Fatigue, cognitive issues, neurological symptoms. They might trace back to B12 and folate metabolism — and rare variants most tests miss.
Whole genome sequencing identifies rare pathogenic variants in folate and B12 metabolism that cause severe neurological disease, distinguishing them from common variants with debated clinical significance.
Methylation & B12 Metabolism
The folate, methylation, and cobalamin (B12) metabolism pathways are central to DNA synthesis, methylation reactions, and energy metabolism. These pathways involve multiple genes including MTHFR, which encodes methylenetetrahydrofolate reductase; MTR, encoding methionine synthase; MTRR, encoding methionine synthase reductase; and CBS, encoding cystathionine β-synthase. Genetic variants in these genes can disrupt the pathway, but the clinical significance depends critically on variant type: rare biallelic loss-of-function variants cause severe disease, while common polymorphisms have limited proven clinical utility despite widespread testing.
The most frequently tested variant is MTHFR C677T, a polymorphism present in approximately 10-15% of Caucasians homozygously (TT genotype), ~25% of Hispanic populations, with varying frequencies across other ancestries. Despite its prevalence, ACMG guidelines issued in 2013 explicitly recommend AGAINST routine MTHFR genotyping for thrombophilia or recurrent pregnancy loss, noting that homocysteine level measurement is more clinically actionable than genotype alone. The clinical impact of common MTHFR, MTR, and MTRR polymorphisms on thrombosis, cardiovascular disease, and recurrent pregnancy loss has been largely disproven by recent large meta-analyses.
In contrast, rare pathogenic variants in these genes cause distinct clinical entities with profound neurological consequences. Biallelic MTHFR deficiency causes severe homocysteinuria (plasma homocysteine often >100 μmol/L; normal <15 μmol/L), associated with developmental delay, seizures, thrombosis, and vision loss. CBS deficiency similarly produces markedly elevated homocysteine and neurological disease. Identification of rare biallelic variants enables specific treatment: high-dose folate and B12 supplementation, betaine therapy for certain forms, and dietary methionine restriction can prevent or slow neurological deterioration when diagnosed early.
MTHFR variants span a spectrum: common polymorphisms with minimal clinical effect and rare biallelic loss-of-function mutations causing severe homocystinuria — Genome Test captures both to enable proper clinical interpretation.
Standard panels test common polymorphisms with debated utility. They risk missing rare pathogenic variants that cause severe neurological disease.
Common variants dominate testing despite limited clinical evidence
Standard one-carbon metabolism panels focus on common polymorphisms like MTHFR C677T, MTR 2756A>G, and MTRR 66A>G. These variants are present in significant percentages of the population but their clinical consequences remain disputed. Large meta-analyses have failed to establish strong associations between these common variants and thrombosis, cardiovascular disease, or recurrent pregnancy loss. The ACMG issued explicit guidance against routine MTHFR testing for these indications, yet testing remains widespread. Whole genome sequencing captures not only common variants but also rare pathogenic variants that definitively cause disease — enabling clinicians to distinguish between benign polymorphisms and disease-causing mutations requiring immediate intervention.
Rare mutations demand detection before neurological damage develops
Biallelic loss-of-function variants in MTHFR, MTR, MTRR, or CBS cause severe homocystinuria with plasma homocysteine exceeding 100 μmol/L, typically accompanied by neurological symptoms including developmental delay, seizures, vision loss, and thrombosis. Early identification of these rare variants enables life-changing intervention: high-dose folate and B12 supplementation, betaine therapy, and dietary modification can prevent or dramatically slow neurological deterioration. Standard panels testing only common polymorphisms miss these critical rare variants entirely. Genome Test provides comprehensive detection of all variants in the pathway, enabling proper distinction between benign polymorphisms and disease-causing mutations requiring urgent treatment.
Your full DNA (not just a part of it)
Traditional genetic testing looks at narrow sets of genes, missing most parts of your genome. We sequence your full genome — every gene and every region between genes.
Comprehensive insights and specialized reports
Easy to read and with answers you and your doctor can act on. Not a file to interpret — 200+ clinical reports, organized by category.
Your test becomes more valuable every year
Your DNA does not change, but genome science is accelerating. Every month, new variant-disease associations are discovered. We validate these findings and update your reports automatically. Your test becomes more valuable every year.
The results doctors bring to their hardest cases.
Forty years of uncertainty. One test.
A patient had spent decades in the UK healthcare system without a diagnosis. Dante data, accepted by NHS clinical teams at Queen Elizabeth University Hospital Glasgow, identified Noonan Syndrome and a RUNX1 leukemia-associated variant that had gone undetected. After 40 years, they finally had an answer.
A complete read delivers a complete picture.
