The purpose of this research use only (RUO) study is to detect genomic structural variants (SVs) in human DNA by Optical Genome Mapping (OGM) using the Bionano Genomics Saphyr system. SVs are a type of genetic alternation that includes deletions, duplications, and both balanced and unbalanced rearrangements (ex: inversions or translocations), as well as specific repeat expansions and contractions. The results of OGM analysis will be compared to prior clinical genetic test results to determine how OGM compares to current standard of care (SOC) clinical test methods such as chromosomal microarray analysis (CMA), karyotyping, Southern blot analysis, polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), and/or next generation sequencing (NGS), etc.

Optical genome mapping (OGM) is an emerging next-generation cytogenomic tool that enables a comprehensive analysis of structural variants (SVs) in the genome. OGM, in its current iteration, is performed on the Saphyr system, which is developed and marketed by Bionano Genomics (San Diego, CA). OGM employs imaging of ultra-long DNA molecules (>150 kbp) that are labeled at a unique 6 base-pair sequence motif (CTTAAG) that occurs throughout the genome. The images of the labeled DNA molecules are used to generate a de novo assembly that can be compared to a reference genome to identify all classes of SVs, such as deletions, duplications, balanced/ unbalanced genomic rearrangements (insertions, inversions, and translocations), and repeat array expansions/contractions). In addition, a separate coverage-based algorithm enables the detection of genome-wide copy number analysis (similar to CMA), and the absence of heterozygosity (AOH) analysis. In the same assay, a concurrent or stepwise data analysis pipeline allows for sizing pathogenic CGG repeat expansions (consistent with fragile X syndrome) as well as D4Z4 repeat contractions which are consistent with facioscapulohumeral muscular dystrophy type 1 (FSHD1). Recently, in several studies, OGM has demonstrated excellent concordance with standard-of-care testing. Importantly, the OGM workflow can provide results within three-five days.

The aim of this double-blinded, multi-site, retrospective, observational, Institutional Review Board (IRB)-approved study is to evaluate the concordance of structural variant detection by OGM compared to standard of care tests (such as CMA, karyotyping, Southern blot analysis, PCR, FISH, and/or NGS, etc.), in a large cohort containing a variety of SVs including aneuploidies, intragenic and contiguous deletions, duplications, balanced and unbalanced translocations, inversions, isochromosomes, ring chromosomes, repeat expansions, repeat contractions, and more. This study is also designed to assess the sensitivity, specificity, and reproducibility of OGM analysis conducted at multiple sites, by numerous operators, and on different Saphyr instruments. Consensus testing and interpretation protocols were developed and implemented at all sites.

Inclusion Criteria:

1. Individual with a genomic aberration identified by CMA, karyotyping, Southern blot analysis, PCR, FISH, and/or NGS or other standard of care (SOC) genetic testing technology whose clinical test results are available to compare with results from OGM.
2. Patients with prior negative SOC genetic testing results whose results are available to compare with results from OGM.

Exclusion Criteria:

1. Any individual who opted-out of research at the testing laboratory.
2. An individual whose genetic test contains the following variants: pathogenic sequence variants, abnormalities involving acrocentric p-arms and centromeres, below 20% for mosaicism, and tetraploidy.

Individuals will be recruited if they have standard of care genetic test results (such as CMA, karyotyping, Southern blot analysis, PCR, FISH, and/or NGS, etc.) to compare to optical genome mapping results.