Thiopurine S-methyltransferase Deficiency

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Classifications

Harrison's Part

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Mappings

MONDO

MONDO:0012503 thiopurine S-methyltransferase deficiency

Primary MONDO disease identifier for this thiopurine S-methyltransferase deficiency entry.

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Inheritance

1

Autosomal codominant HP:0000006

TPMT activity segregates as a monogenic autosomal codominant trait: homozygous wild-type individuals have high activity, heterozygotes intermediate activity, and homozygous or compound heterozygous carriers of low-activity alleles have undetectable activity. Codominance rather than simple recessiveness is the clinically important point, because heterozygotes are not unaffected — they have a real, intermediate risk of thiopurine toxicity and warrant dose reduction. Note on the ontology binding: HPO has no "autosomal codominant inheritance" term. HP:0000006 is bound here because the heterozygote has a distinct intermediate phenotype rather than being a silent carrier, which is the property that matters clinically. It should not be read as a claim that the trait is dominant in the usual sense.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:7191632 SUPPORT Human Clinical

"subjects homozygous for TPMT(H) would have high enzyme activity, subjects heterozygous for the two alleles would have intermediate activity, and subjects homozygous for TPMT(L) would have undetectable activity"

States the codominant genotype-to-activity mapping across all three genotype classes.

PMID:7191632 SUPPORT Human Clinical

"The segregation of RBC TPMT activity among 215 first-degree relatives in 50 randomly selected families"

Family segregation analysis underpinning the monogenic codominant model.

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Discussions and Knowledge Gaps

1

What fraction of thiopurine-induced myelosuppression is actually attributable to TPMT deficiency, and what accounts for the remainder?

KNOWLEDGE GAP OPEN gap_tpmt_attributable_fraction_myelosuppression

Attached to

pathophysiology#Bone Marrow Suppression pathophysiology#Multilineage Cytopenias

In a cohort of 41 Crohn disease patients who developed leukopenia or thrombocytopenia on azathioprine or mercaptopurine, only 27% carried any TPMT mutant allele and just 10% were biallelic; 73% had no known TPMT mutation at all. The authors' own conclusion is that myelosuppression is more often caused by other factors. NUDT15 deficiency, since characterized and now co-recommended with TPMT by CPIC, explains part of the remainder — particularly in East Asian and Hispanic populations where NUDT15 variants are considerably more common than TPMT variants — but the residual is not fully accounted for. This matters for how the entry is used: TPMT deficiency is a well-understood mechanism for a minority of a common toxicity, not the explanation for that toxicity.

Proposed experiments

Joint TPMT/NUDT15 attributable-fraction study in a multi-ancestry thiopurine cohort

exp_tpmt_nudt15_joint_attributable_fraction

Prospectively genotype a multi-ancestry cohort starting thiopurines for both TPMT and NUDT15 across the full CPIC allele definitions, sequence rather than panel-genotype the discordant cases, and measure 6-TGN and methylated metabolite concentrations alongside serial counts. Report the attributable fraction of grade 3-4 myelosuppression for each gene separately, jointly, and the residual unexplained — stratified by ancestry, since the two genes' allele frequencies vary in opposite directions across populations.

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Pathophysiology

7

TPMT Loss-of-Function Variant

Low-activity TPMT alleles reduce or abolish enzyme activity, chiefly by destabilizing the protein and accelerating its proteasomal degradation rather than by abolishing catalysis outright. Three alleles account for almost all deficiency in European-ancestry populations: TPMT*3A (the commonest, carrying two missense changes in cis), TPMT*3C and TPMT*2. Every deficient subject in a 1,214-donor cohort was homozygous or compound heterozygous for one of these three. Allele frequencies differ substantially by ancestry, so a genotyping panel validated in one population under-detects deficiency in another.

TPMT hgnc:12014

thiopurine S-methyltransferase activity GO:0008119 ⇓ LOSS OF FUNCTION

Downstream

Accelerated Proteasomal Degradation of Variant TPMT The variant proteins are destabilized rather than catalytically dead, so the loss of activity is mediated by loss of protein.

Show evidence (2 references)

PMID:15226673 SUPPORT Human Clinical

"All seven TPMT deficient subjects were homozygous or compound heterozygous carriers for these alleles."

Establishes that the *2/*3A/*3C allele set accounts for the deficient phenotype in this population.

PMID:15226673 SUPPORT Human Clinical

"The frequencies of the mutant alleles were 4.4% (*3A), 0.4% (*3C) and 0.2% (*2)."

Gives the relative frequencies of the three principal low-activity alleles.

Accelerated Proteasomal Degradation of Variant TPMT

The low-activity alleles do not abolish catalysis directly — they destabilize the protein. TPMT*2 and TPMT*3A produce normal mRNA levels and are translated at a normal rate, but their degradation half-life falls from about 18 hours to roughly 15 minutes, and the degradation is proteasome- and ATP-dependent rather than lysosomal. Erythrocyte TPMT activity tracks TPMT protein amount almost perfectly across the activity range. This node is what justifies treating the star alleles as one pathograph rather than as subtypes: they differ in sequence but converge on the same proximal event, less enzyme.

proteasome-mediated degradation of variant TPMT GO:0030163 ↑ INCREASED

Downstream

Impaired Thiopurine S-Methylation Reduced steady-state TPMT protein lowers methylation capacity in proportion.

Show evidence (3 references)

PMID:9177237 SUPPORT In Vitro

"pulse-chase experiments revealed significantly shorter degradation half-lives for TPMT*2 and TPMT*3A ( approximately 0.25 hr) compared with wild-type TPMT*1 (18 hr)"

Quantifies the destabilization that is the proximate consequence of the two principal low-activity alleles.

PMID:9177237 SUPPORT In Vitro

"The degradation of mutant proteins was impaired by ATP depletion and in yeast with mutant proteasomes (pre-1 strain) but unaffected by the lysosomal inhibitor chloroquine."

Localizes the degradation to the proteasome rather than the lysosome.

PMID:9177237 SUPPORT Human Clinical

"erythrocyte TPMT activity was significantly related to the amount of TPMT protein on Western blots of erythrocytes from patients"

Establishes in patient erythrocytes that activity is a readout of protein amount, connecting the in vitro degradation mechanism to the clinical assay.

Impaired Thiopurine S-Methylation

TPMT catalyses S-methylation of thiopurines, one of the two competing inactivating routes (the other being xanthine oxidase) that divert drug away from the activating hypoxanthine-guanine phosphoribosyltransferase pathway. When methylation capacity is lost, the competing routes do not compensate and a larger fraction of each administered dose is committed to activation. This node is the point at which the trait becomes conditional on exposure: no thiopurine, no flux, no downstream pathology.

thiopurine S-methylation GO:0032259 ↓ DECREASED

Downstream

6-Thioguanine Nucleotide Accumulation Drug not consumed by methylation is shunted into the activating pathway, raising 6-TGN concentrations far above those expected for the dose given.

Show evidence (2 references)

PMID:7191632 SUPPORT Human Clinical

"Thiopurine methyltransferase (TPMT) catalyzes thiopurine S-methylation, an important metabolic pathway for drugs such as 6-mercaptopurine."

Establishes S-methylation by TPMT as a principal metabolic route for thiopurine drugs.

