A New Lens in Rare Disease Diagnosis: Integrating DNA Methylation into Genomic Diagnostics

When we think about genetic testing, we often focus on DNA as the body’s “blueprint.” But for some patients with suspected rare diseases, that blueprint alone doesn’t give us all the answers.

A newer approach looks at how genes are functioning, not just their sequence. One important way to do this is by analyzing DNA methylation—a process that adds tiny chemical tags “on top of” DNA to help control how genes are turned on or off. When used alongside standard genetic testing, this can improve the chances of finding a diagnosis.¹

In this blog, we explore how methylation provides an added layer of functional insight that can reveal diagnoses sequencing alone might miss—and how MyOme is leveraging it to help families find answers.

 How Methylation Insights Can Inform Rare Disease Diagnosis

In certain rare diseases, methylation patterns become disrupted. By analyzing these patterns—known as methylation signatures—clinicians can detect changes in gene function that may not be identified through DNA sequencing alone. These signatures may occur in specific regions or across the genome and can point to an underlying condition, helping diagnose cases that were previously unresolved.^2,3

Moving from Serial Tests to Integrated Analysis

Historically, detecting methylation required separate, complex testing methods that were not part of standard genetic testing workflows. However, the landscape has recently shifted with the emergence of long-read sequencing (LRS). Unlike standard DNA sequencing methods that read short pieces of DNA, newer long-read approaches analyze intact DNA molecules, which enables the detection of subtle signals, including methylation tags.⁴ This allows for the simultaneous detection of both the DNA sequence and associated methylation patterns without the need for additional testing, thus streamlining analysis and expediting results.

Resolving Unclear Genetic Results

One of the most persistent challenges in genetic testing is the interpretation of unclear results, referred to as variants of uncertain significance (VUS). These occur when a DNA change is identified in a disease-linked gene but lacks sufficient evidence to be classified as benign or pathogenic, leaving uncertainty around whether the variant is responsible for the patient's condition.⁵

Some rare conditions have well-defined methylation patterns. By comparing a patient’s methylation profile to these known patterns, clinicians can better understand whether a variant is likely disease-causing. If the patient’s pattern matches a known signature, it can provide strong supporting evidence that may help reclassify a VUS and move closer to a diagnosis.²

Distinguishing Imprinting Disorders

Methylation analysis is especially helpful for diagnosing imprinting disorders—conditions where gene activity depends on whether the gene was inherited from the mother or the father. In these conditions, the DNA sequence may appear normal, but the gene is not functioning properly due to changes in methylation.

For example, two conditions—Prader-Willi syndrome and Angelman syndrome—affect the same region of DNA but differ based on which parent’s gene copy is active. Methylation testing can distinguish between them by identifying which copy is turned off, allo™wing for an accurate diagnosis.³

Integrating Methylation into Routine Testing

In March 2026 at the ACMG Annual Meeting, MyOme announced the integration of methylation signatures into the Zenith™ diagnostic platform for rare diseases, powered by a strategic partnership with Natera.⁶ This advancement builds on MyOme’s core philosophy of a genome-first, multiomic platform by incorporating epigenetic insights directly into the existing diagnostic workflow.

To streamline rare disease diagnostics, MyOme has added automatic follow-up LRS to its genome and exome analyses. If the initial test identifies a VUS in a gene with a known methylation pattern, or suggests a possible imprinting disorder, the workflow automatically initiates additional LRS for further evaluation.

Currently, MyOme uses this reflexive LRS approach to:

• Resolve VUS in methylation-related conditions, such as Sotos and Coffin-Siris syndromes

• Confirm and distinguish imprinting conditions, specifically Prader-Willi and Angelman syndromes

Importantly, this additional testing is triggered within the same lab workflow, helping increase the diagnostic yield and shorten the time to diagnosis.

Expanding the Role of Methylation

Through a strategic partnership with Natera, MyOme is making this advanced testing approach more accessible. By combining MyOme’s strengths in LRS and methylation analysis with Natera’s broad clinical reach, providers can more easily offer genomic testing that looks beyond just the DNA sequence.

Looking ahead, methylation analysis is expected to play a much larger role in diagnosis. In the near term, MyOme is increasing the number of conditions where methylation patterns can help confirm a diagnosis.

Over time, LRS may become the standard approach, allowing methylation to be analyzed from the start rather than as a follow-up step. This would enable a single, comprehensive test to assess multiple types of genetic variation at once. For clinicians and patients, this means a higher chance of finding answers and a faster path to diagnosis.

References

1. Kerkhof J, Rastin C, Levy MA, et al. Diagnostic utility and reporting recommendations for clinical DNA methylation episignature testing in genetically undiagnosed rare diseases. Genet Med. 2024;26(5):101075. doi:10.1016/j.gim.2024.101075
2. Sadikovic B, Levy MA, Kerkhof J, et al. Clinical epigenomics: genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders. Genet Med. 2021;23(6):1065-1074. doi:10.1038/s41436-020-01096-4
3. Aref-Eshghi E, Kerkhof J, Pedro VP, et al. Evaluation of DNA methylation episignatures for diagnosis and phenotype correlations in 42 Mendelian neurodevelopmental disorders. Am J Hum Genet. 2020;106(3):356-370. doi:10.1016/j.ajhg.2020.01.019
4. Tafazoli A, Hemmati M, Rafigh M, et al. Leveraging long-read sequencing technologies for pharmacogenomic testing: applications, analytical strategies, challenges, and future perspectives. Front Genet. 2025;16:1435416. Published 2025 Apr 30. doi:10.3389/fgene.2025.1435416
5. Basel-Salmon L. Phenotypic compatibility and specificity in genomic variant classification. Eur J Hum Genet. 2024;32(5):471-473. doi:10.1038/s41431-024-01534-4
6. MyOme Inc. MyOme debuts Zenith™ portfolio with Natera and launches long-read methylation analysis at ACMG 2026. PR Newswire. March 12, 2026. Accessed March 17, 2026. https://www.prnewswire.com/news-releases/myome-debuts-zenith-portfolio-with-natera-and-launches-long-read-methylation-analysis-at-acmg-2026-302711880.html
7. Pandey R, Brennan NF, Trachana K, et al. A meta-analysis of diagnostic yield and clinical utility of genome and exome sequencing in pediatric rare and undiagnosed genetic diseases. Genet Med. 2025;27(6):101398. doi:10.1016/j.gim.2025.101398