Genome sequencing with gene panel-based analysis for rare inherited conditions in a publicly funded healthcare system: implications for future testing

Abstract

NHS genetics centres in Scotland sought to investigate the Genomics England 100,000 Genomes Project diagnostic utility to evaluate genome sequencing for in rare, inherited conditions. Four regional services recruited 999 individuals from 394 families in 200 rare phenotype categories, with negative historic genetic testing. Genome sequencing was performed at Edinburgh Genomics, and phenotype and sequence data were transferred to Genomics England for variant calling, gene-based filtering and variant prioritisation. NHS Scotland genetics laboratories performed interpretation, validation and reporting. New diagnoses were made in 23% cases – 19% in genes implicated in disease at the time of variant prioritisation, and 4% from later review of additional genes. Diagnostic yield varied considerably between phenotype categories and was minimal in cases with prior exome testing. Genome sequencing with gene panel filtering and reporting achieved improved diagnostic yield over previous historic testing but not over now routine trio-exome sequence tests. Re-interpretation of genomic data with updated gene panels modestly improved diagnostic yield at minimal cost. However, to justify the additional costs of genome vs exome sequencing, efficient methods for analysis of structural variation will be required and / or cost of genome analysis and storage will need to decrease.

Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families

“…This study is a step towards shedding light on the factors that render genome sequencing non-diagnostic through deep analysis of real-world data from a large Mendelian program with excellent sampling representation from one of the largest countries in the Middle East. Contrary to the common belief that the missing diagnostic yield of exome is mostly related to technical limitations 36 , 37 , we have previously shown using an unbiased positional mapping approach that at least in the setting of autosomal recessive phenotypes in consanguineous populations, more than 90% of causal variants should in theory be detectable by exome sequencing 5 . Indeed, we and others have shown that reanalysis of “negative” exome sequencing uncovers causal variants that were missed at the interpretation rather than capture stages 38 – 42 .…”

At-Risk Genomic Findings for Pediatric-Onset Disorders From Genome Sequencing vs Medically Actionable Gene Panel in Proactive Screening of Newborns and Children

“…7,8 Diagnostic GS yield from large, rare disease cohort studies is 20% to 40% depending on disease subtypes. [9][10][11][12][13] Although the actual magnitude is still debatable, the diagnostic sensitivity of GS surpasses that of other genetic testing options, including ES. 11,12,[14][15][16][17][18] The clinical utility of rapid GS has been best demonstrated for critically ill pediatric patients, affecting health care management and resulting in better outcomes and significant health care cost savings.…”

“…Diagnostic GS yield from large, rare disease cohort studies is 20% to 40% depending on disease subtypes . Although the actual magnitude is still debatable, the diagnostic sensitivity of GS surpasses that of other genetic testing options, including ES .…”

2023 in the European Journal of Human Genetics

“…Short stature associated with PRMT7 variants may respond to growth hormone [5]. Genome sequencing is the available first line genome test in the UK National Health Service; but Hocking et al provide further evidence that the increased cost does not perhaps result in an increased diagnostic yield [6]. Using genomic testing in post-natal settings is well established, but its use prenatally is controversial.…”