PMID:41618934 SUPPORT Human Clinical

"Thiopurine methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) are key enzymes that catabolize thiopurines."

Confirms TPMT as a catabolic (inactivating) enzyme for thiopurines, the loss of which shifts flux toward activation.

6-Thioguanine Nucleotide Accumulation

Thiopurines are prodrugs: therapeutic and toxic effects alike are mediated by the 6-thioguanine nucleotides (6-TGN) formed downstream of HGPRT. In a TPMT-deficient patient given a standard dose, 6-TGN concentrations rise to levels that would ordinarily follow a many-fold higher dose. The nucleotides are incorporated into DNA and RNA, and the resulting thioguanine-substituted DNA triggers cytotoxicity in dividing cells. Because the same metabolite mediates efficacy, this is a therapeutic-index problem rather than an off-target toxicity — dose reduction preserves the intended effect while avoiding the toxic exposure, which is precisely why genotype-guided dosing works rather than requiring a different drug class.

purine nucleotide salvage GO:0032261 ↑ INCREASED

Downstream

Haematopoietic Progenitor Cytotoxicity 6-TGN incorporation into the DNA of rapidly dividing marrow progenitors produces lethal DNA damage.

Show evidence (1 reference)

PMID:41618934 SUPPORT Human Clinical

"Decreased or no-function alleles in TPMT and NUDT15 are associated with reduced or no enzyme activity and predictive of pronounced adverse effects, including severe myelosuppression, that may occur among individuals treated with standard doses of thiopurines."

Links reduced enzyme activity at standard doses to severe myelosuppression, the exposure-driven step this node encodes.

Haematopoietic Progenitor Cytotoxicity

Proliferating haematopoietic stem and progenitor cells are the tissue most sensitive to 6-TGN-mediated DNA damage, because thioguanine incorporation is replication-dependent and marrow turnover is high. This is the disorder-specific substitution into the conserved cytotoxic-myelosuppression pattern: the cytotoxic driver is an endogenously over-activated prodrug rather than an externally dosed cytotoxic agent, but the progenitor-level insult is the same.

hematopoietic stem cell CL:0000037 hematopoietic precursor cell CL:0008001

apoptotic process GO:0006915 ↑ INCREASED

Downstream

Bone Marrow Suppression Progenitor depletion collapses marrow output across lineages.

Show evidence (1 reference)

PMID:41618934 SUPPORT Human Clinical

"predictive of pronounced adverse effects, including severe myelosuppression"

Supports severe myelosuppression as the consequence; the progenitor-level localisation of the insult is inference from the conserved myelosuppression mechanism rather than a direct measurement in this citation.

Bone Marrow Suppression

Loss of the proliferating progenitor compartment produces marrow hypocellularity and a fall in production across the myeloid, erythroid and megakaryocytic lineages.

Downstream

Multilineage Cytopenias Reduced marrow output appears in the peripheral blood after the transit time of each lineage.

Show evidence (1 reference)

PMID:10833476 SUPPORT Human Clinical

"The delay between administration of the drug and occurrence of bone marrow toxicity was less than 1.5 months in the 4 patients with 2 mutant alleles"

Documents bone marrow toxicity in biallelic-variant patients and gives the short latency that distinguishes it from idiosyncratic late myelosuppression.

Multilineage Cytopenias

Leukopenia and thrombocytopenia are the presenting cytopenias; anaemia and frank pancytopenia follow in severe cases. In biallelic-variant patients the onset is rapid — under six weeks from starting the drug — whereas heterozygotes and normal metabolizers who develop myelosuppression do so over a much wider and later window. That timing difference is diagnostically useful and is a genuine finding rather than a restatement of the genotype.

Show evidence (2 references)

PMID:10833476 SUPPORT Human Clinical

"They developed leukopenia or thrombocytopenia during azathioprine or 6-mercaptopurine treatment."

Identifies leukopenia and thrombocytopenia as the observed cytopenias in the thiopurine-exposed cohort.

PMID:10833476 SUPPORT Human Clinical

"ranged from 1 to 18 months in patients with 1 mutant allele and from 0.5 to 87 months in patients with normal genotype"

Contrasts the latency distributions by genotype class, supporting the timing claim in this node.

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Pathograph

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Phenotypes

3

Leukopenia Hematologic HP:0001882

Show evidence (1 reference)

PMID:10833476 SUPPORT Human Clinical

"They developed leukopenia or thrombocytopenia during azathioprine or 6-mercaptopurine treatment."

Cohort inclusion criterion; leukopenia is one of the two defining haematological toxicities.

Thrombocytopenia Hematologic HP:0001873

Show evidence (1 reference)

PMID:10833476 SUPPORT Human Clinical

"They developed leukopenia or thrombocytopenia during azathioprine or 6-mercaptopurine treatment."

Cohort inclusion criterion; thrombocytopenia is the second defining haematological toxicity.

Severe Myelosuppression Hematologic HP:0001876

Show evidence (1 reference)

PMID:41618934 SUPPORT Human Clinical

"predictive of pronounced adverse effects, including severe myelosuppression, that may occur among individuals treated with standard doses of thiopurines"

Supports severe myelosuppression at standard doses; the guideline states the severity but does not itself specify pancytopenia, so the HP term is narrower than the cited sentence.

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Genetic Associations

1

TPMT (Causative)

Gene: TPMT hgnc:12014

Show evidence (2 references)

PMID:15226673 SUPPORT Human Clinical

"Specificity, sensitivity and the positive and negative predictive power of the genotyping test were estimated to be higher than 90%."

Quantifies the predictive performance of TPMT genotyping against the activity phenotype.

PMID:15226673 SUPPORT Human Clinical

"In 17 individuals with intermediate TPMT activity discordant to TPMT genotype, four novel variants were identified leading to amino acid changes (K119T, Q42E, R163H, G71R)."

Documents genotype-phenotype discordance resolved by sequencing, the basis for the caveat that a standard panel is not exhaustive.

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External Assertions

1

OMIM thiopurines, poor metabolism of, 1

OMIM disease record OMIM:610460

OMIM phenotype entry for TPMT-related poor metabolism of thiopurines (THPM1).

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Medical Actions

3

Genotype-Guided Thiopurine Dose Reduction

Action: Pharmacotherapy NCIT:C15986

Agent: azathioprine CHEBI:2948 mercaptopurine CHEBI:50667

Where a thiopurine is still indicated, the starting dose is set from metabolizer status rather than the drug being withheld. This is the recommendation for intermediate metabolizers, and for poor metabolizers it applies only where the thiopurine is not readily replaceable — in malignant disease, where CPIC calls for drastic dose reduction rather than substitution. In nonmalignant disease a poor metabolizer is switched to a different drug class instead; see "Alternative Nonthiopurine Agent for Poor Metabolizers". Dose reduction is what makes TPMT testing actionable in the intermediate range: efficacy and toxicity share the same metabolite, so a lower dose can reach a therapeutic 6-TGN concentration without reaching a toxic one. That logic does not extend to poor metabolizers, in whom 6-TGN stays above tolerated concentrations even at markedly reduced doses.

