Rotor Syndrome

Mendelian MONDO:0009379 Pathograph 6 Show in embeddings browser Liver Disease Inherited Metabolic Disorder

A benign, non-progressive autosomal recessive disorder of bilirubin transport caused by the simultaneous loss of both sinusoidal organic anion uptake transporters OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3). Because the two transporters are functionally redundant, Rotor syndrome requires biallelic loss of both genes - most often through a single deletion spanning the adjacent SLCO1B1 and SLCO1B3 loci - which distinguishes it genetically from every other hereditary hyperbilirubinaemia. Loss of hepatic reuptake of the bilirubin conjugates that normally re-enter the hepatocyte from sinusoidal blood produces chronic, predominantly conjugated hyperbilirubinaemia with normal liver tests, no haemolysis, and, unlike Dubin-Johnson syndrome, a normally coloured liver. It requires no treatment. The clinical importance is twofold: making the diagnosis prevents an escalating and invasive workup for more serious liver disease, and OATP1B1/1B3 are major hepatic uptake transporters for many drugs, so their complete absence is expected to alter drug disposition.

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2
Inheritance
2
Pathophys.
2
Phenotypes
1
Gaps
6
Pathograph
2
Genes
1
Medical Actions
1
References
👪

Inheritance

2
Autosomal recessive inheritance HP:0000007
Rotor syndrome is transmitted in an autosomal recessive manner. Because two functionally redundant transporters must both be lost, the practical requirement is biallelic inactivation of SLCO1B1 and SLCO1B3 together - frequently satisfied by a homozygous deletion spanning both adjacent loci.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:36157610 SUPPORT Other
"Rotor and Dubin-Johnson syndromes are rare autosomal recessive liver diseases characterized by chronic conjugated hyperbilirubinemia"
States the mode of inheritance. Evidence source is OTHER because this sentence states the general property of the two disorders rather than a pedigree finding in the reported patient.
Digenic inheritance HP:0010984
Rotor syndrome is formally DIGENIC: pathogenic variants are required in both SLCO1B1 and SLCO1B3, because the OATP1B1 and OATP1B3 transporters they encode are functionally redundant and loss of either alone is silent. It resembles monogenic autosomal recessive inheritance in practice only because the two genes are adjacent on chromosome 12 and so are unlikely to segregate independently - a homozygous deletion commonly removes both. This makes Rotor syndrome one of the clearest examples of digenic inheritance among the hereditary hyperbilirubinaemias, and distinguishes it from Dubin-Johnson syndrome, whose conjugated hyperbilirubinaemia arises from a single gene.
Digenic inheritance
Show evidence (2 references)
PMID:23236639 SUPPORT Human Clinical
"Rotor syndrome is inherited in an autosomal recessive digenic manner that clinically resembles monogenic autosomal recessive inheritance."
GeneReviews states the digenic mode explicitly and explains why it presents as though monogenic. Evidence source is HUMAN_CLINICAL because GeneReviews chapters synthesise clinical and molecular findings in affected individuals.
PMID:23236639 SUPPORT Human Clinical
"(Although Rotor syndrome is a digenic disorder, pathogenic variants in SLCO1B1 and SLCO1B3 are unlikely to segregate independently."
Gives the reason the digenic disorder behaves as a monogenic recessive one in pedigrees - the two loci are adjacent and co-segregate. Evidence source is HUMAN_CLINICAL because this is GeneReviews genetic counselling guidance derived from affected families.
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Discussions and Knowledge Gaps

1
How reliably does urinary coproporphyrin isomer analysis distinguish Rotor syndrome from Dubin-Johnson syndrome in individual patients?
KNOWLEDGE GAP rotor_coproporphyrin_discriminator_unreliable
Attached to
pathophysiology#Combined OATP1B1 and OATP1B3 Deficiency
The textbook rule - increased total coproporphyrin with isomer I below 75-80% in Rotor syndrome, normal total with isomer I above 80% in Dubin-Johnson syndrome - has been contradicted by a genetically confirmed Rotor patient whose profile matched the Dubin-Johnson pattern exactly. The reported explanation invokes a coincidental heterozygous ABCC2 variant modulating porphyrin excretion, which if generally true would mean the discriminator is sensitive to common variation in a third gene. No study quantifies the test's performance against molecular diagnosis. Curators should not treat the coproporphyrin pattern as diagnostic.
Proposed experiments
Coproporphyrin pattern versus molecular diagnosis in a genotyped cohort
coproporphyrin_vs_molecular_diagnosis_cohort
Measuring urinary coproporphyrin total and isomer fractions in a cohort of patients with molecularly confirmed Rotor or Dubin-Johnson syndrome, and reporting sensitivity and specificity against genotype, would establish whether the classical discriminator has any residual diagnostic value.
⚙

