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Pharmacogenomics in children: advantages and challenges of next generation sequencing applications.

ABSTRACT: Pharmacogenetics is considered as a prime example of how personalized medicine nowadays can be put into practice. However, genotyping to guide pharmacological treatment is relatively uncommon in the routine clinical practice. Several reasons can be found why the application of pharmacogenetics is less than initially anticipated, which include the contradictory results obtained for certain variants and the lack of guidelines for clinical implementation. However, more reproducible results are being generated, and efforts have been made to establish working groups focussing on evidence-based clinical guidelines. For another pharmacogenetic hurdle, the speed by which a pharmacogenetic profile for a certain drug can be obtained in an individual patient, there has been a revolution in molecular genetics through the introduction of next generation sequencing (NGS), making it possible to sequence a large number of genes up to the complete genome in a single reaction. Besides the enthusiasm due to the tremendous increase of our sequencing capacities, several considerations need to be made regarding quality and interpretation of the sequence data as well as ethical aspects of this technology. This paper will focus on the different NGS applications that may be useful for pharmacogenomics in children and the challenges that they bring on.

SUBMITTER: Vanakker OM

PROVIDER: S-EPMC3562678 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Pharmacogenomics in children: advantages and challenges of next generation sequencing applications.

Vanakker O M OM De Paepe A A

International journal of pediatrics 20130117

Pharmacogenetics is considered as a prime example of how personalized medicine nowadays can be put into practice. However, genotyping to guide pharmacological treatment is relatively uncommon in the routine clinical practice. Several reasons can be found why the application of pharmacogenetics is less than initially anticipated, which include the contradictory results obtained for certain variants and the lack of guidelines for clinical implementation. However, more reproducible results are bein ...[more]

PMID: 23401694

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Project description:Retinoblastoma (RB) is the most common malignant childhood tumor of the eye and results from inactivation of both alleles of the RB1 gene. Nowadays RB genetic diagnosis requires classical chromosome investigations, Multiplex Ligation-dependent Probe Amplification analysis (MLPA) and Sanger sequencing. Nevertheless, these techniques show some limitations. We report our experience on a cohort of RB patients using a combined approach of Next-Generation Sequencing (NGS) and RB1 custom array-Comparative Genomic Hybridization (aCGH).A total of 65 patients with retinoblastoma were studied: 29 cases of bilateral RB and 36 cases of unilateral RB. All patients were previously tested with conventional cytogenetics and MLPA techniques. Fifty-three samples were then analysed using NGS. Eleven cases were analysed by RB1 custom aCGH. One last case was studied only by classic cytogenetics. Finally, it has been tested, in a lab sensitivity assay, the capability of NGS to detect artificial mosaicism series in previously recognized samples prepared at 3 different mosaicism frequencies: 10, 5, 1 %.Of the 29 cases of bilateral RB, 28 resulted positive (96.5 %) to the genetic investigation: 22 point mutations and 6 genomic rearrangements (four intragenic and two macrodeletion). A novel germline intragenic duplication, from exon18 to exon 23, was identified in a proband with bilateral RB. Of the 36 available cases of unilateral RB, 8 patients resulted positive (22 %) to the genetic investigation: 3 patients showed point mutations while 5 carried large deletion. Finally, we successfully validated, in a lab sensitivity assay, the capability of NGS to accurately measure level of artificial mosaicism down to 1 %.NGS and RB1-custom aCGH have demonstrated to be an effective combined approach in order to optimize the overall diagnostic procedures of RB. Custom aCGH is able to accurately detect genomic rearrangements allowing the characterization of their extension. NGS is extremely accurate in detecting single nucleotide variants, relatively simple to perform, cost savings and efficient and has confirmed a high sensitivity and accuracy in identifying low levels of artificial mosaicisms.

Dataset Information

Pharmacogenomics in children: advantages and challenges of next generation sequencing applications.

Publications

Pharmacogenomics in children: advantages and challenges of next generation sequencing applications.

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