Mechanism Target:

MODULATES 6-Thioguanine Nucleotide Accumulation — Setting the dose from metabolizer status keeps 6-TGN within the therapeutic window instead of allowing it to reach the toxic concentrations a standard dose would produce. The link is to the metabolite node rather than to the enzyme, because dose reduction does not restore TPMT activity — it lowers the flux the residual activity has to handle. In poor metabolizers this only partially controls the node, which is why substitution is preferred wherever an alternative agent exists.

Show evidence (1 reference)

PMID:41618934 SUPPORT Human Clinical

"we provide recommendations for adjusting starting doses of mercaptopurine, thioguanine, and azathioprine based on TPMT and NUDT15 genotypes"

Genotype-guided starting-dose adjustment is the intervention acting on the metabolite-accumulation node.

Show evidence (4 references)

PMID:41618934 SUPPORT Human Clinical

"we provide recommendations for adjusting starting doses of mercaptopurine, thioguanine, and azathioprine based on TPMT and NUDT15 genotypes, including for individuals with variants in both genes"

Establishes genotype-guided dose adjustment, including the compound TPMT/NUDT15 case, as the recommended management.

PMID:41618934 SUPPORT Human Clinical

"On average, TPMT or NUDT15 IM patients can tolerate ~60% of the standard dose of thiopurine, even though it ranges from 30% to 80% across patients."

Quantifies the intermediate-metabolizer starting dose this treatment describes qualitatively: ~60% of standard on average, over a 30-80% range.

PMID:41618934 SUPPORT Human Clinical

"We acknowledge that our recommended dose range (30–80%) is broad but also believe it is necessary to account for the significant interindividual variability in thiopurine tolerance observed in the IM patient population"

CPIC's own rationale for why the intermediate-metabolizer dose is a broad range rather than a single figure, so the number above is not read as a fixed dose.

+ 1 more reference

Alternative Nonthiopurine Agent for Poor Metabolizers

Action: Pharmacotherapy NCIT:C15986

For TPMT poor metabolizers treated for a nonmalignant condition, CPIC recommends switching to a nonthiopurine agent rather than prescribing a reduced thiopurine dose, because alternative agents are available and because 6-TGN concentrations in poor metabolizers remain well above tolerated levels even at markedly reduced doses. For azathioprine the same recommendation is phrased as considering alternative immunosuppressant therapy. This is the one situation in TPMT deficiency where the correct action is to withhold the drug class outright rather than dose around the enzyme defect; in malignant disease, where thiopurines are not readily replaceable, drastic dose reduction is used instead.

Mechanism Target:

INHIBITS 6-Thioguanine Nucleotide Accumulation — Substituting a drug that is not a TPMT substrate stops the accumulating metabolite from being formed at all, rather than trying to hold it inside a therapeutic window the residual enzyme activity cannot support.

Show evidence (1 reference)

PMID:41618934 SUPPORT Human Clinical

"even at these markedly reduced dosages, erythrocyte TGN concentrations in TPMT poor metabolizers remain well above those tolerated and achieved by the majority of patients"

States why dose reduction does not adequately control the 6-TGN accumulation node in poor metabolizers, which is the rationale for substitution acting on that node instead.

Show evidence (2 references)

PMID:41618934 SUPPORT Human Clinical

"this guideline recommends alternative nonthiopurine agents for TPMT poor metabolizers and/or NUDT15 poor metabolizers rather than administering reduced doses of mercaptopurine"

The CPIC recommendation for mercaptopurine in nonmalignant conditions is substitution, not dose reduction.

PMID:41618934 SUPPORT Human Clinical

"Clinicians should consider alternative immunosuppressant therapy in TPMT and/or NUDT15 poor metabolizers rather than a decreased dose of azathioprine"

The same substitution recommendation stated for azathioprine, the agent used in the autoimmune indications this entry's cohort data come from.

Continued Blood Count Monitoring

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Serial full blood counts remain mandatory in every thiopurine-treated patient regardless of TPMT status. This is not belt-and-braces: TPMT variants explain only a minority of thiopurine myelosuppression, so a normal TPMT result gives no licence to stop monitoring.

Show evidence (1 reference)

PMID:10833476 SUPPORT Human Clinical

"Continued monitoring of blood cell counts remains mandatory in patients treated with azathioprine."

Explicit recommendation that TPMT testing does not replace count monitoring.

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Environmental Factors

1

Thiopurine administration

Administration of azathioprine, mercaptopurine or thioguanine. This is the trigger that converts a latent metabolic difference into a life-threatening illness, and it is the only reason a TPMT-deficient person ever comes to medical attention. It is modelled as an environmental exposure rather than as part of the constitutive chain because the entire toxicity arm is inert without it.

Show evidence (1 reference)

PMID:9177237 SUPPORT Human Clinical

"patients inheriting TPMT deficiency are at high risk of potentially fatal hematopoietic toxicity"

Evidence that the exposure is harmful in this population specifically, which is the claim the exposure entry itself makes, separate from the mechanism link above.

Mechanism Target:

TRIGGERS 6-Thioguanine Nucleotide Accumulation — Supplies the prodrug whose activating route the deficient enzyme can no longer compete with. Without administration there is no flux to shunt and no toxicity, however low the enzyme activity.

Show evidence (1 reference)

PMID:41618934 SUPPORT Human Clinical

"predictive of pronounced adverse effects, including severe myelosuppression, that may occur among individuals treated with standard doses of thiopurines"

States the exposure-dependence this link asserts: the adverse effect occurs among individuals treated with thiopurines.

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Biochemical Markers

1

Erythrocyte TPMT activity

Show evidence (2 references)

PMID:7191632 SUPPORT Human Clinical

"Erythrocyte (RBC) TPMT activity was measured in blood samples from 298 randomly selected subjects."

Defines the red-cell activity assay used to establish the trait.

PMID:15226673 SUPPORT Human Clinical

"TPMT red blood cell activity was measured in all samples and genotype was determined for the TPMT alleles *2 and *3."

Confirms red-cell activity as the reference phenotype against which genotyping is validated.

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Diagnosis

1

Pre-Prescription TPMT Genotyping or Activity Testing

Determining TPMT status before the first thiopurine dose is what makes this latent trait actionable, and it is a diagnostic procedure rather than a therapy: it identifies the metabolizer phenotype, and a separate decision then sets the dose or substitutes the drug. Two assay routes exist — genotyping against the CPIC allele definitions, and direct measurement of erythrocyte TPMT activity. CPIC provides genotype-stratified starting-dose recommendations for mercaptopurine, thioguanine and azathioprine. Because the genotype-phenotype relationship is pharmacokinetic rather than disease-specific, the recommendations are extrapolated across all conditions treated with thiopurines, not only the few in which the dosing studies were done. A TPMT-only result is not a complete answer to thiopurine-toxicity risk. CPIC issues joint TPMT/NUDT15 recommendations because NUDT15 accounts for most severe thiopurine-related myelosuppression in patients of Asian descent, so testing TPMT alone leaves the dominant risk allele unmeasured in a large part of the world's population. NUDT15 deficiency remains a separate entity and is not curated here; see the notes.

genetic testing NCIT:C15709

Markers: Erythrocyte TPMT activity; TPMT genotype (CPIC allele definitions)

Results: Assigns a normal, intermediate or poor metabolizer phenotype, which sets the thiopurine starting dose or triggers substitution with a nonthiopurine agent.