Pathophysiology

2
Combined OATP1B1 and OATP1B3 Deficiency
Complete loss of both sinusoidal organic anion transporting polypeptides OATP1B1 (encoded by SLCO1B1) and OATP1B3 (encoded by SLCO1B3) abolishes hepatocellular reuptake of organic anions, including the bilirubin conjugates that normally re-enter the hepatocyte from sinusoidal blood after MRP3-mediated basolateral efflux. Both transporters must be lost: they are functionally redundant, so a lesion in either alone is insufficient. The genes are adjacent on chromosome 12, and a single homozygous deletion spanning both loci has been reported as a cause.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
SLCO1B1 hgnc:10959 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLCO1B1 (hgnc:10959). hgnc:10959 is a gene from the HUGO Gene Nomenclature Committee. SLCO1B3 hgnc:10961 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLCO1B3 (hgnc:10961). hgnc:10961 is a gene from the HUGO Gene Nomenclature Committee.
bilirubin transport GO:0015723 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased bilirubin transport (GO:0015723). GO:0015723 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Failure of Hepatic Bilirubin Conjugate Reuptake and Storage Without OATP1B1 and OATP1B3 the hepatocyte cannot recapture bilirubin conjugates from sinusoidal blood.
Show evidence (3 references)
PMID:25315738 SUPPORT Other
"In patients with Rotor syndrome, bilirubin (re)uptake is impaired due to the deficiency of two basolateral/sinusoidal hepatocellular membrane proteins, organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3."
States the two deficient transporters, their membrane localisation, and the transport step lost - the defining claim of this node. Evidence source is OTHER because this is a review.
PMID:35860851 SUPPORT Other
"Rotor syndrome (caused by the simultaneous presence of mutations in SLCO1B1 and SLCO1B3 genes)"
Establishes that simultaneous lesions in both genes are required, the genetic feature that separates Rotor syndrome from the single-gene hereditary hyperbilirubinaemias. Evidence source is OTHER because this is a narrative review.
PMID:36157610 SUPPORT Human Clinical
"Additional extended molecular analysis of genes implicated in bilirubin metabolism found a homozygous deletion of a region encompassing exons 4-16 of SLCO1B3 gene (encoding OATP1B3) and all SLCO1B1 exons (encoding OATP1B1), thereby establishing Rotor syndrome diagnosis."
A genetically confirmed human example showing that a single deletion spanning both adjacent loci produces the required double deficiency. Evidence source is HUMAN_CLINICAL because this is a patient case report with molecular analysis.
Failure of Hepatic Bilirubin Conjugate Reuptake and Storage
Even under physiological conditions a fraction of newly formed bilirubin conjugates is secreted across the sinusoidal membrane into blood by MRP3 and then recaptured by OATP1B1 and OATP1B3 for re-excretion into bile. Rotor syndrome breaks that recapture limb, so conjugates that leave the hepatocyte are not retrieved and accumulate in plasma. Conjugation and canalicular export are intact, which is why the liver is not pigmented and why the disorder is mechanistically distinct from Dubin-Johnson syndrome despite an almost identical biochemical presentation.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
bilirubin transport GO:0015723 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated bilirubin transport (GO:0015723). GO:0015723 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Show evidence (3 references)
PMID:36157610 SUPPORT Other
"Rotor and Dubin-Johnson syndromes are rare autosomal recessive liver diseases characterized by chronic conjugated hyperbilirubinemia, caused by the absence of the hepatic function OATP1B1/B3 (leading to impaired hepatic bilirubin reuptake and storage) and MRP2 transporters (leading to impaired..."
States precisely the mechanism of this node - impaired hepatic reuptake and storage - and contrasts it with the excretion defect of Dubin-Johnson syndrome. Evidence source is OTHER because this sentence states the general mechanism of the two disorders rather than the reported patient's own findings.
PMID:24459177 SUPPORT Other
"Human MRP3 is the only basolateral efflux pump shown to transport bilirubin glucuronides."
Identifies the efflux limb whose conjugates the OATP transporters normally recapture, completing the sinusoidal cycle this node interrupts. Evidence source is OTHER because this is a review of hepatobiliary transport.
PMID:25315738 SUPPORT Other
"Both disorders are benign and not progressive and are characterised by elevated serum levels of mainly conjugated bilirubin."
Records the biochemical outcome of this node and its benign, non-progressive course - the guardrail against curating Rotor syndrome as a progressive liver disease. Evidence source is OTHER because this is a review.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Rotor Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

