Multisite Study of Optical Genome Mapping of Retrospective and Prospective Constitutional Disorder Cohorts

Abstract

Several medical societies including the American College of Medical Genetics and Genomics, the American Academy of Neurology, and the Association of Molecular Pathology recommend chromosomal microarray (CMA) as the first-tier test in the genetic work-up for individuals with neurodevelopmental disorders such as developmental delay and intellectual disability, autism spectrum disorder, as well as other disorders suspected to be of genetic etiology. Although CMA has significantly increased the diagnostic yield for these disorders, limitations in the technology preclude detection of certain structural variations in the genome and requires reflexing to other cytogenomic and molecular methods. Optical genome mapping (OGM) is a high-resolution technology that utilizes ultra-high molecular weight DNA, fluorescently labeled at a hexamer motif found throughout the genome, to create a barcode pattern, analogous to G-banded karyotyping, that can detect all classes of structural variations at very high resolution by comparison to a reference genome. A multisite study, partially published previously, with a total of n=1037 datapoints was conducted and showed 99.6% concordance between OGM and standard-of-care (SOC) testing for completed cases. The current phase of this study included cases from individuals with suspected genetic conditions referred for cytogenomic testing in a prospective postnatal cohort (79 cases with OGM and SOC results) and a retrospective postnatal cohort (262; same criteria). Among these cohorts were an autism spectrum disorder cohort (135) group with negative or uninformative results on previous testing (72). Prospective cases referred for CMA were included in this study as an unbiased comparison, OGM results show 100% concordance with variants of uncertain significance, pathogenic variants, and likely pathogenic variants reported by CMA other SOC and found reportable variants in an additional 10.1% of cases. Among the autism spectrum disorder cohort, OGM found reportable variants in an additional 14.8% of cases. Based on this demonstration of the analytic validity and clinical utility of OGM by this multi-site assessment, and considering clinical diagnostics often require iterative testing for detection and diagnosis in postnatal constitutional disorders, OGM should be considered as a first-tier test for neurodevelopmental disorders and/or suspicion of a genetic disease.

Optical genome mapping for detection of chromosomal aberrations in prenatal diagnosis

“…In addition, Newman et al reported that 17% of duplications are not tandem, but rather complex rearrangements such as insertional translocations, which may result in fusion or disrupted genes with clinical phenotypes 24 . Recently, Broeckel et al reported that OGM identified a 69‐kbp duplication from chromosome 4 inserted in the X‐chromosome, leading to potential fusion with BCLAF3 on the X‐chromosome 25 . Stevenson et al reported that OGM revealed a 43.1 Mb gain of 2q31.2q36.1 inserted interstitially in an inverted orientation into 14q32.33, disrupting the JAG2 gene 21 (OMIM*602570).…”

“…24 Recently, Broeckel et al reported that OGM identified a 69kbp duplication from chromosome 4 inserted in the X-chromosome, leading to potential fusion with BCLAF3 on the X-chromosome. 25 Stevenson et al reported that OGM revealed a 43.1 Mb gain of 2q31.2q36.1 inserted interstitially in an inverted orientation into 14q32.33, disrupting the JAG2 gene 21 (OMIM*602570). Although these insertional duplications found by OGM are reported as variants of unknown significance, we believe that the ability of OGM to localize the additional duplicated fragments would be beneficial for exploring pathogenic duplications omitted by SOC testing.…”

Optical Genome Mapping for Applications in Repeat Expansion Disorders

“…Therefore, versions of Basic Protocol 1 (with slight variations depending on the cell types covered) have also been published in previous Current Protocols manuscripts that describe methods using Bionano OGM (Koppikar et al, 2023;Sahajpal et al, 2023). In addition, future Current Protocols manuscripts describing the Bionano OGM method will contain the same Basic Protocol 1 (Broeckel, 2024;Kanagal-Shamanna, 2024).…”