Show evidence (2 references)

PMID:41618934 SUPPORT Human Clinical

"Genetic variants in these genes are present in all world populations; however, their frequency varies by ancestry."

Supports testing across populations while noting the ancestry-dependent allele frequencies that make a single fixed panel inadequate.

PMID:41618934 SUPPORT Human Clinical

"Decreased and no‐function alleles in NUDT15 explain the majority of severe thiopurine‐related myelosuppression in patients of Asian descent and are common in patients with Amerindian genetic ancestry."

Cited support for the scope limit stated in this entry's notes: a TPMT-only test does not measure the dominant thiopurine-toxicity risk allele in patients of Asian or Amerindian ancestry.

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Prevalence

3

Northern European Caucasian blood donors

Point Prevalence 600.0 per 100,000 >1 in 1,000

Deficient (poor metabolizer) phenotype in 0.6% of 1,214 German-Caucasian healthy blood donors; a further 9.9% had intermediate activity. Note this is the prevalence of the metabolic trait, not of clinical disease — the latter depends entirely on thiopurine exposure.

Show evidence (1 reference)

PMID:15226673 SUPPORT Human Clinical

"A clearly defined trimodal frequency distribution of TPMT activity was found with 0.6% deficient, 9.9% intermediate and 89.5% normal to high methylators."

Gives the trimodal population distribution and the deficient-phenotype frequency in a 1,214-subject cohort.

United States, randomly selected subjects

Point Prevalence 300.0 per 100,000 >1 in 1,000

The original 298-subject survey found undetectable erythrocyte TPMT activity in 0.3% and intermediate activity in 11.1%.

Show evidence (1 reference)

PMID:7191632 SUPPORT Human Clinical

"11.1% were included in a subgroup with intermediate activity (7.20 +/- 1.08 U), and 0.3% had undetectable activity"

Reports deficient and intermediate metabolizer frequencies in the founding population survey.

Populations of European descent

Point Prevalence 190.0 per 100,000 >1 in 1,000

CPIC's own 2025 figure for the TPMT poor metabolizer phenotype in European-descent populations, given as the comparator for the NUDT15 poor metabolizer frequency (about 1 in 100 in East Asian descent). Lower than the two single-cohort surveys above, which is expected: this is the CPIC frequency-table estimate pooled across studies rather than one cohort. As with those records, this is the prevalence of the metabolic trait, not of clinical disease.

Show evidence (1 reference)

PMID:41618934 SUPPORT Human Clinical

"which is more common than the TPMT poor metabolizer phenotype in populations of European descent (estimated to be 0.19%"

Gives the CPIC-endorsed European-descent TPMT poor metabolizer frequency. The quote is truncated where the source sentence runs into its frequency table citation, so the closing parenthesis is not part of the quoted span.