2
Digestive 1
Intermittent Jaundice HP:0000952 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Jaundice (HP:0000952), qualified as temporality recurrent. HP:0000952 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:36157610 SUPPORT Human Clinical
"A 42-year-old man with no relevant past medical history presented with intermittent mild icterus and no signs of chronic liver disease."
Documents the presenting phenotype in a genetically confirmed patient, including the absence of chronic liver disease signs. Evidence source is HUMAN_CLINICAL because this is a case report.
Other 1
Conjugated Hyperbilirubinaemia Conjugated hyperbilirubinemia HP:0002908 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Conjugated hyperbilirubinemia (HP:0002908), qualified as temporality chronic. HP:0002908 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:36157610 SUPPORT Human Clinical
"Laboratory tests were notable for hyperbilirubinemia (total 7.97 mg/dL, direct 5.37 mg/dL), bilirubinuria, no signs of hemolysis, normal liver tests and lipids profile."
Quantifies the biochemical phenotype and documents the normal liver tests and absent haemolysis that define it as an isolated transport defect. Evidence source is HUMAN_CLINICAL because this is a patient case report.
🧬

Genetic Associations

2
SLCO1B1
Gene: SLCO1B1 hgnc:10959 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLCO1B1 (hgnc:10959). hgnc:10959 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:35860851 SUPPORT Other
"Rotor syndrome (caused by the simultaneous presence of mutations in SLCO1B1 and SLCO1B3 genes)"
Establishes SLCO1B1 as one of the two genes that must both be affected. Evidence source is OTHER because this is a narrative review.
SLCO1B3
Gene: SLCO1B3 hgnc:10961 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLCO1B3 (hgnc:10961). hgnc:10961 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:36157610 SUPPORT Human Clinical
"Additional extended molecular analysis of genes implicated in bilirubin metabolism found a homozygous deletion of a region encompassing exons 4-16 of SLCO1B3 gene (encoding OATP1B3) and all SLCO1B1 exons (encoding OATP1B1), thereby establishing Rotor syndrome diagnosis."
Documents a specific causal lesion affecting both genes in a confirmed patient. Evidence source is HUMAN_CLINICAL because this is a case report with molecular analysis.
💊

Medical Actions

1
Diagnosis and Reassurance
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
No treatment is required. As with Dubin-Johnson syndrome, the benefit of establishing the diagnosis is to reassure the patient and stop an escalating, invasive, and costly workup for more serious liver disease. The unresolved question is drug handling: OATP1B1 and OATP1B3 are major hepatic uptake transporters, and their complete absence is expected to change the disposition of their substrate drugs, though no specific prescribing guidance follows from the current evidence.
Show evidence (2 references)
PMID:36157610 SUPPORT Human Clinical
"With this case, we aim to highlight the necessity of establishing a diagnosis, reassuring the patient, and avoiding unnecessary invasive and costly diagnostic procedures."
States the clinical purpose of diagnosis in a disorder needing no treatment. Evidence source is HUMAN_CLINICAL because this is the conclusion of a patient case report.
PMID:35860851 SUPPORT Other
"Although classically viewed as benign conditions requiring no treatment, they lately gained an increased interest since recent studies suggested that mutations in the responsible genes leading to hyperbilirubinemia, as well as minor genetic variants, may result in an increased susceptibility to..."
Marked PARTIAL because it qualifies the no-treatment position with a suggested, unestablished drug-toxicity susceptibility. Evidence source is OTHER because this is a narrative review.
🔬