A patient came to Dante to investigate periodic paralysis. Reading the complete genome identified a concurrent hereditary cardiac finding — Brugada syndrome — that their doctor confirmed with an ECG. The result also explained a family member's unresolved cardiac history. One test. Every answer in it.
Sequenced in 2019. The data worked in 2021.
Jennifer sequenced her genome with Dante two years before her breast cancer diagnosis. When treatment began, Dante's pharmacogenomics data showed her prescribed chemotherapy would cause serious adverse effects. Her doctor selected an alternative — and she started effective treatment from day one.
Every genetic question deserves a complete answer.
Whether you are searching for answers today or protecting your health for tomorrow, a complete read of your entire genome is the only place to start.
It runs in your family. Now you can know if it runs in your genes.
Your genome contains inherited variants associated with medical conditions like cardiac, cancer, and neurological. We read all of them — with the clinical depth to give the result meaning.
Learn more →When traditional lab tests say you're fine. And you know you're not.
Standard diagnostic tests check for a pre-selected set of answers. We sequence your full DNA — including parts that no test was designed to check. If the answer is in your genome, we will help you find it.
Learn more →Your diagnosis may be right. Your treatment plan may be incomplete.
Your genes determine which treatments are most likely to work — and which are not. We give your doctor the tools and insights to inform your treatment plan.
Learn more →You want to know before something forces the question.
Some people don't wait for a diagnosis or a family history to act. Whole genome sequencing gives you the complete genetic picture now — so you and your doctor can make informed decisions before anything becomes urgent.
Learn more →You already took a DNA test. Here's what it couldn't tell you.
Most consumer DNA tests read less than 0.1% of your genome. We read all of it.
Learn more →Clinical-grade results. Chosen by individuals, trusted by doctors for their most complex cases.
Dante Genome Test helped specialists at a UK national acute hospital in the identification of Noonan Syndrome and a rare leukemia-associated genetic variant that had gone undetected. That result changed the medical care of the patient.
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Common questions about whole genome sequencing.
What is the difference between whole genome sequencing and a targeted genetic test?
Targeted genetic tests — including standard hereditary cancer panels — read a pre-defined list of known variants in a specific set of genes. They are designed to find what they already know to look for. Whole genome sequencing reads your entire genome: all 6 billion base pairs, every gene, every region between genes. A Mayo Clinic study published in JAMA Oncology found that standard testing guidelines missed more than half of patients with inherited cancer mutations. Genome Test does not have a fixed list.
What will I receive when my results are ready?
Your Dante Genome delivers 200+ physician-ready reports organized by clinical category — hereditary cancer, cardiac conditions, rare diseases, pharmacogenomics, carrier status, and more. Reports are delivered to your secure Genome Manager and are formatted for direct clinical use. Your genome data is permanently retained and re-analyzed automatically as science advances.
What happens if a clinically significant variant is found?
If a pathogenic or likely-pathogenic variant is identified, it will be clearly flagged in your physician-ready report with clinical context, published evidence, and recommended next steps. We recommend sharing any clinically significant finding with your physician or a genetic counselor, who can guide decisions about surveillance, risk reduction, or cascade testing for family members.
How is this different from a consumer DNA test like 23andMe or AncestryDNA?
Consumer DNA tests use genotyping chips that read less than 0.1% of your genome — a tiny pre-selected set of common variants. They are optimized for ancestry and population-level traits, not clinical genetic findings. The Dante Genome Test sequences 100% of your genome at 30X coverage, the same standard used in clinical diagnostic settings. The two tests are not comparable in scope, methodology, or clinical utility.
How long does it take to get results, and how are they delivered?
Your collection kit ships within 48 hours of ordering. Once your sample arrives at our CLIA-certified laboratory, sequencing and analysis takes 6–8 weeks. Results are delivered securely to your Genome Manager, where you can access your reports, share them with your physician, and receive automatic updates as new findings are validated against your genome.
We work with patient advocacy groups worldwide.
Dante Labs works with patient advocacy groups of any size — for Methylation & B12 Metabolism and other conditions, rare and common. We support groups in any country, including virtual patient advocacy groups.
We can provide customized reports, group discounts, and packages tailored for your members. Please reach out using the form and we'll be in touch within two business days.
- Custom genomic reports for your members
- Group discounts and tailored packages
- Any country — including virtual groups
- Rare and common conditions covered
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One test.
A lifetime of answers.
One kit, sent to your home. Your entire genome sequenced at the clinical standard used for diagnostic decisions. 200+ physician-ready reports delivered to your Genome Manager in 6–8 weeks — permanent and updated as science advances.
Ships within 48 hours · Results in 6–8 weeks
