Rare Structural Variants Uncovered by Optical Genome Mapping in Multisystem Inflammatory Syndrome in Children (MIS-C)

Catherine A Brownstein^{1

2}, Caspar I van der Made³, Kristin Cabral¹, Shira Rockowitz^{1

2}, Donghun Kang¹, Maximilian Schieck^{4

5}, Andy Wing Chun Pang⁶, Jeffrey M Robinson⁶, Alex R Hastie⁶, Alka Chaubey⁶; C.O.V.I.D19hostgenomeS.V. Consortium; Alexander Hoischen³, Alan H Beggs^{1

2}, Clement A Adebamowo^{1

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6}, Ali Andalibi^{1

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6}, Silviu-Alin Bacanu^{1

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6}, Vineet Bafna^{1

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6}, Justin Bahl^{1

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6}, Hayk Barseghyan^{1

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6}, Alan Beggs^{1

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6}, Laurie Burdette^{1

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6}, Manish Butte^{1

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6}, Pantelis Constantoulakis^{1

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6}, Keith A Crandall^{1

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6}, Siavash R Dehkordi^{1

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6}, Megan Dennis^{1

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6}, Gang Fang^{1

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6}, Olivier Fedrigo^{1

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6}, Darren Finlay^{1

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6}, Michael A Goldman^{1

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6}, Umamaheswaran Gurusamy^{1

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6}, Vanessa Hayes^{1

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6}, Glenn Hickey^{1

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6}, Alexander Hoischen^{1

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6}, Thomas Illig^{1

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6}, Alexander Ioannidis^{1

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6}, Erich Jarvis^{1

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6}, Naoru Koizumi^{1

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6}, Ravindra Kolhe^{1

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6}, Meriem Laamarti^{1

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6}, Celia Labranche^{1

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6}, Sandra Leibel^{1

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6}, Brynn Levy^{1

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6}, Matthew Loose^{1

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6}, Claudio Mello^{1

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6}, Jamal Nasir^{1

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6}, Thuy L Phung^{1

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6}, Chethan P Venkatasubba Rao^{1

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6}, Ted Ross^{1

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6}, Nikhil S Sahajpal^{1

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6}, Rashmi K Shamanna^{1

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6}, Daniela C Soto^{1

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6}, Amir Trablesi^{1

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6}, Zi-Xuan Wang^{1

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6}, Sion Llewelyn Williams^{1

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6}, Victoria Wright^{1

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6}, Hua Zhao^{1

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6}, Michael Zody^{1

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Affiliations

¹ Division of Genetics and Genomics The Manton Center For Orphan Disease Research Harvard Medical School Boston Children's Hospital Boston Massachusetts USA.
² Children's Rare Disease Collaborative Boston Children's Hospital Boston Massachusetts USA.
³ Department of Human Genetics Radboud University Medical Center Nijmegen the Netherlands.
⁴ CAIMed - Lower Saxony Center for Artificial Intelligence and Causal Methods in Medicine (CAIMed) Hannover Germany.
⁵ Hannover Unified Biobank Hannover Medical School Hannover Germany.
⁶ Bionano Genomics San Diego California USA.

PMID: 41473684
PMCID: PMC12747551
DOI: 10.1002/ggn2.202500023

Rare Structural Variants Uncovered by Optical Genome Mapping in Multisystem Inflammatory Syndrome in Children (MIS-C)

Catherine A Brownstein et al. Adv Genet (Hoboken). 2025.

. 2025 Dec 8;6(4):e00023.

doi: 10.1002/ggn2.202500023. eCollection 2025 Dec.

Authors

Affiliations

¹ Division of Genetics and Genomics The Manton Center For Orphan Disease Research Harvard Medical School Boston Children's Hospital Boston Massachusetts USA.
² Children's Rare Disease Collaborative Boston Children's Hospital Boston Massachusetts USA.
³ Department of Human Genetics Radboud University Medical Center Nijmegen the Netherlands.
⁴ CAIMed - Lower Saxony Center for Artificial Intelligence and Causal Methods in Medicine (CAIMed) Hannover Germany.
⁵ Hannover Unified Biobank Hannover Medical School Hannover Germany.
⁶ Bionano Genomics San Diego California USA.

PMID: 41473684
PMCID: PMC12747551
DOI: 10.1002/ggn2.202500023

Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a pediatric complication of SARS-CoV-2 infection characterized by multiorgan inflammation and frequently by cardiovascular dysfunction. In a single-center prospective cohort study, optical genome mapping (OGM) was performed on 14 patients, including 11 meeting CDC criteria for MIS-C and 3 with MIS-C-like (MIS-CL) presentations. SVs and CNVs were filtered against population and internal OGM control databases. Seven patients (50%) harbored prioritized variants within or near genes implicated in immune regulation or SARS-CoV-2 response. These included intronic insertions or deletions in ORAI1, STAT4, and ITPR1 (n = 4 patients); a heterozygous insertion disrupting BATF; a large deletion spanning exons 2-10 of CFHR5; and an upstream insertion near DOCK2. Application of OGM to patients with MIS-C and MIS-CL revealed SVs potentially impacting inflammation, COVID-19 severity, and Kawasaki Disease susceptibility. Although causality cannot yet be assigned, the identification of rare structural variants highlights biologically plausible mechanisms that may contribute to disease heterogeneity. These findings establish the feasibility and value of OGM in the assessment of complex pediatric syndromes, such as children with MIS-C or a severe course of SARS-CoV-2 infection.

Keywords: MIS‐C; SARS‐CoV‐2; optical genome mapping.

PubMed Disclaimer

Conflict of interest statement

A.P., J.M.R., A.H., and A.C. are or were salaried employees and hold equity in Bionano Genomics, Inc. The remaining authors declare no conflicts of relevance to this study.

Figures

**FIGURE 1**
Schematic overview of the optical genome mapping (OGM) process. Steps include: (1) extraction of ultra‐high molecular weight DNA using Bionano Prep SP, (2) fluorescent labeling with Direct Labeling Enzyme 1 (DLE‐1), (3) loading of labeled DNA onto a Saphyr cartridge, (4) imaging of DNA molecules in nanochannels, (5) processing of images to extract DNA molecule maps and fluorophore positions, (6) assembly into consensus maps via *de novo* and rare variant pipelines, and (7) variant visualization using Bionano Access software v1.6.1. Data are presented as a schematic workflow created by the authors; no statistical tests were performed (*n = 14 patients; 11 MIS‐C, 3 MIS‐CL*).

**FIGURE 2**
Copy number variant in *CFHR5* detected by optical genome mapping (OGM). (A) Genome browser view of the *CFHR5* locus in patient MISC011 showing a ∼20.6 kb heterozygous deletion spanning exons 2–10. (B) Circos plot summarizing the distribution of rare structural variants across the genome for this patient. Data are representative of OGM readouts; no statistical tests were performed (*n = 1 patient*).

See this image and copyright information in PMC

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Rare Structural Variants Uncovered by Optical Genome Mapping in Multisystem Inflammatory Syndrome in Children (MIS-C)

Affiliations

Rare Structural Variants Uncovered by Optical Genome Mapping in Multisystem Inflammatory Syndrome in Children (MIS-C)

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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