Biochemical Markers

2
Conjugated Bilirubin (INCREASED)
Context: Predominantly conjugated (direct) hyperbilirubinaemia with bilirubinuria. One genetically confirmed patient presented with total bilirubin 7.97 mg/dL and direct 5.37 mg/dL alongside entirely normal AST, ALT, GGT, alkaline phosphatase, albumin, and prothrombin time.
Pathograph Readouts
Readout Of Failure of Hepatic Bilirubin Conjugate Reuptake and Storage Positive Diagnostic
A raised direct bilirubin fraction with wholly normal liver biochemistry and no haemolysis reports an isolated defect of bilirubin conjugate handling rather than hepatocellular injury or biliary obstruction.
Show evidence (1 reference)
PMID:36157610 SUPPORT Human Clinical
"Laboratory tests were notable for hyperbilirubinemia (total 7.97 mg/dL, direct 5.37 mg/dL), bilirubinuria, no signs of hemolysis, normal liver tests and lipids profile."
Provides the measured readout in a confirmed case. Evidence source is HUMAN_CLINICAL because this is a patient case report.
Urinary Coproporphyrin (INCREASED)
Context: Classically, total urinary coproporphyrin excretion is increased two- to five-fold in Rotor syndrome with isomer I usually below 75-80% of the total - the pattern that historically distinguished it from Dubin-Johnson syndrome, where total excretion is normal but isomer I exceeds 80%. This discriminator is not reliable in individual patients: a genetically confirmed Rotor case has been reported with normal total coproporphyrin and 86% isomer I, a profile that reads as Dubin-Johnson syndrome. Molecular testing, not coproporphyrin analysis, establishes the diagnosis.
Pathograph Readouts
Readout Of Combined OATP1B1 and OATP1B3 Deficiency Positive Diagnostic
Altered coproporphyrin handling reports loss of OATP-dependent organic anion uptake, but the isomer pattern overlaps with Dubin-Johnson syndrome often enough that it cannot stand alone.
Show evidence (2 references)
PMID:36157610 SUPPORT Other
"Contrary to DJS, in RS, total coproporphyrin excretion in urine is increased and isomer I is usually <75-80%, in line with the interaction of several porphyrins with OATP1B1"
States the classical Rotor coproporphyrin signature and links it mechanistically to OATP1B1. Evidence source is OTHER because this sentence reports the general rule from the literature rather than the case patient's own measurement.
PMID:36157610 SUPPORT Human Clinical
"Total urinary coproporphyrin was normal with predominance of isomer I (86% of total urinary coproporphyrin output)."
Marked PARTIAL because it refutes the reliability of this readout in individual patients: these values are the Dubin-Johnson pattern, yet the patient had genetically confirmed Rotor syndrome. Evidence source is HUMAN_CLINICAL because this is a measurement in a reported patient.
{ }

