Case for genome sequencing in infants and children with rare, undiagnosed or genetic diseases

Abstract

Up to 350 million people worldwide suffer from a rare disease, and while the individual diseases are rare, in aggregate they represent a substantial challenge to global health systems. The majority of rare disorders are genetic in origin, with children under the age of five disproportionately affected. As these conditions are difficult to identify clinically, genetic and genomic testing have become the backbone of diagnostic testing in this population. In the last 10 years, next-generation sequencing technologies have enabled testing of multiple disease genes simultaneously, ranging from targeted gene panels to exome sequencing (ES) and genome sequencing (GS). GS is quickly becoming a practical first-tier test, as cost decreases and performance improves. A growing number of studies demonstrate that GS can detect an unparalleled range of pathogenic abnormalities in a single laboratory workflow. GS has the potential to deliver unbiased, rapid and accurate molecular diagnoses to patients across diverse clinical indications and complex presentations. In this paper, we discuss clinical indications for testing and historical testing paradigms. Evidence supporting GS as a diagnostic tool is supported by superior genomic coverage, types of pathogenic variants detected, simpler laboratory workflow enabling shorter turnaround times, diagnostic and reanalysis yield, and impact on healthcare.

Abnormal expression of GABAAreceptor sub-units and hypomotility upon loss ofgabra1in zebrafish

“…Rare disorders affect 4-8% of the global population (Boycott et al, 2013) and approximately 80% of these disorders are predicted to have a genetic etiology (Bick et al, 2019). In recent years, whole exome sequencing (WES) emerged as a diagnostic tool for patients with rare disorders of unknown origin (Sawyer et al, 2015; Tetreault et al, 2015).…”

Genome-wide rare variant analysis for thousands of phenotypes in over 70,000 exomes from two cohorts

“…It has been shown that as allele frequencies drop, the effect sizes of associated variants can increase beyond the limits imposed by natural selection on more common variants [4][5][6] . In rare disease and family-based studies, aggregating phenotypically-similar probands to identify associated groups of rare variants has been crucial to our understanding of disease; exome and genome-based approaches are now standard of care for evaluating these patients [7][8][9][10] . However, the impact of rare variants on common traits and sub-clinical phenotypes has only been examined for selected phenotypes as large exome and phenotypic datasets have not been available [11][12][13] .…”

The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease

“…34 Genome sequencing was previously shown to have adequate coverage for clinically relevant gene sets, 9 and can overcome several technical limitations of exome sequencing and chromosomal microarray analysis, particularly for small structural variations. 35 In this study, we demonstrate the detection and finemapping of a wide size range of potentially disease-related CNVs (9.1 kb to 8.3 Mb), with reliable detection rates previously shown to exceed microarrays. 36 For the majority of individuals in this study, the etiology of their heart defects remained unknown.…”