Application of full-genome analysis to diagnose rare monogenic disorders

Abstract

Current genetic testenhancer and narrows the diagnostic intervals for rare diseases provide a diagnosis in only a modest proportion of cases. The Full-Genome Analysis method, FGA, combines long-range assembly and whole-genome sequencing to detect small variants, structural variants with breakpoint resolution, and phasing. We built a variant prioritization pipeline and tested FGA’s utility for diagnosis of rare diseases in a clinical setting. FGA identified structural variants and small variants with an overall diagnostic yield of 40% (20 of 50 cases) and 35% in exome-negative cases (8 of 23 cases), 4 of these were structural variants. FGA detected and mapped structural variants that are missed by short reads, including non-coding duplication, and phased variants across long distances of more than 180 kb. With the prioritization algorithm, longer DNA technologies could replace multiple tests for monogenic disorders and expand the range of variants detected. Our study suggests that genomes produced from technologies like FGA can improve variant detection and provide higher resolution genome maps for future application.

Comparative benchmarking of optical genome mapping and chromosomal microarray reveals high technological concordance in CNV identification and structural variant refinement

“…In a single assay, OGM can accurately identify both balanced and unbalanced SVs, triploidy, and large AOHs, thereby mitigating the need of additional testing. Taken together, these results and other studies showing high concordance of OGM with standard of care 27 and increased ability to detect pathogenic findings 28 . This study is in agreement with published findings from multiple investigators recommending the implementation of OGM as a first-tier testing method that provides comprehensive results in a cost effective and streamlined workflow.…”

Optical genome mapping in acute myeloid leukemia: a multicenter evaluation

“…MPseq is a powerful technique for detection of genomic fusions in a whole genome approach and obviates some of the ambiguity of short read sequencing [39]. Our study was not directed at a comparison of OGM with any of the NGS-based approaches, but other studies have shown that OGM and WGS identify different, albeit overlapping, sets of SVs, suggesting potential synergy of the two methods [38,[40][41][42]. However, all NGS based approaches share several major hurdles, including equipment price, complexity of the sequence library preparation, and data analysis intricacy.…”

An automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases

“…The consequences of this for genetic disease diagnosis is not yet known. Further studies are needed to compare the diagnostic performance of these methods versus hybrid methods with short read sequencing and complementary technologies, such as long-read sequencing and optical mapping 74 , 77 , 78 .…”