Source YAML

click to show 
name: Rotor Syndrome
creation_date: "2026-08-22T00:00:00Z"
category: Mendelian
description: >-
  A benign, non-progressive autosomal recessive disorder of bilirubin transport
  caused by the simultaneous loss of both sinusoidal organic anion uptake
  transporters OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3). Because the two
  transporters are functionally redundant, Rotor syndrome requires biallelic
  loss of both genes - most often through a single deletion spanning the
  adjacent SLCO1B1 and SLCO1B3 loci - which distinguishes it genetically from
  every other hereditary hyperbilirubinaemia. Loss of hepatic reuptake of the
  bilirubin conjugates that normally re-enter the hepatocyte from sinusoidal
  blood produces chronic, predominantly conjugated hyperbilirubinaemia with
  normal liver tests, no haemolysis, and, unlike Dubin-Johnson syndrome, a
  normally coloured liver. It requires no treatment. The clinical importance is
  twofold: making the diagnosis prevents an escalating and invasive workup for
  more serious liver disease, and OATP1B1/1B3 are major hepatic uptake
  transporters for many drugs, so their complete absence is expected to alter
  drug disposition.
disease_term:
  preferred_term: Rotor syndrome
  term:
    id: MONDO:0009379
    label: Rotor syndrome
parents:
- Liver Disease
- Inherited Metabolic Disorder
pathophysiology:
- name: Combined OATP1B1 and OATP1B3 Deficiency
  description: >-
    Complete loss of both sinusoidal organic anion transporting polypeptides
    OATP1B1 (encoded by SLCO1B1) and OATP1B3 (encoded by SLCO1B3) abolishes
    hepatocellular reuptake of organic anions, including the bilirubin
    conjugates that normally re-enter the hepatocyte from sinusoidal blood after
    MRP3-mediated basolateral efflux. Both transporters must be lost: they are
    functionally redundant, so a lesion in either alone is insufficient. The
    genes are adjacent on chromosome 12, and a single homozygous deletion
    spanning both loci has been reported as a cause.
  role: trigger
  biological_scale: MOLECULAR
  conforms_to: "bilirubin_conjugation_transport#Conjugated Bilirubin Transport Failure"
  genes:
  - preferred_term: SLCO1B1
    term:
      id: hgnc:10959
      label: SLCO1B1
  - preferred_term: SLCO1B3
    term:
      id: hgnc:10961
      label: SLCO1B3
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: bilirubin transport
    term:
      id: GO:0015723
      label: bilirubin transport
    modifier: DECREASED
  evidence:
  - reference: PMID:25315738
    reference_title: "Gene replacement therapy for genetic hepatocellular jaundice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In patients with Rotor syndrome, bilirubin (re)uptake is impaired due to
      the deficiency of two basolateral/sinusoidal hepatocellular membrane
      proteins, organic anion-transporting polypeptide 1B1 (OATP1B1) and
      OATP1B3.
    explanation: >-
      States the two deficient transporters, their membrane localisation, and
      the transport step lost - the defining claim of this node. Evidence source
      is OTHER because this is a review.
  - reference: PMID:35860851
    reference_title: "Benign inheritable disorders of bilirubin metabolism manifested by conjugated hyperbilirubinemia-A narrative review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rotor syndrome (caused by the simultaneous presence of mutations in
      SLCO1B1 and SLCO1B3 genes)
    explanation: >-
      Establishes that simultaneous lesions in both genes are required, the
      genetic feature that separates Rotor syndrome from the single-gene
      hereditary hyperbilirubinaemias. Evidence source is OTHER because this is
      a narrative review.
  - reference: PMID:36157610
    reference_title: "Rotor Syndrome Presenting as Dubin-Johnson Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional extended molecular analysis of genes implicated in bilirubin
      metabolism found a homozygous deletion of a region encompassing exons 4-16
      of SLCO1B3 gene (encoding OATP1B3) and all SLCO1B1 exons (encoding
      OATP1B1), thereby establishing Rotor syndrome diagnosis.
    explanation: >-
      A genetically confirmed human example showing that a single deletion
      spanning both adjacent loci produces the required double deficiency.
      Evidence source is HUMAN_CLINICAL because this is a patient case report
      with molecular analysis.
  downstream:
  - target: Failure of Hepatic Bilirubin Conjugate Reuptake and Storage
    causal_link_type: DIRECT
    description: >-
      Without OATP1B1 and OATP1B3 the hepatocyte cannot recapture bilirubin
      conjugates from sinusoidal blood.