{ }

Source YAML

click to show

name: Thiopurine S-methyltransferase Deficiency
creation_date: "2026-08-20T00:00:00Z"
category: Mendelian
description: >-
  Thiopurine S-methyltransferase (TPMT) deficiency is an inherited
  pharmacogenomic disorder of drug metabolism in which reduced or absent activity
  of the cytosolic enzyme TPMT impairs S-methylation of the thiopurine drugs
  azathioprine, mercaptopurine and thioguanine. TPMT activity is trimodally
  distributed in the population and is inherited as an autosomal codominant trait:
  roughly 90% of individuals have normal to high activity, about 10% are
  heterozygous with intermediate activity, and roughly 1 in 300 is deficient. When
  a deficient individual receives a conventional thiopurine dose, drug that would
  normally be inactivated by methylation is instead shunted down the activating
  route to cytotoxic 6-thioguanine nucleotides, which accumulate, are incorporated
  into DNA and RNA, and kill dividing haematopoietic progenitors — producing
  severe, sometimes fatal, myelosuppression within weeks. The defining feature of
  this entry is that the pathograph is conditional on drug exposure: a
  TPMT-deficient person who never receives a thiopurine has no disease. TPMT
  genotyping or activity assay before thiopurine initiation, with genotype-guided dose
  reduction, is one of the earliest and most firmly established applications of
  clinical pharmacogenomics.
parents:
- Genetic Disease
- Metabolic Disease
disease_term:
  preferred_term: thiopurine S-methyltransferase deficiency
  term:
    id: MONDO:0012503
    label: thiopurine S-methyltransferase deficiency
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0012503
      label: thiopurine S-methyltransferase deficiency
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO disease identifier for this thiopurine S-methyltransferase
      deficiency entry.
external_assertions:
- name: OMIM thiopurines, poor metabolism of, 1
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:610460
  description: >-
    OMIM phenotype entry for TPMT-related poor metabolism of thiopurines (THPM1).
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:7191632
      reference_title: "Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This distribution conforms to Hardy-Weinberg predictions for the autosomal codominant inheritance of a pair of alleles for low and high TPMT activity"
      explanation: >-
        The founding family study establishes TPMT activity as a monogenic
        inherited trait, supporting classification under genetics.
inheritance:
- name: Autosomal codominant
  description: >-
    TPMT activity segregates as a monogenic autosomal codominant trait: homozygous
    wild-type individuals have high activity, heterozygotes intermediate activity,
    and homozygous or compound heterozygous carriers of low-activity alleles have
    undetectable activity. Codominance rather than simple recessiveness is the
    clinically important point, because heterozygotes are not unaffected — they
    have a real, intermediate risk of thiopurine toxicity and warrant dose
    reduction. Note on the ontology binding: HPO has no "autosomal codominant
    inheritance" term. HP:0000006 is bound here because the heterozygote has a
    distinct intermediate phenotype rather than being a silent carrier, which is
    the property that matters clinically. It should not be read as a claim that
    the trait is dominant in the usual sense.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:7191632
    reference_title: "Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "subjects homozygous for TPMT(H) would have high enzyme activity, subjects heterozygous for the two alleles would have intermediate activity, and subjects homozygous for TPMT(L) would have undetectable activity"
    explanation: >-
      States the codominant genotype-to-activity mapping across all three
      genotype classes.
  - reference: PMID:7191632
    reference_title: "Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The segregation of RBC TPMT activity among 215 first-degree relatives in 50 randomly selected families"
    explanation: >-
      Family segregation analysis underpinning the monogenic codominant model.
prevalence:
- population: Northern European Caucasian blood donors
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 600.0
  notes: >-
    Deficient (poor metabolizer) phenotype in 0.6% of 1,214 German-Caucasian
    healthy blood donors; a further 9.9% had intermediate activity. Note this is
    the prevalence of the metabolic trait, not of clinical disease — the latter
    depends entirely on thiopurine exposure.
  evidence:
  - reference: PMID:15226673
    reference_title: "Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A clearly defined trimodal frequency distribution of TPMT activity was found with 0.6% deficient, 9.9% intermediate and 89.5% normal to high methylators."
    explanation: >-
      Gives the trimodal population distribution and the deficient-phenotype
      frequency in a 1,214-subject cohort.
- population: United States, randomly selected subjects
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 300.0
  notes: >-
    The original 298-subject survey found undetectable erythrocyte TPMT activity
    in 0.3% and intermediate activity in 11.1%.
  evidence:
  - reference: PMID:7191632
    reference_title: "Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "11.1% were included in a subgroup with intermediate activity (7.20 +/- 1.08 U), and 0.3% had undetectable activity"
    explanation: >-
      Reports deficient and intermediate metabolizer frequencies in the founding
      population survey.
- population: Populations of European descent
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 190.0
  notes: >-
    CPIC's own 2025 figure for the TPMT poor metabolizer phenotype in
    European-descent populations, given as the comparator for the NUDT15 poor
    metabolizer frequency (about 1 in 100 in East Asian descent). Lower than the
    two single-cohort surveys above, which is expected: this is the CPIC
    frequency-table estimate pooled across studies rather than one cohort. As
    with those records, this is the prevalence of the metabolic trait, not of
    clinical disease.
  evidence:
  - reference: PMID:41618934
    reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which is more common than the TPMT poor metabolizer phenotype in populations of European descent (estimated to be 0.19%"
    explanation: >-
      Gives the CPIC-endorsed European-descent TPMT poor metabolizer frequency.
      The quote is truncated where the source sentence runs into its frequency
      table citation, so the closing parenthesis is not part of the quoted span.
pathophysiology:
- name: TPMT Loss-of-Function Variant
  biological_scale: MOLECULAR
  description: >
    Low-activity TPMT alleles reduce or abolish enzyme activity, chiefly by
    destabilizing the protein and accelerating its proteasomal degradation rather
    than by abolishing catalysis outright. Three alleles account for almost all
    deficiency in European-ancestry populations: TPMT*3A (the commonest, carrying
    two missense changes in cis), TPMT*3C and TPMT*2. Every deficient subject in a
    1,214-donor cohort was homozygous or compound heterozygous for one of these
    three. Allele frequencies differ substantially by ancestry, so a genotyping
    panel validated in one population under-detects deficiency in another.
  genes:
  - preferred_term: TPMT
    term:
      id: hgnc:12014
      label: TPMT
  molecular_functions:
  - preferred_term: thiopurine S-methyltransferase activity
    term:
      id: GO:0008119
      label: thiopurine S-methyltransferase activity
    modifier: LOSS_OF_FUNCTION
  downstream:
  - target: Accelerated Proteasomal Degradation of Variant TPMT
    description: >
      The variant proteins are destabilized rather than catalytically dead, so
      the loss of activity is mediated by loss of protein.
  evidence:
  - reference: PMID:15226673
    reference_title: "Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All seven TPMT deficient subjects were homozygous or compound heterozygous carriers for these alleles."
    explanation: >-
      Establishes that the *2/*3A/*3C allele set accounts for the deficient
      phenotype in this population.
  - reference: PMID:15226673
    reference_title: "Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The frequencies of the mutant alleles were 4.4% (*3A), 0.4% (*3C) and 0.2% (*2)."
    explanation: Gives the relative frequencies of the three principal low-activity alleles.
- name: Accelerated Proteasomal Degradation of Variant TPMT
  biological_scale: MOLECULAR
  description: >
    The low-activity alleles do not abolish catalysis directly — they destabilize
    the protein. TPMT*2 and TPMT*3A produce normal mRNA levels and are translated
    at a normal rate, but their degradation half-life falls from about 18 hours
    to roughly 15 minutes, and the degradation is proteasome- and ATP-dependent
    rather than lysosomal. Erythrocyte TPMT activity tracks TPMT protein amount
    almost perfectly across the activity range. This node is what justifies
    treating the star alleles as one pathograph rather than as subtypes: they
    differ in sequence but converge on the same proximal event, less enzyme.
  biological_processes:
  - preferred_term: proteasome-mediated degradation of variant TPMT
    term:
      id: GO:0030163
      label: protein catabolic process
    modifier: INCREASED
  downstream:
  - target: Impaired Thiopurine S-Methylation
    description: >
      Reduced steady-state TPMT protein lowers methylation capacity in proportion.
  evidence:
  - reference: PMID:9177237
    reference_title: "Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic polymorphism of TPMT activity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "pulse-chase experiments revealed significantly shorter degradation half-lives for TPMT*2 and TPMT*3A ( approximately 0.25 hr) compared with wild-type TPMT*1 (18 hr)"
    explanation: >-
      Quantifies the destabilization that is the proximate consequence of the two
      principal low-activity alleles.
  - reference: PMID:9177237
    reference_title: "Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic polymorphism of TPMT activity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The degradation of mutant proteins was impaired by ATP depletion and in yeast with mutant proteasomes (pre-1 strain) but unaffected by the lysosomal inhibitor chloroquine."
    explanation: >-
      Localizes the degradation to the proteasome rather than the lysosome.
  - reference: PMID:9177237
    reference_title: "Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic polymorphism of TPMT activity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "erythrocyte TPMT activity was significantly related to the amount of TPMT protein on Western blots of erythrocytes from patients"
    explanation: >-
      Establishes in patient erythrocytes that activity is a readout of protein
      amount, connecting the in vitro degradation mechanism to the clinical assay.
- name: Impaired Thiopurine S-Methylation
  biological_scale: MOLECULAR
  description: >
    TPMT catalyses S-methylation of thiopurines, one of the two competing
    inactivating routes (the other being xanthine oxidase) that divert drug away
    from the activating hypoxanthine-guanine phosphoribosyltransferase pathway.
    When methylation capacity is lost, the competing routes do not compensate and
    a larger fraction of each administered dose is committed to activation. This
    node is the point at which the trait becomes conditional on exposure: no
    thiopurine, no flux, no downstream pathology.
  biological_processes:
  - preferred_term: thiopurine S-methylation
    term:
      id: GO:0032259
      label: methylation
    modifier: DECREASED
  downstream:
  - target: 6-Thioguanine Nucleotide Accumulation
    description: >
      Drug not consumed by methylation is shunted into the activating pathway,
