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Next generation sequencing and the future of genetic diagnosis.

ABSTRACT: The introduction of next generation sequencing (NGS) has led to an exponential increase of elucidated genetic causes in both extremely rare diseases and common but heterogeneous disorders. It can be applied to the whole or to selected parts of the genome (genome or exome sequencing, gene panels). NGS is not only useful in large extended families with linkage information, but may also be applied to detect de novo mutations or mosaicism in sporadic patients without a prior hypothesis about the mutated gene. Currently, NGS is applied in both research and clinical settings, and there is a rapid transition of research findings to diagnostic applications. These developments may greatly help to minimize the "diagnostic odyssey" for patients as whole-genome analysis can be performed in a few days at reasonable costs compared with gene-by-gene analysis based on Sanger sequencing following diverse clinical tests. Despite the enthusiasm about NGS, one has to keep in mind its limitations, such as a coverage and accuracy of?

SUBMITTER: Lohmann K

PROVIDER: S-EPMC4391380 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Next generation sequencing and the future of genetic diagnosis.

Lohmann Katja K Klein Christine C

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20141001 4

The introduction of next generation sequencing (NGS) has led to an exponential increase of elucidated genetic causes in both extremely rare diseases and common but heterogeneous disorders. It can be applied to the whole or to selected parts of the genome (genome or exome sequencing, gene panels). NGS is not only useful in large extended families with linkage information, but may also be applied to detect de novo mutations or mosaicism in sporadic patients without a prior hypothesis about the mut ...[more]

PMID: 25052068

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Project description:BackgroundNext generation sequencing (NGS) is now being used for detecting chromosomal abnormalities in blastocyst trophectoderm (TE) cells from in vitro fertilized embryos. However, few data are available regarding the clinical outcome, which provides vital reference for further application of the methodology. Here, we present a clinical evaluation of NGS-based preimplantation genetic diagnosis/screening (PGD/PGS) compared with single nucleotide polymorphism (SNP) array-based PGD/PGS as a control.ResultsA total of 395 couples participated. They were carriers of either translocation or inversion mutations, or were patients with recurrent miscarriage and/or advanced maternal age. A total of 1,512 blastocysts were biopsied on D5 after fertilization, with 1,058 blastocysts set aside for SNP array testing and 454 blastocysts for NGS testing. In the NGS cycles group, the implantation, clinical pregnancy and miscarriage rates were 52.6% (60/114), 61.3% (49/80) and 14.3% (7/49), respectively. In the SNP array cycles group, the implantation, clinical pregnancy and miscarriage rates were 47.6% (139/292), 56.7% (115/203) and 14.8% (17/115), respectively. The outcome measures of both the NGS and SNP array cycles were the same with insignificant differences. There were 150 blastocysts that underwent both NGS and SNP array analysis, of which seven blastocysts were found with inconsistent signals. All other signals obtained from NGS analysis were confirmed to be accurate by validation with qPCR. The relative copy number of mitochondrial DNA (mtDNA) for each blastocyst that underwent NGS testing was evaluated, and a significant difference was found between the copy number of mtDNA for the euploid and the chromosomally abnormal blastocysts. So far, out of 42 ongoing pregnancies, 24 babies were born in NGS cycles; all of these babies are healthy and free of any developmental problems.ConclusionsThis study provides the first evaluation of the clinical outcomes of NGS-based pre-implantation genetic diagnosis/screening, and shows the reliability of this method in a clinical and array-based laboratory setting. NGS provides an accurate approach to detect embryonic imbalanced segmental rearrangements, to avoid the potential risks of false signals from SNP array in this study.

Dataset Information

Next generation sequencing and the future of genetic diagnosis.

Publications

Next generation sequencing and the future of genetic diagnosis.

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