- name: Failure of Hepatic Bilirubin Conjugate Reuptake and Storage
  description: >-
    Even under physiological conditions a fraction of newly formed bilirubin
    conjugates is secreted across the sinusoidal membrane into blood by MRP3 and
    then recaptured by OATP1B1 and OATP1B3 for re-excretion into bile. Rotor
    syndrome breaks that recapture limb, so conjugates that leave the hepatocyte
    are not retrieved and accumulate in plasma. Conjugation and canalicular
    export are intact, which is why the liver is not pigmented and why the
    disorder is mechanistically distinct from Dubin-Johnson syndrome despite an
    almost identical biochemical presentation.
  role: central_effector
  biological_scale: CELLULAR
  conforms_to: "bilirubin_conjugation_transport#Hyperbilirubinaemia"
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: bilirubin transport
    term:
      id: GO:0015723
      label: bilirubin transport
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:36157610
    reference_title: "Rotor Syndrome Presenting as Dubin-Johnson Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rotor and Dubin-Johnson syndromes are rare autosomal recessive liver
      diseases characterized by chronic conjugated hyperbilirubinemia, caused by
      the absence of the hepatic function OATP1B1/B3 (leading to impaired
      hepatic bilirubin reuptake and storage) and MRP2 transporters (leading to
      impaired hepatic bilirubin excretion), respectively.
    explanation: >-
      States precisely the mechanism of this node - impaired hepatic reuptake
      and storage - and contrasts it with the excretion defect of Dubin-Johnson
      syndrome. Evidence source is OTHER because this sentence states the
      general mechanism of the two disorders rather than the reported patient's
      own findings.
  - reference: PMID:24459177
    reference_title: "The roles of MRP2, MRP3, OATP1B1, and OATP1B3 in conjugated hyperbilirubinemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Human MRP3 is the only basolateral efflux pump shown to transport
      bilirubin glucuronides.
    explanation: >-
      Identifies the efflux limb whose conjugates the OATP transporters normally
      recapture, completing the sinusoidal cycle this node interrupts. Evidence
      source is OTHER because this is a review of hepatobiliary transport.
  - reference: PMID:25315738
    reference_title: "Gene replacement therapy for genetic hepatocellular jaundice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Both disorders are benign and not progressive and are characterised by
      elevated serum levels of mainly conjugated bilirubin.
    explanation: >-
      Records the biochemical outcome of this node and its benign,
      non-progressive course - the guardrail against curating Rotor syndrome as
      a progressive liver disease. Evidence source is OTHER because this is a
      review.
phenotypes:
- category: Clinical
  name: Intermittent Jaundice
  description: >-
    Mild, intermittent icterus, often with no other symptoms and no stigmata of
    chronic liver disease. Notably there is no pruritus, which is what separates
    this from cholestasis at the bedside.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
    temporality: RECURRENT
  evidence:
  - reference: PMID:36157610
    reference_title: "Rotor Syndrome Presenting as Dubin-Johnson Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 42-year-old man with no relevant past medical history presented with
      intermittent mild icterus and no signs of chronic liver disease.
    explanation: >-
      Documents the presenting phenotype in a genetically confirmed patient,
      including the absence of chronic liver disease signs. Evidence source is
      HUMAN_CLINICAL because this is a case report.
- category: Laboratory
  name: Conjugated Hyperbilirubinaemia
  description: >-
    Chronic predominantly conjugated hyperbilirubinaemia with bilirubinuria, in
    the presence of normal transaminases, alkaline phosphatase, GGT, albumin,
    and prothrombin time, and no haemolysis.
  phenotype_term:
    preferred_term: Conjugated hyperbilirubinemia
    term:
      id: HP:0002908
      label: Conjugated hyperbilirubinemia
    temporality: CHRONIC
  evidence:
  - reference: PMID:36157610
    reference_title: "Rotor Syndrome Presenting as Dubin-Johnson Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Laboratory tests were notable for hyperbilirubinemia (total 7.97 mg/dL,
      direct 5.37 mg/dL), bilirubinuria, no signs of hemolysis, normal liver
      tests and lipids profile.
    explanation: >-
      Quantifies the biochemical phenotype and documents the normal liver tests
      and absent haemolysis that define it as an isolated transport defect.
      Evidence source is HUMAN_CLINICAL because this is a patient case report.
biochemical:
- name: Conjugated Bilirubin
  presence: INCREASED
  context: >-
    Predominantly conjugated (direct) hyperbilirubinaemia with bilirubinuria.
    One genetically confirmed patient presented with total bilirubin 7.97 mg/dL
    and direct 5.37 mg/dL alongside entirely normal AST, ALT, GGT, alkaline
    phosphatase, albumin, and prothrombin time.
  biomarker_term:
    preferred_term: conjugated bilirubin
    term:
      id: CHEBI:16990
      label: bilirubin IXalpha
  readouts:
  - target: Failure of Hepatic Bilirubin Conjugate Reuptake and Storage
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      A raised direct bilirubin fraction with wholly normal liver biochemistry
      and no haemolysis reports an isolated defect of bilirubin conjugate
