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Review
. 2022 Nov;43(11):1507-1518.
doi: 10.1002/humu.24466. Epub 2022 Sep 23.

Rapid genome sequencing for pediatrics

Jana Jezkova  1 , Sophie Shaw  1 , Nicola V Taverner  1   2 , Hywel J Williams  3
Affiliations
Review

Rapid genome sequencing for pediatrics

Jana Jezkova et al. Hum Mutat. 2022 Nov.

Abstract

The advancements made in next-generation sequencing (NGS) technology over the past two decades have transformed our understanding of genetic variation in humans and had a profound impact on our ability to diagnose patients with rare genetic diseases. In this review, we discuss the recently developed application of rapid NGS techniques, used to diagnose pediatric patients with suspected rare diseases who are critically ill. We highlight the challenges associated with performing such clinical diagnostics tests in terms of the laboratory infrastructure, bioinformatic analysis pipelines, and the ethical considerations that need to be addressed. We end by looking at what future developments in this field may look like and how they can be used to augment the genetic data to further improve the diagnostic rates for these high-priority patients.

Keywords: bioinformatics; ethics; next-generation sequencing (NGS); rare disease; variant interpretation; whole exome sequencing (WES); whole genome sequencing (WGS).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Typical bioinformatics whole genome sequencing analysis pipeline. After sequencing, fastq files are produced. These are aligned to the reference genome to produce alignment files, typically in BAM (binary alignment) format. These are used for variant calling to produce VCF (variant call format) files, which are then annotated and filtered to produce the final variant list.
Figure 2
Figure 2
Example filtering strategy for genome sequencing analysis
Figure 3
Figure 3
Laboratory pathway for Wales Infants' and ChildreN's Genome Service (WINGS). Rapid whole genome sequencing (WGS) is available for acutely unwell children with a likely underlying genetic cause. Genomic DNA extracted from the child's and parent's blood samples undergoes genomic sequencing using the Illumina NovaSeq. 6000 system. Sequences are aligned to human genome assembly GRCh38 (hg38), and variants identified with the Illumina DRAGEN (Dynamic Read Analysis for GENomics) Bio‐IT Platform (v.3.7; Illumina). Analysis includes evaluation of variants that are identified to be de novo, compound heterozygous, homozygous, and X‐linked using in‐house bioinformatic pipelines. Variants are interpreted and reported following the latest ACGS/American College of Medical Genetics and Genomics (ACMG) guidelines (Ellard et al., ; Richards et al., 2015). Only causative pathogenic and likely pathogenic variants are reported, variants of uncertain significance (VUS) that are potentially related to the child's illness are discussed at a multidisciplinary meeting and may also be reported. The reporting time for this test is 14 calendar days.
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