      raising 6-TGN concentrations far above those expected for the dose given.
  evidence:
  - reference: PMID:7191632
    reference_title: "Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thiopurine methyltransferase (TPMT) catalyzes thiopurine S-methylation, an important metabolic pathway for drugs such as 6-mercaptopurine."
    explanation: >-
      Establishes S-methylation by TPMT as a principal metabolic route for
      thiopurine drugs.
  - reference: PMID:41618934
    reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thiopurine methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) are key enzymes that catabolize thiopurines."
    explanation: >-
      Confirms TPMT as a catabolic (inactivating) enzyme for thiopurines,
      the loss of which shifts flux toward activation.
- name: 6-Thioguanine Nucleotide Accumulation
  biological_scale: MOLECULAR
  description: >
    Thiopurines are prodrugs: therapeutic and toxic effects alike are mediated by
    the 6-thioguanine nucleotides (6-TGN) formed downstream of HGPRT. In a
    TPMT-deficient patient given a standard dose, 6-TGN concentrations rise to levels
    that would ordinarily follow a many-fold higher dose. The nucleotides are
    incorporated into DNA and RNA, and the resulting thioguanine-substituted DNA
    triggers cytotoxicity in dividing cells. Because the same metabolite mediates
    efficacy, this is a therapeutic-index problem rather than an off-target
    toxicity — dose reduction preserves the intended effect while avoiding the
    toxic exposure, which is precisely why genotype-guided dosing works rather
    than requiring a different drug class.
  biological_processes:
  - preferred_term: purine nucleotide salvage
    term:
      id: GO:0032261
      label: purine nucleotide salvage
    modifier: INCREASED
  downstream:
  - target: Haematopoietic Progenitor Cytotoxicity
    description: >
      6-TGN incorporation into the DNA of rapidly dividing marrow progenitors
      produces lethal DNA damage.
  evidence:
  - reference: PMID:41618934
    reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Decreased or no-function alleles in TPMT and NUDT15 are associated with reduced or no enzyme activity and predictive of pronounced adverse effects, including severe myelosuppression, that may occur among individuals treated with standard doses of thiopurines."
    explanation: >-
      Links reduced enzyme activity at standard doses to severe myelosuppression,
      the exposure-driven step this node encodes.
- name: Haematopoietic Progenitor Cytotoxicity
  biological_scale: CELLULAR
  conforms_to: "myelosuppression#Cytotoxic Insult to Proliferating Hematopoietic Progenitors"
  description: >
    Proliferating haematopoietic stem and progenitor cells are the tissue most
    sensitive to 6-TGN-mediated DNA damage, because thioguanine incorporation is
    replication-dependent and marrow turnover is high. This is the
    disorder-specific substitution into the conserved cytotoxic-myelosuppression
    pattern:
    the cytotoxic driver is an endogenously over-activated prodrug rather than an
    externally dosed cytotoxic agent, but the progenitor-level insult is the same.
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  - preferred_term: hematopoietic precursor cell
    term:
      id: CL:0008001
      label: hematopoietic precursor cell
  downstream:
  - target: Bone Marrow Suppression
    description: >
      Progenitor depletion collapses marrow output across lineages.
  evidence:
  - reference: PMID:41618934
    reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "predictive of pronounced adverse effects, including severe myelosuppression"
    explanation: >-
      Supports severe myelosuppression as the consequence; the progenitor-level
      localisation of the insult is inference from the conserved myelosuppression
      mechanism rather than a direct measurement in this citation.
- name: Bone Marrow Suppression
  biological_scale: TISSUE
  conforms_to: "myelosuppression#Bone Marrow Hematopoietic Suppression"
  description: >
    Loss of the proliferating progenitor compartment produces marrow
    hypocellularity and a fall in production across the myeloid, erythroid and
    megakaryocytic lineages.
  downstream:
  - target: Multilineage Cytopenias
    description: >
      Reduced marrow output appears in the peripheral blood after the transit time
      of each lineage.
  evidence:
  - reference: PMID:10833476
    reference_title: "Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The delay between administration of the drug and occurrence of bone marrow toxicity was less than 1.5 months in the 4 patients with 2 mutant alleles"
    explanation: >-
      Documents bone marrow toxicity in biallelic-variant patients and gives the
      short latency that distinguishes it from idiosyncratic late myelosuppression.
- name: Multilineage Cytopenias
  biological_scale: ORGANISM
  conforms_to: "myelosuppression#Multilineage Peripheral Cytopenias"
  description: >
    Leukopenia and thrombocytopenia are the presenting cytopenias; anaemia and
    frank pancytopenia follow in severe cases. In biallelic-variant patients the
    onset is rapid — under six weeks from starting the drug — whereas
    heterozygotes and normal metabolizers who develop myelosuppression do so over
    a much wider and later window. That timing difference is diagnostically useful
    and is a genuine finding rather than a restatement of the genotype.
  downstream: []
  evidence:
  - reference: PMID:10833476
    reference_title: "Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They developed leukopenia or thrombocytopenia during azathioprine or 6-mercaptopurine treatment."
    explanation: >-
      Identifies leukopenia and thrombocytopenia as the observed cytopenias in
      the thiopurine-exposed cohort.
  - reference: PMID:10833476
    reference_title: "Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ranged from 1 to 18 months in patients with 1 mutant allele and from 0.5 to 87 months in patients with normal genotype"
    explanation: >-
      Contrasts the latency distributions by genotype class, supporting the
      timing claim in this node.
phenotypes:
- category: Hematologic
  name: Leukopenia
  description: >
    A fall in total leukocyte count is one of the two usual presenting cytopenias
    of thiopurine toxicity in TPMT deficiency, and the one that carries the
    infection risk. No frequency band is asserted: the cited cohort was selected
    for having developed a cytopenia, so it cannot estimate how often a
    thiopurine-exposed TPMT-deficient patient develops one.
  phenotype_term:
    preferred_term: Leukopenia
    term:
      id: HP:0001882
      label: Decreased total leukocyte count
  evidence:
  - reference: PMID:10833476
    reference_title: "Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They developed leukopenia or thrombocytopenia during azathioprine or 6-mercaptopurine treatment."
    explanation: >-
      Cohort inclusion criterion; leukopenia is one of the two defining
      haematological toxicities.
- category: Hematologic
  name: Thrombocytopenia
  description: >
    Reduced platelet count from megakaryocytic suppression, with attendant
    bleeding risk. No frequency band is asserted, for the same
    selected-cohort reason given under Leukopenia.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:10833476
    reference_title: "Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They developed leukopenia or thrombocytopenia during azathioprine or 6-mercaptopurine treatment."
    explanation: >-
      Cohort inclusion criterion; thrombocytopenia is the second defining
      haematological toxicity.
- category: Hematologic
  name: Severe Myelosuppression
  description: >
    In deficient patients given a conventional thiopurine dose the marrow
    suppression can be profound and life-threatening, extending to pancytopenia.
    It is the outcome the whole pre-prescription testing strategy exists to
    prevent.
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  evidence:
  - reference: PMID:41618934
    reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "predictive of pronounced adverse effects, including severe myelosuppression, that may occur among individuals treated with standard doses of thiopurines"
    explanation: >-
      Supports severe myelosuppression at standard doses; the guideline states
      the severity but does not itself specify pancytopenia, so the HP term is
      narrower than the cited sentence.
biochemical:
- name: Erythrocyte TPMT activity
  notes: >
    Red-cell TPMT activity is the classical phenotypic assay and the measurement
    on which the entire trait was originally defined. Its trimodal distribution is
    what revealed the underlying genetic polymorphism. The assay is confounded by
    recent transfusion, since it measures activity in donor erythrocytes, which is
    the main practical reason genotyping has largely displaced it.
  evidence:
  - reference: PMID:7191632
    reference_title: "Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erythrocyte (RBC) TPMT activity was measured in blood samples from 298 randomly selected subjects."
    explanation: Defines the red-cell activity assay used to establish the trait.
  - reference: PMID:15226673
    reference_title: "Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TPMT red blood cell activity was measured in all samples and genotype was determined for the TPMT alleles *2 and *3."
    explanation: >-
      Confirms red-cell activity as the reference phenotype against which
      genotyping is validated.
genetic:
- name: TPMT
  gene_term:
    preferred_term: TPMT
    term:
      id: hgnc:12014
      label: TPMT
  association: Causative
  notes: >
    TPMT encodes the cytosolic S-adenosyl-L-methionine-dependent enzyme
    thiopurine S-methyltransferase. Three low-activity alleles — TPMT*3A, *3C and
    *2 — account for the great majority of deficiency in European-ancestry
    populations, with respective frequencies of 4.4%, 0.4% and 0.2% in a
    German-Caucasian donor cohort. Genotyping for *2 and *3 predicted the
    activity phenotype with better than 90% sensitivity and specificity in that
    cohort, and 98.4% concordance once four newly identified variants (K119T,
    Q42E, R163H, G71R) were taken into account — the residual discordance being
    the reason a negative panel result does not fully exclude deficiency.
  evidence:
  - reference: PMID:15226673
    reference_title: "Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Specificity, sensitivity and the positive and negative predictive power of the genotyping test were estimated to be higher than 90%."
    explanation: >-
      Quantifies the predictive performance of TPMT genotyping against the
      activity phenotype.
  - reference: PMID:15226673
    reference_title: "Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 17 individuals with intermediate TPMT activity discordant to TPMT genotype, four novel variants were identified leading to amino acid changes (K119T, Q42E, R163H, G71R)."
    explanation: >-
      Documents genotype-phenotype discordance resolved by sequencing, the basis
      for the caveat that a standard panel is not exhaustive.
diagnosis:
- name: Pre-Prescription TPMT Genotyping or Activity Testing
  description: >
    Determining TPMT status before the first thiopurine dose is what makes this
    latent trait actionable, and it is a diagnostic procedure rather than a
    therapy: it identifies the metabolizer phenotype, and a separate decision
    then sets the dose or substitutes the drug. Two assay routes exist —
    genotyping against the CPIC allele definitions, and direct measurement of
    erythrocyte TPMT activity. CPIC provides genotype-stratified starting-dose
    recommendations for mercaptopurine, thioguanine and azathioprine. Because
    the genotype-phenotype relationship is pharmacokinetic rather than
    disease-specific, the recommendations are extrapolated across all conditions
    treated with thiopurines, not only the few in which the dosing studies were
    done.

