# Optical Genome Mapping (OGM) for Concurrent Genetic and Epigenetic Diagnosis of Inborn Disorders

> **NIH NIH R21** · CHILDREN'S RESEARCH INSTITUTE · 2020 · $490,875

## Abstract

Project Summary/Abstract
 Short-read exome/genome sequencing (SRS) and chromosomal microarrays (CMA) have helped
increase diagnostic rates across many genetic disorders. However, despite this success, about half of the
cases remain undiagnosed. Due to the methodological limitations of both technologies (SRS, CMA), they fail to
sensitively identify many structural variants and balanced rearrangements, respectively. Additionally, both
technologies have limitations in assessment of epigenetic changes. For example, short-read based bisulfite
sequencing or methylation arrays do not provide long-range haplotype specific methylation states, rather the
detected signals are averaged for individual genomic positions.
 These limitations can be alleviated with a novel dual-label optical genome mapping (DL-OGM)
technology for detection of both genetic and epigenetic variations in one assay over long stretches of single
DNA molecules and phased haplotypes. The method relies on differential labeling of high molecular weight
DNA. First, long DNA molecules are nicked with BspQI endonuclease and labeled with red fluorescent
nucleotides. Second, the same DNA molecules undergo treatment with M.TaqI methyltransferase that attaches
green fluorescent cofactor onto non-methylated CpGs in ATCG sequences throughout the genome. Third, the
pattern of fluorescent labels is captured in nanochannel arrays for de novo genome assembly, variant calling
and quantification of epigenetic marks.
 Here, we will show the ability of DL-OGM to detect large copy number variants and methylation levels
for Facioscapulohumeral muscular dystrophy (FSHD) and Beckwith-Wiedemann syndrome (BWS). We
successfully identified the molecular diagnosis (constriction of D4Z4 array and associated hypomethylation) in
FSHD case/control samples in the sub-telomeric region of chromosome 4q35. Additionally, we tested the
method for a case diagnosed with BWS, where DL-OGM identified a duplication in the paternally inherited
allele carrying epigenetic states resulting in the syndrome. DL-OGM technology offers substantial advantages
over the current clinical diagnostic practices for specific disorders tested here (FSHD, BWS) and can be
broadly applied to other disorders with characteristic DNA methylation patterns such as CHARGE syndrome,
disorders with skewed X-inactivation, and imprinting disorders.

## Key facts

- **NIH application ID:** 10071467
- **Project number:** 1R21HG011424-01
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Eric J. Vilain
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $490,875
- **Award type:** 1
- **Project period:** 2020-09-01 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071467

## Citation

> US National Institutes of Health, RePORTER application 10071467, Optical Genome Mapping (OGM) for Concurrent Genetic and Epigenetic Diagnosis of Inborn Disorders (1R21HG011424-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10071467. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*