Epigenetic disorders, environment and methylation testing
Diseases can come from faulty epigenetic marks or from genes that write and read them; methylation tests now diagnose many of them.
Key facts
- Imprinting disorders arise from deletions, uniparental disomy or imprinting-centre defects: Prader–Willi, Angelman, Beckwith–Wiedemann and Silver–Russell syndromes.
- Disorders of the epigenetic machinery («chromatinopathies») come from variants in genes that methylate DNA or modify histones: Rett (MECP2), Kabuki (KMT2D), Sotos (NSD1), CHARGE (CHD7).
- Repeat expansions can silence a gene by methylation: in fragile X syndrome the expanded FMR1 promoter is methylated and the gene switched off.
- Methylation tests at an imprinted locus detect deletion, uniparental disomy and imprinting defects together; for Prader–Willi syndrome they find almost all cases.
- Episignatures are genome-wide methylation patterns typical of many chromatinopathies; they confirm a diagnosis and help reclassify uncertain variants.
In detail
- Environment and epigenome: famine, maternal diabetes and smoking in pregnancy leave methylation changes associated with later metabolic and cardiovascular risk, the idea behind the developmental origins of health and disease.
- Skewed X inactivation can make a carrier woman show an X-linked disease.
- In cancer, promoter methylation silences tumour suppressors: MLH1 methylation explains most sporadic colorectal cancers with mismatch-repair loss (and argues against Lynch syndrome), and MGMT methylation predicts response to temozolomide in glioblastoma.
- Drugs that change epigenetic marks are used in cancer (DNA methyltransferase and histone deacetylase inhibitors); trofinetide is approved for Rett syndrome, and gene therapies are in trials.
- Also called
- Chromatinopathies and imprinting disorders, Episignatures
Clinical notes
- A child with hypotonia, feeding difficulty in infancy and later hyperphagia should have a methylation test of 15q11–q13.
- In a colorectal tumour with loss of MLH1, testing MLH1 promoter methylation (or BRAF) helps decide whether germline testing for Lynch syndrome is needed.
Test yourself
Think of the answer, then tap the question to see it.
Why is a methylation test the first test for suspected Prader–Willi syndrome?
It detects all three main causes, deletion, maternal uniparental disomy and imprinting defects, in one test.
What is an episignature?
A genome-wide DNA methylation pattern typical of a specific disorder of the epigenetic machinery, used to confirm a diagnosis or classify a variant.
What does MLH1 promoter methylation in a colorectal cancer suggest?
A sporadic tumour with silenced MLH1, rather than Lynch syndrome.
Connections
Educational information, not medical advice. For any symptom, see a health professional.
Sources: What is epigenetics?: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); What are genomic imprinting and uniparental disomy?: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Epigenetics (National Human Genome Research Institute (NHGRI), 2026); Methylation (National Human Genome Research Institute (NHGRI), 2026).
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Representative model, for educational purposes only.