      handling rather than hepatocellular injury or biliary obstruction.
    evidence:
    - reference: PMID:36157610
      reference_title: "Rotor Syndrome Presenting as Dubin-Johnson Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Laboratory tests were notable for hyperbilirubinemia (total 7.97 mg/dL,
        direct 5.37 mg/dL), bilirubinuria, no signs of hemolysis, normal liver
        tests and lipids profile.
      explanation: >-
        Provides the measured readout in a confirmed case. Evidence source is
        HUMAN_CLINICAL because this is a patient case report.
- name: Urinary Coproporphyrin
  presence: INCREASED
  context: >-
    Classically, total urinary coproporphyrin excretion is increased two- to
    five-fold in Rotor syndrome with isomer I usually below 75-80% of the total
    - the pattern that historically distinguished it from Dubin-Johnson
    syndrome, where total excretion is normal but isomer I exceeds 80%. This
    discriminator is not reliable in individual patients: a genetically
    confirmed Rotor case has been reported with normal total coproporphyrin and
    86% isomer I, a profile that reads as Dubin-Johnson syndrome. Molecular
    testing, not coproporphyrin analysis, establishes the diagnosis.
  readouts:
  - target: Combined OATP1B1 and OATP1B3 Deficiency
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Altered coproporphyrin handling reports loss of OATP-dependent organic
      anion uptake, but the isomer pattern overlaps with Dubin-Johnson syndrome
      often enough that it cannot stand alone.
    evidence:
    - reference: PMID:36157610
      reference_title: "Rotor Syndrome Presenting as Dubin-Johnson Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Contrary to DJS, in RS, total coproporphyrin excretion in urine is
        increased and isomer I is usually <75-80%, in line with the interaction
        of several porphyrins with OATP1B1
      explanation: >-
        States the classical Rotor coproporphyrin signature and links it
        mechanistically to OATP1B1. Evidence source is OTHER because this
        sentence reports the general rule from the literature rather than the
        case patient's own measurement.
    - reference: PMID:36157610
      reference_title: "Rotor Syndrome Presenting as Dubin-Johnson Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Total urinary coproporphyrin was normal with predominance of isomer I
        (86% of total urinary coproporphyrin output).
      explanation: >-
        Marked PARTIAL because it refutes the reliability of this readout in
        individual patients: these values are the Dubin-Johnson pattern, yet the
        patient had genetically confirmed Rotor syndrome. Evidence source is
        HUMAN_CLINICAL because this is a measurement in a reported patient.
genetic:
- name: SLCO1B1
  notes: >-
    Encodes OATP1B1. Rotor syndrome requires loss of this transporter together
    with OATP1B3; loss of SLCO1B1 alone does not cause the disorder because the
    two transporters are functionally redundant. A reported homozygous deletion
    removed all SLCO1B1 exons together with exons 4-16 of the adjacent SLCO1B3.
  gene_term:
    preferred_term: SLCO1B1
    term:
      id: hgnc:10959
      label: SLCO1B1
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:35860851
    reference_title: "Benign inheritable disorders of bilirubin metabolism manifested by conjugated hyperbilirubinemia-A narrative review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rotor syndrome (caused by the simultaneous presence of mutations in
      SLCO1B1 and SLCO1B3 genes)
    explanation: >-
      Establishes SLCO1B1 as one of the two genes that must both be affected.
      Evidence source is OTHER because this is a narrative review.
- name: SLCO1B3
  notes: >-
    Encodes OATP1B3, adjacent to SLCO1B1 on chromosome 12. Must be lost together
    with SLCO1B1 for the Rotor phenotype to appear.
  gene_term:
    preferred_term: SLCO1B3
    term:
      id: hgnc:10961
      label: SLCO1B3
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:36157610
    reference_title: "Rotor Syndrome Presenting as Dubin-Johnson Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional extended molecular analysis of genes implicated in bilirubin
      metabolism found a homozygous deletion of a region encompassing exons 4-16
      of SLCO1B3 gene (encoding OATP1B3) and all SLCO1B1 exons (encoding
      OATP1B1), thereby establishing Rotor syndrome diagnosis.
    explanation: >-
      Documents a specific causal lesion affecting both genes in a confirmed
      patient. Evidence source is HUMAN_CLINICAL because this is a case report
      with molecular analysis.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Rotor syndrome is transmitted in an autosomal recessive manner. Because two
    functionally redundant transporters must both be lost, the practical
    requirement is biallelic inactivation of SLCO1B1 and SLCO1B3 together -
    frequently satisfied by a homozygous deletion spanning both adjacent loci.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:36157610
    reference_title: "Rotor Syndrome Presenting as Dubin-Johnson Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rotor and Dubin-Johnson syndromes are rare autosomal recessive liver
      diseases characterized by chronic conjugated hyperbilirubinemia
    explanation: >-
      States the mode of inheritance. Evidence source is OTHER because this
      sentence states the general property of the two disorders rather than a
      pedigree finding in the reported patient.
