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The role of next-generation sequencing in the investigation of ultrasound-identified fetal structural anomalies.

ABSTRACT: Fetal structural anomalies have an impact on fetal mortality and morbidity. Next-generation sequencing (NGS) may be incorporated into clinical pathways for investigation of paediatric morbidity but can also be used to delineate the prognosis of fetal anomalies. This paper reviews the role of NGS in the investigation of fetal malformations, the literature defining the clinical utility, the technique most commonly used and potential promise and challenges for implementation into clinical practice. Prospective case selection with informative pre-test counselling by multidisciplinary teams is imperative. Regulated laboratory sequencing, bioinformatic pathways with potential variant identification and conservative matching with the phenotype is important. TWEETABLE ABSTRACT: Prenatal exome sequencing in fetal structural anomalies yields diagnostic information in up to 20% of cases.

SUBMITTER: Kilby MD

PROVIDER: S-EPMC8607475 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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The role of next-generation sequencing in the investigation of ultrasound-identified fetal structural anomalies.

Kilby M D MD

BJOG : an international journal of obstetrics and gynaecology 20210101 2

Fetal structural anomalies have an impact on fetal mortality and morbidity. Next-generation sequencing (NGS) may be incorporated into clinical pathways for investigation of paediatric morbidity but can also be used to delineate the prognosis of fetal anomalies. This paper reviews the role of NGS in the investigation of fetal malformations, the literature defining the clinical utility, the technique most commonly used and potential promise and challenges for implementation into clinical practice. ...[more]

PMID: 32975887

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Project description:BackgroundWith the expanded availability of next generation sequencing (NGS)-based clinical genetic tests, clinicians seeking to test patients with Mendelian diseases must weigh the superior coverage of targeted gene panels with the greater number of genes included in whole exome sequencing (WES) when considering their first-tier testing approach. Here, we use an in silico analysis to predict the analytic sensitivity of WES using pathogenic variants identified on targeted NGS panels as a reference.MethodsCorresponding nucleotide positions for 1533 different alterations classified as pathogenic or likely pathogenic identified on targeted NGS multi-gene panel tests in our laboratory were interrogated in data from 100 randomly-selected clinical WES samples to quantify the sequence coverage at each position. Pathogenic variants represented 91 genes implicated in hereditary cancer, X-linked intellectual disability, primary ciliary dyskinesia, Marfan syndrome/aortic aneurysms, cardiomyopathies and arrhythmias.ResultsWhen assessing coverage among 100 individual WES samples for each pathogenic variant (153,300 individual assessments), 99.7% (n = 152,798) would likely have been detected on WES. All pathogenic variants had at least some coverage on exome sequencing, with a total of 97.3% (n = 1491) detectable across all 100 individuals. For the remaining 42 pathogenic variants, the number of WES samples with adequate coverage ranged from 35 to 99. Factors such as location in GC-rich, repetitive, or homologous regions likely explain why some of these alterations were not detected across all samples. To validate study findings, a similar analysis was performed against coverage data from 60,706 exomes available through the Exome Aggregation Consortium (ExAC). Results from this validation confirmed that 98.6% (91,743,296/93,062,298) of pathogenic variants demonstrated adequate depth for detection.ConclusionsResults from this in silico analysis suggest that exome sequencing may achieve a diagnostic yield similar to panel-based testing for Mendelian diseases.

Project description:Accurate normalization of the gene expression assays, using housekeeping genes (HKGs), is critically necessary. To do so, selection of a proper set of HKGs for a specific experiment is of great importance. Despite many studies, there is no consensus about the suitable set of HKGs for implementing in the quantitative real-time PCR analyses of chicken tissues. A limited number of HKGs have been widely used. However, wide utilization of a little number of HKGs for all tissues is challenging. The emergence of high-throughput gene expression RNA-seq data has enabled the simultaneous comparison of the stability of multiple HKGs. Therefore, employing the average coefficient of variations of at least three datasets per tissue, we sorted all reliably expressed genes (REGs; with FPKM ≥ 1 in at least one sample) and introduced the top 10 most suitable and stable reference genes for each of the 16 chicken tissues. We evaluated the consistency of the results of five tissues using the same methodology on other datasets. Furthermore, we assessed 96 previously widely used HKGs (WU-HKGs) in order to challenge the accuracy of the previous studies. The New Tuxedo software suite was used for the main analyses. The results revealed novel, different sets of reference genes for each of the tissues with 17 common genes among the top 10 genes lists of 16 tissues. The results did disprove the suitability of WU-HKGs such as Actb, Ldha, Scd, B2m, and Hprt1 for any of the tissues examined. On the contrary, a total of 6, 13, 14, 23, and 32 validated housekeeping genes (V-HKGs) were discovered as the most stable and suitable reference genes for muscle, spleen, liver, heart, and kidney tissues, respectively. Although we identified a few new HKGs usable for multiple tissues, the selection of suitable HKGs is required to be tissue specific. The newly introduced reference genes from the present study, despite lacking experimental validation, will be able to contribute to the more accurate normalization for future expression analysis of chicken genes.

Dataset Information

The role of next-generation sequencing in the investigation of ultrasound-identified fetal structural anomalies.

Publications

The role of next-generation sequencing in the investigation of ultrasound-identified fetal structural anomalies.

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