A Post-Hoc Comparison of the Utility of Sanger Sequencing and Exome Sequencing for the Diagnosis of Heterogeneous Diseases

Abstract

The advent of massive parallel sequencing is rapidly changing the strategies employed for the genetic diagnosis and research of rare diseases that involve a large number of genes. So far it is not clear whether these approaches perform significantly better than conventional single gene testing as requested by clinicians. The current yield of this traditional diagnostic approach depends on a complex of factors that include gene-specific phenotype traits, and the relative frequency of the involvement of specific genes. To gauge the impact of the paradigm shift that is occurring in molecular diagnostics, we assessed traditional Sanger-based sequencing (in 2011) and exome sequencing followed by targeted bioinformatics analysis (in 2012) for five different conditions that are highly heterogeneous, and for which our center provides molecular diagnosis. We find that exome sequencing has a much higher diagnostic yield than Sanger sequencing for deafness, blindness, mitochondrial disease, and movement disorders. For microsatellite-stable colorectal cancer, this was low under both strategies. Even if all genes that could have been ordered by physicians had been tested, the larger number of genes captured by the exome would still have led to a clearly superior diagnostic yield at a fraction of the cost.

Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature

“…3,[31][32][33][34][35][36][37][38][39][40][41][42] Seven studies presented data on the costs of WES or WGS testing pathways, [24][25][26][27][43][44][45] and eight studies presented data on clinically relevant outcome measures for these tests. 5,6,[8][9][10][46][47][48] Of the eight full economic evaluations, two were CUAs 22,23 and six were CEAs, published between 2014 and 2017 in Australia (2), the United States (1), the UK (1), the Netherlands (1), and Canada (1).…”

“…While all 13 publications reported cost estimates for WES or WGS, only 3 stated the methods and sources underlying these estimates. 35,37,42 Of the seven studies that presented data on the costs of WES or WGS testing pathways, four evaluated WGS. Chrystoja and Diamandis 24 reviewed the potential of WGS and summarized cost data extracted from previously published scientific studies and commercial sources.…”

Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature

“…9 Exome capture was performed with the Agilent SureSelect Human All Exon v4 enrichment kit (Agilent Technologies). WES was performed on the Illumina HiSeq platform (BGI, Copenhagen, Denmark).…”

Youngest presenting patient with dystonia 24 and review of the literature

“…These diagnoses are also more difficult secondary to the genetic heterogeneity that is seen in many diseases. The diagnostic yield of WES is higher in patients with heterogeneous diseases that include blindness, deafness, and (as in our patient) movement disorders 13. Determining specific diagnoses is useful to determine etiologies, prognosis, inheritance patterns, and effective treatments.…”