- name: Digenic inheritance
  description: >-
    Rotor syndrome is formally DIGENIC: pathogenic variants are required in both
    SLCO1B1 and SLCO1B3, because the OATP1B1 and OATP1B3 transporters they
    encode are functionally redundant and loss of either alone is silent. It
    resembles monogenic autosomal recessive inheritance in practice only because
    the two genes are adjacent on chromosome 12 and so are unlikely to segregate
    independently - a homozygous deletion commonly removes both. This makes
    Rotor syndrome one of the clearest examples of digenic inheritance among the
    hereditary hyperbilirubinaemias, and distinguishes it from Dubin-Johnson
    syndrome, whose conjugated hyperbilirubinaemia arises from a single gene.
  inheritance_term:
    preferred_term: Digenic inheritance
    term:
      id: HP:0010984
      label: Digenic inheritance
  evidence:
  - reference: PMID:23236639
    reference_title: Rotor Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rotor syndrome is inherited in an autosomal recessive digenic manner that
      clinically resembles monogenic autosomal recessive inheritance.
    explanation: >-
      GeneReviews states the digenic mode explicitly and explains why it
      presents as though monogenic. Evidence source is HUMAN_CLINICAL because
      GeneReviews chapters synthesise clinical and molecular findings in
      affected individuals.
  - reference: PMID:23236639
    reference_title: Rotor Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      (Although Rotor syndrome is a digenic disorder, pathogenic variants in
      SLCO1B1 and SLCO1B3 are unlikely to segregate independently.
    explanation: >-
      Gives the reason the digenic disorder behaves as a monogenic recessive one
      in pedigrees - the two loci are adjacent and co-segregate. Evidence source
      is HUMAN_CLINICAL because this is GeneReviews genetic counselling
      guidance derived from affected families.
treatments:
- name: Diagnosis and Reassurance
  description: >-
    No treatment is required. As with Dubin-Johnson syndrome, the benefit of
    establishing the diagnosis is to reassure the patient and stop an
    escalating, invasive, and costly workup for more serious liver disease. The
    unresolved question is drug handling: OATP1B1 and OATP1B3 are major hepatic
    uptake transporters, and their complete absence is expected to change the
    disposition of their substrate drugs, though no specific prescribing
    guidance follows from the current evidence.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:36157610
    reference_title: "Rotor Syndrome Presenting as Dubin-Johnson Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      With this case, we aim to highlight the necessity of establishing a
      diagnosis, reassuring the patient, and avoiding unnecessary invasive and
      costly diagnostic procedures.
    explanation: >-
      States the clinical purpose of diagnosis in a disorder needing no
      treatment. Evidence source is HUMAN_CLINICAL because this is the
      conclusion of a patient case report.
  - reference: PMID:35860851
    reference_title: "Benign inheritable disorders of bilirubin metabolism manifested by conjugated hyperbilirubinemia-A narrative review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although classically viewed as benign conditions requiring no treatment,
      they lately gained an increased interest since recent studies suggested
      that mutations in the responsible genes leading to hyperbilirubinemia, as
      well as minor genetic variants, may result in an increased susceptibility
      to drug toxicity.
    explanation: >-
      Marked PARTIAL because it qualifies the no-treatment position with a
      suggested, unestablished drug-toxicity susceptibility. Evidence source is
      OTHER because this is a narrative review.
discussions:
- discussion_id: rotor_coproporphyrin_discriminator_unreliable
  kind: KNOWLEDGE_GAP
  prompt: >-
    How reliably does urinary coproporphyrin isomer analysis distinguish Rotor
    syndrome from Dubin-Johnson syndrome in individual patients?
  attaches_to:
  - "pathophysiology#Combined OATP1B1 and OATP1B3 Deficiency"
  rationale: >-
    The textbook rule - increased total coproporphyrin with isomer I below
    75-80% in Rotor syndrome, normal total with isomer I above 80% in
    Dubin-Johnson syndrome - has been contradicted by a genetically confirmed
    Rotor patient whose profile matched the Dubin-Johnson pattern exactly. The
    reported explanation invokes a coincidental heterozygous ABCC2 variant
    modulating porphyrin excretion, which if generally true would mean the
    discriminator is sensitive to common variation in a third gene. No study
    quantifies the test's performance against molecular diagnosis. Curators
    should not treat the coproporphyrin pattern as diagnostic.
  proposed_experiments:
  - experiment_id: coproporphyrin_vs_molecular_diagnosis_cohort
    name: Coproporphyrin pattern versus molecular diagnosis in a genotyped cohort
    description: >-
      Measuring urinary coproporphyrin total and isomer fractions in a cohort of
      patients with molecularly confirmed Rotor or Dubin-Johnson syndrome, and
      reporting sensitivity and specificity against genotype, would establish
      whether the classical discriminator has any residual diagnostic value.

references:
- reference: PMID:23236639
  title: Rotor Syndrome.
  tags:
  - GeneReviews
📚

References & Deep Research

References

1
PMID:23236639
Rotor Syndrome.
No top-level findings curated for this source.