six‐base‐pair deletion in GNPTG was identified, the gene implicated in mucolipidosis type IIIγ, demonstrating the clinical utility of next‐generation sequencing to diagnose rare genetic diseases.
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