    A TPMT-only result is not a complete answer to thiopurine-toxicity risk. CPIC
    issues joint TPMT/NUDT15 recommendations because NUDT15 accounts for most
    severe thiopurine-related myelosuppression in patients of Asian descent, so
    testing TPMT alone leaves the dominant risk allele unmeasured in a large part
    of the world's population. NUDT15 deficiency remains a separate entity and is
    not curated here; see the notes.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  markers: Erythrocyte TPMT activity; TPMT genotype (CPIC allele definitions)
  results: >-
    Assigns a normal, intermediate or poor metabolizer phenotype, which sets the
    thiopurine starting dose or triggers substitution with a nonthiopurine agent.
  evidence:
  - reference: PMID:41618934
    reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic variants in these genes are present in all world populations; however, their frequency varies by ancestry."
    explanation: >-
      Supports testing across populations while noting the ancestry-dependent
      allele frequencies that make a single fixed panel inadequate.
  - reference: PMID:41618934
    reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Decreased and no‐function alleles in NUDT15 explain the majority of severe thiopurine‐related myelosuppression in patients of Asian descent and are common in patients with Amerindian genetic ancestry."
    explanation: >-
      Cited support for the scope limit stated in this entry's notes: a TPMT-only
      test does not measure the dominant thiopurine-toxicity risk allele in
      patients of Asian or Amerindian ancestry.
treatments:
- name: Genotype-Guided Thiopurine Dose Reduction
  description: >
    Where a thiopurine is still indicated, the starting dose is set from
    metabolizer status rather than the drug being withheld. This is the
    recommendation for intermediate metabolizers, and for poor metabolizers it
    applies only where the thiopurine is not readily replaceable — in malignant
    disease, where CPIC calls for drastic dose reduction rather than
    substitution. In nonmalignant disease a poor metabolizer is switched to a
    different drug class instead; see "Alternative Nonthiopurine Agent for Poor
    Metabolizers". Dose reduction is what makes TPMT testing actionable in the
    intermediate range: efficacy and toxicity share the same metabolite, so a
    lower dose can reach a therapeutic 6-TGN concentration without reaching a
    toxic one. That logic does not extend to poor metabolizers, in whom 6-TGN
    stays above tolerated concentrations even at markedly reduced doses.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: azathioprine
      term:
        id: CHEBI:2948
        label: azathioprine
    - preferred_term: mercaptopurine
      term:
        id: CHEBI:50667
        label: mercaptopurine
  target_mechanisms:
  - target: 6-Thioguanine Nucleotide Accumulation
    treatment_effect: MODULATES
    description: >
      Setting the dose from metabolizer status keeps 6-TGN within the
      therapeutic window instead of allowing it to reach the toxic
      concentrations a standard dose would produce. The link is to the
      metabolite node rather than to the enzyme, because dose reduction does not
      restore TPMT activity — it lowers the flux the residual activity has to
      handle. In poor metabolizers this only partially controls the node, which
      is why substitution is preferred wherever an alternative agent exists.
    evidence:
    - reference: PMID:41618934
      reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we provide recommendations for adjusting starting doses of mercaptopurine, thioguanine, and azathioprine based on TPMT and NUDT15 genotypes"
      explanation: >-
        Genotype-guided starting-dose adjustment is the intervention acting on
        the metabolite-accumulation node.
  evidence:
  - reference: PMID:41618934
    reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we provide recommendations for adjusting starting doses of mercaptopurine, thioguanine, and azathioprine based on TPMT and NUDT15 genotypes, including for individuals with variants in both genes"
    explanation: >-
      Establishes genotype-guided dose adjustment, including the compound
      TPMT/NUDT15 case, as the recommended management.
  - reference: PMID:41618934
    reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On average, TPMT or NUDT15 IM patients can tolerate ~60% of the standard dose of thiopurine, even though it ranges from 30% to 80% across patients."
    explanation: >-
      Quantifies the intermediate-metabolizer starting dose this treatment
      describes qualitatively: ~60% of standard on average, over a 30-80%
      range.
  - reference: PMID:41618934
    reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We acknowledge that our recommended dose range (30–80%) is broad but also believe it is necessary to account for the significant interindividual variability in thiopurine tolerance observed in the IM patient population"
    explanation: >-
      CPIC's own rationale for why the intermediate-metabolizer dose is a broad
      range rather than a single figure, so the number above is not read as a
      fixed dose.
  - reference: PMID:41618934
    reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For malignancy: initiate therapy with drastically reduced starting doses. Reduce starting dose by 10‐fold and reduce frequency to thrice weekly instead of daily"
    explanation: >-
      Quantifies the poor-metabolizer malignant-disease arm this treatment
      describes as "drastic dose reduction": a 10-fold starting-dose cut plus a
      switch from daily to thrice-weekly dosing.
- name: Alternative Nonthiopurine Agent for Poor Metabolizers
  description: >
    For TPMT poor metabolizers treated for a nonmalignant condition, CPIC
    recommends switching to a nonthiopurine agent rather than prescribing a
    reduced thiopurine dose, because alternative agents are available and
    because 6-TGN concentrations in poor metabolizers remain well above tolerated
    levels even at markedly reduced doses. For azathioprine the same
    recommendation is phrased as considering alternative immunosuppressant
    therapy. This is the one situation in TPMT deficiency where the correct
    action is to withhold the drug class outright rather than dose around the
    enzyme defect; in malignant disease, where thiopurines are not readily
    replaceable, drastic dose reduction is used instead.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: 6-Thioguanine Nucleotide Accumulation
    treatment_effect: INHIBITS
    description: >
      Substituting a drug that is not a TPMT substrate stops the accumulating
      metabolite from being formed at all, rather than trying to hold it inside a
      therapeutic window the residual enzyme activity cannot support.
    evidence:
    - reference: PMID:41618934
      reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "even at these markedly reduced dosages, erythrocyte TGN concentrations in TPMT poor metabolizers remain well above those tolerated and achieved by the majority of patients"
      explanation: >-
        States why dose reduction does not adequately control the 6-TGN
        accumulation node in poor metabolizers, which is the rationale for
        substitution acting on that node instead.
  evidence:
  - reference: PMID:41618934
    reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this guideline recommends alternative nonthiopurine agents for TPMT poor metabolizers and/or NUDT15 poor metabolizers rather than administering reduced doses of mercaptopurine"
    explanation: >-
      The CPIC recommendation for mercaptopurine in nonmalignant conditions is
      substitution, not dose reduction.
  - reference: PMID:41618934
    reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinicians should consider alternative immunosuppressant therapy in TPMT and/or NUDT15 poor metabolizers rather than a decreased dose of azathioprine"
    explanation: >-
      The same substitution recommendation stated for azathioprine, the agent
      used in the autoimmune indications this entry's cohort data come from.
- name: Continued Blood Count Monitoring
  description: >
    Serial full blood counts remain mandatory in every thiopurine-treated patient
    regardless of TPMT status. This is not belt-and-braces: TPMT variants explain
    only a minority of thiopurine myelosuppression, so a normal TPMT result gives
    no licence to stop monitoring.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:10833476
    reference_title: "Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Continued monitoring of blood cell counts remains mandatory in patients treated with azathioprine."
    explanation: >-
      Explicit recommendation that TPMT testing does not replace count
      monitoring.
environmental:
- name: Thiopurine administration
  description: >-
    Administration of azathioprine, mercaptopurine or thioguanine. This is the
    trigger that converts a latent metabolic difference into a life-threatening
    illness, and it is the only reason a TPMT-deficient person ever comes to
    medical attention. It is modelled as an environmental exposure rather than as
    part of the constitutive chain because the entire toxicity arm is inert
    without it.
  influences_mechanisms:
  - target: 6-Thioguanine Nucleotide Accumulation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Supplies the prodrug whose activating route the deficient enzyme can no
      longer compete with. Without administration there is no flux to shunt and
      no toxicity, however low the enzyme activity.
    evidence:
    - reference: PMID:41618934
      reference_title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "predictive of pronounced adverse effects, including severe myelosuppression, that may occur among individuals treated with standard doses of thiopurines"
      explanation: >-
        States the exposure-dependence this link asserts: the adverse effect
        occurs among individuals treated with thiopurines.
  evidence:
  - reference: PMID:9177237
    reference_title: "Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic polymorphism of TPMT activity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients inheriting TPMT deficiency are at high risk of potentially fatal hematopoietic toxicity"
    explanation: >-
      Evidence that the exposure is harmful in this population specifically,
      which is the claim the exposure entry itself makes, separate from the
      mechanism link above.
discussions:
- discussion_id: gap_tpmt_attributable_fraction_myelosuppression
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What fraction of thiopurine-induced myelosuppression is actually attributable
    to TPMT deficiency, and what accounts for the remainder?
  attaches_to:
  - pathophysiology#Bone Marrow Suppression
  - pathophysiology#Multilineage Cytopenias
  rationale: >
    In a cohort of 41 Crohn disease patients who developed leukopenia or
    thrombocytopenia on azathioprine or mercaptopurine, only 27% carried any TPMT
    mutant allele and just 10% were biallelic; 73% had no known TPMT mutation at
    all. The authors' own conclusion is that myelosuppression is more often caused
    by other factors. NUDT15 deficiency, since characterized and now co-recommended
    with TPMT by CPIC, explains part of the remainder — particularly in East Asian
    and Hispanic populations where NUDT15 variants are considerably more common
    than TPMT variants — but the residual is not fully accounted for. This matters
    for how the entry is used: TPMT deficiency is a well-understood mechanism for a
    minority of a common toxicity, not the explanation for that toxicity.
  proposed_experiments:
  - experiment_id: exp_tpmt_nudt15_joint_attributable_fraction
    name: Joint TPMT/NUDT15 attributable-fraction study in a multi-ancestry thiopurine cohort
    description: >
      Prospectively genotype a multi-ancestry cohort starting thiopurines for both
      TPMT and NUDT15 across the full CPIC allele definitions, sequence rather than
      panel-genotype the discordant cases, and measure 6-TGN and methylated
      metabolite concentrations alongside serial counts. Report the attributable
      fraction of grade 3-4 myelosuppression for each gene separately, jointly, and
      the residual unexplained — stratified by ancestry, since the two genes'
      allele frequencies vary in opposite directions across populations.
notes: >
  Scope and framing caveats a curator should preserve:

