Evaluation of Genomic Proximity Mapping (GPM) for Detecting Genomic and Chromosomal Structural Variants in Constitutional Disorders

Abstract Genomic structural variants (SVs) are critical contributors to genetic diversity and disease, yet their detection remains challenging with conventional cytogenetic techniques, such as karyotyping, fluorescence in situ hybridization (FISH), and chromosome microarray analysis (CMA). These methods often lack the resolution and sensitivity needed for comprehensive characterization of chromosomal aberrations. To address these limitations, we implemented genomic proximity mapping (GPM), a genome-wide chromosome conformation capture technology, in a clinical setting. In this study, we applied GPM to a cohort of 123 patients with constitutional disorders, achieving a 100% concordance rate in detecting 411 CNVs and 39 structural rearrangements, in addition to novel findings missed by standard methods. GPM demonstrated unique advantages, such as resolving both balanced and unbalanced chromosomal rearrangements with precise (<5kb) breakpoint resolution, maintaining robust performance with challenging samples, including formalin-fixed, paraffin-embedded (FFPE) tissues, and detecting mosaicism with high sensitivity. Furthermore, GPM reliably provided detailed copy number and loss-of-heterozygosity profiles, streamlining workflows and enhancing diagnostic resolution. GPM represents a transformative tool for genomic diagnostics, offering a high-resolution, comprehensive approach to detecting diverse genomic alterations. Its ability to address limitations of conventional cytogenetics methods positions GPM as a needed advance in the diagnosis, prognosis, and therapeutic management of genetic disorders. Competing Interest Statement SME is an employee of Phase Genomics, Inc, the developer of the GPM technology Funding Statement This work was funded in part by a grant from the Brotman Baty Institute (BBI) to YJL and HF, NICHD/NIH R44HD104323 to SME. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of University of Washington gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data availability statement Anonymized data can be made available upon request and with appropriate agreements and human research ethics committee approval.