Genetic characterization for DM1 trials and registries
A diagnostic report gives one number: the repeat length. Current evidence ties several features to when DM1 begins, how it progresses and how patients respond to treatment: the repeat length inherited at conception, how the repeat length varies from cell to cell as it expands over a lifetime (the somatic distribution), interruptions in the repeat, variants in DNA-repair genes that modify the disease, and methylation at the CTCF sites on either side of the repeat. 3X measures all of these for each participant and returns one integrated record that shows where every measurement came from.
What we measure
| Marker | What is measured | Platform |
|---|---|---|
| DMPK repeat, both alleles | Repeat count on each molecule; carrier status against the standard size bands | Targeted long-read sequencing |
| Progenitor allele estimate | A low percentile of the per-molecule length distribution, used to estimate the length inherited at conception | Targeted long-read sequencing |
| Somatic distribution | The per-molecule spread of the expanded allele, with an instability index | Targeted long-read sequencing |
| Interruptions | Whether variant repeats interrupt the tract, how many and where, placed on each molecule with its base quality | Targeted long-read sequencing |
| Flanking CTCF sites | Methylation at CTCF1 and CTCF2 (the CTCF protein binding sites on either side of the repeat), read directly from native DNA with no conversion step; whether the site sequences are intact | Targeted long-read sequencing |
| Flanking haplotype | Which of the two chromosome copies carries the expansion | Targeted long-read sequencing |
| DNA-repair modifier genotypes | Published onset variants in MSH3, FAN1, MLH1, PMS2, LIG1 and related genes | Short-read genome, partner laboratory |
| Genetic ancestry | Ancestry principal components calculated from the genome | Short-read genome |
Why these features
| Feature | Published finding |
|---|---|
| Progenitor allele length | Explained 52.3 percent of the variation in age at onset, against 40.5 percent for the modal length that a diagnostic laboratory reports, in the same 82 people (Morales 2012) |
| Somatic instability | Accounts for about 4.7 percent of the variation in age at onset, independent of inherited length (Cumming 2019) |
| Interrupting variant repeats | Present in 3 to 12 percent of patients and associated with onset delayed by 13.2 years (Cumming 2019). The authors of a Canadian cohort study recommend balancing carriers across trial arms (Overend 2019) |
| DNA-repair modifier genotypes | In the Huntington disease cohorts, FAN1 variant rs146353869 shifts age at onset by 6.1 years per copy of the minor allele (GeM-HD 2015) |
| Flanking CTCF-site methylation | Switches on above an inherited (progenitor) length of about 518 repeats, and separates congenital from classical DM1 (Morales 2022) |
In the 2026 trial-readiness study, 80 percent of investigators judged repeat composition and modifier loci likely to influence disease severity, and pharmaceutical partners named the lack of a standardized DMPK repeat-length assay as a limitation (Wrenn 2026).
Samples and read depth
Blood, saliva, tissue and cell-line DNA run together on the same flow cell, with no amplification (PCR) at any step. Each sample can be read at one of two levels:
| Level | Deliverable | Target reads per sample | Input DNA |
|---|---|---|---|
| Genotype | Detection and class (normal, intermediate, expanded) with both allele sizes | 20 on-target reads, at least 5 of them from the expanded allele | 2 to 10 µg |
| Deep | Central size with a confidence interval, progenitor allele estimate and the full somatic distribution | 200 on-target reads, at least 50 of them from the expanded allele | 10 µg or more |
At the genotype level, 12 to 25 sample libraries share one flow cell; the deep level pools fewer. Up to four loci can be measured on one flow cell. In a 72-hour run of 13 human samples across two loci, every call agreed with the independent TP-PCR and STR methods.
The participant record
For each participant you receive one integrated record. It holds the core marker panel drawn from both platforms; the result of every analysis program (caller), kept even where they disagree; and a data dictionary that defines each field, how it is measured, what evidence interprets it and its limits. The record is built to sit next to a phenotype record in a registry, and to support inclusion criteria and stratification in a trial.
Where this stands
Our DMPK and TCF4 assays are in analytical validation in our CLIA-registered laboratory (CLIA ID 22D2345868). Research characterization is available now; clinical reporting opens after the Massachusetts state licensure survey. Our DM1 white paper (April 2026) reports 14 subjects and about 1,800 individually sequenced molecules, compared across three independent methods.
To discuss a trial or registry program, contact Steven Oldenburg, PhD, President and Co-Founder: [email protected]