  This is a latent trait, not a disease with a spontaneous course. TPMT deficiency
  produces no phenotype whatsoever in the absence of thiopurine exposure. The
  pathograph below the "Impaired Thiopurine S-Methylation" node is therefore
  intervention-conditioned in the same sense as the antisense-oligonucleotide
  module's therapy chain: it describes what happens when a drug is given, not a
  natural history. Do not curate the cytopenia nodes as though they were
  spontaneous features of the genotype.

  NUDT15 deficiency is a separate entity and is deliberately not folded in here.
  NUDT15 variants cause a clinically indistinguishable thiopurine-toxicity
  phenotype through a different enzyme acting at a different step, and CPIC now
  issues joint TPMT/NUDT15 recommendations. Their ancestry distributions differ
  sharply — NUDT15 variants predominate in East Asian and Hispanic populations,
  TPMT variants in European-ancestry ones — so merging them would produce exactly
  the blended entity the project avoids and would obscure the reason a
  TPMT-only test is insufficient in much of the world. If a grouping over
  thiopurine-toxicity pharmacogenes is wanted, kb/groupings/ is the place for it.

  Codominance and the heterozygote. The heterozygote is not a silent carrier: ~10%
  of the population has intermediate activity and a genuinely elevated toxicity
  risk warranting dose reduction. The HP inheritance binding is discussed in the
  inheritance block's notes; the substantive point is that "recessive" framing
  would clinically mislead.

  Testing does not replace monitoring. The 27%/73% split in PMID:10833476 is the
  key number to carry forward and is recorded as an open KNOWLEDGE_GAP above.
references:
- reference: PMID:7191632
  title: "Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity."
- reference: PMID:15226673
  title: "Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants."
- reference: PMID:10833476
  title: "Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy."
- reference: PMID:41618934
  title: "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update."

📚

References & Deep Research

References

4

PMID:7191632

Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity.

No top-level findings curated for this source.

PMID:15226673

Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants.

No top-level findings curated for this source.

PMID:10833476

Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy.

No top-level findings curated for this source.

PMID:41618934

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update.

No top-level findings curated for this source.

Thiopurine S-methyltransferase Deficiency

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