TY - JOUR
T1 - Genome annotation for clinical genomic diagnostics
T2 - Strengths and weaknesses
AU - Steward, Charles A.
AU - Parker, Alasdair P.J.
AU - Minassian, Berge A.
AU - Sisodiya, Sanjay M.
AU - Frankish, Adam
AU - Harrow, Jennifer
N1 - Funding Information:
We thank Jane Rogers for her guidance, Eugene Bragin for his informatics input, and Imogen Steward, who is still awaiting her genetic diagnosis, but instrumental in the undertaking of this manuscript. We hope that this paper will support patients such as Imogen, now and in the future. This work is funded by the National Institutes of Health grant U41HG007234 to the GENCODE project, and Wellcome Trust grant (WT098051) to the Sanger Institute and the European Molecular Biology Laboratory. Part of this work was undertaken at University College London Hospitals, which received a proportion of funding from the NIHR Biomedical Research Centres funding scheme. We are grateful for support from the Epilepsy Society.
PY - 2017/5/30
Y1 - 2017/5/30
N2 - The Human Genome Project and advances in DNA sequencing technologies have revolutionized the identification of genetic disorders through the use of clinical exome sequencing. However, in a considerable number of patients, the genetic basis remains unclear. As clinicians begin to consider whole-genome sequencing, an understanding of the processes and tools involved and the factors to consider in the annotation of the structure and function of genomic elements that might influence variant identification is crucial. Here, we discuss and illustrate the strengths and weaknesses of approaches for the annotation and classification of important elements of protein-coding genes, other genomic elements such as pseudogenes and the non-coding genome, comparative-genomic approaches for inferring gene function, and new technologies for aiding genome annotation, as a practical guide for clinicians when considering pathogenic sequence variation. Complete and accurate annotation of structure and function of genome features has the potential to reduce both false-negative (from missing annotation) and false-positive (from incorrect annotation) errors in causal variant identification in exome and genome sequences. Re-analysis of unsolved cases will be necessary as newer technology improves genome annotation, potentially improving the rate of diagnosis.
AB - The Human Genome Project and advances in DNA sequencing technologies have revolutionized the identification of genetic disorders through the use of clinical exome sequencing. However, in a considerable number of patients, the genetic basis remains unclear. As clinicians begin to consider whole-genome sequencing, an understanding of the processes and tools involved and the factors to consider in the annotation of the structure and function of genomic elements that might influence variant identification is crucial. Here, we discuss and illustrate the strengths and weaknesses of approaches for the annotation and classification of important elements of protein-coding genes, other genomic elements such as pseudogenes and the non-coding genome, comparative-genomic approaches for inferring gene function, and new technologies for aiding genome annotation, as a practical guide for clinicians when considering pathogenic sequence variation. Complete and accurate annotation of structure and function of genome features has the potential to reduce both false-negative (from missing annotation) and false-positive (from incorrect annotation) errors in causal variant identification in exome and genome sequences. Re-analysis of unsolved cases will be necessary as newer technology improves genome annotation, potentially improving the rate of diagnosis.
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U2 - 10.1186/s13073-017-0441-1
DO - 10.1186/s13073-017-0441-1
M3 - Review article
C2 - 28558813
AN - SCOPUS:85019973466
VL - 9
JO - Genome Medicine
JF - Genome Medicine
SN - 1756-994X
IS - 1
M1 - 49
ER -