CYCS-Related Thrombocytopenia

name: CYCS-Related Thrombocytopenia
category: Mendelian
creation_date: "2026-07-06T01:49:38Z"
synonyms:
- Thrombocytopenia 4
- THC4
- CYCS thrombocytopenia
- Autosomal dominant non-syndromic thrombocytopenia 4
- Autosomal isolated thrombocytopenia with normal platelet size
description: >-
  CYCS-related thrombocytopenia (thrombocytopenia 4, THC4) is an
  autosomal-dominant inherited thrombocytopenia caused by heterozygous missense
  variants in CYCS, the nuclear gene encoding somatic cytochrome c. Public
  disease sources anchor OMIM:612004 and ORPHA:168629 to this thrombocytopenia
  entity, not to a cytochrome c oxidase holoenzyme-assembly disorder. The
  disease is mechanistically mitochondrial because cytochrome c transfers
  electrons in the respiratory chain and participates in intrinsic apoptosis,
  but the dominant clinical phenotype is mild-to-moderate isolated
  thrombocytopenia with normal platelet size and low bleeding risk. Model and
  patient-cell data support a dual mechanism: CYCS variants reduce respiratory
  performance and increase apoptotic activity, while megakaryocyte-bone-marrow
  interactions promote premature platelet-like release into extravascular marrow
  space, lowering circulating platelet number.
classifications:
  icimd_category:
  - classification_value: cytochrome_c
    notes: >-
      WP-023 / ICIMD code 8.3.03.01 places this seed under disorders of
      mitochondrial cytochrome c. The curated DisMech disease identity follows
      MONDO:0012775 / OMIM:612004 as CYCS-related thrombocytopenia; it is kept
      separate from the Complex IV deficiency grouping because CYCS encodes the
      soluble electron carrier cytochrome c rather than a COX structural subunit
      or assembly factor.
disease_term:
  preferred_term: CYCS-related thrombocytopenia (THC4)
  term:
    id: MONDO:0012775
    label: thrombocytopenia 4
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0012775
      label: thrombocytopenia 4
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0012775 is defined as thrombocytopenia caused by mutation in CYCS
      and carries the OMIM:612004 cross-reference for thrombocytopenia 4.
parents:
- Inherited thrombocytopenia
- Mitochondrial Disease
external_assertions:
- name: Orphanet CYCS disease-gene record
  source: Orphanet
  assertion_type: disease_gene_record
  external_id: ORPHA:168629
  url: https://www.orpha.net/en/disease/detail/168629
  description: >-
    Orphanet identifies ORPHA:168629 as autosomal isolated thrombocytopenia with
    normal platelet size and links CYCS as a disease-causing germline gene.
prevalence:
- population: Reported CYCS families
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Published cohorts describe THC4 as extremely rare, with only a few families
    reported before the 2024 expansion series.
  evidence:
  - reference: PMID:38815995
    reference_title: "Thrombocytopenia 4 (THC4): Six novel families with mutations of the cytochrome c gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "THC4 is considered an extremely rare condition since only a few patients have been reported so far."
    explanation: The 2024 cohort review supports an ultra-rare, cases-in-literature prevalence characterization.
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    THC4 is caused by monoallelic heterozygous CYCS variants segregating with
    thrombocytopenia in affected pedigrees.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:38815995
    reference_title: "Thrombocytopenia 4 (THC4): Six novel families with mutations of the cytochrome c gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thrombocytopenia 4 (THC4) is an autosomal-dominant thrombocytopenia caused by mutations in CYCS"
    explanation: Establishes autosomal-dominant inheritance for CYCS-related thrombocytopenia.
pathophysiology:
- name: CYCS Missense Variant Alters Cytochrome c
  role: trigger
  description: >-
    Heterozygous missense variants in CYCS alter somatic cytochrome c, a small
    mitochondrial heme protein that shuttles electrons in oxidative
    phosphorylation and also participates in intrinsic apoptotic signaling after
    mitochondrial release.
  gene:
    preferred_term: CYCS
    term:
      id: hgnc:19986
      label: CYCS
  biological_processes:
  - preferred_term: respiratory electron transport chain
    term:
      id: GO:0022904
      label: respiratory electron transport chain
    modifier: DECREASED
  - preferred_term: intrinsic apoptotic signaling pathway
    term:
      id: GO:0097193
      label: intrinsic apoptotic signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:38815995
    reference_title: "Thrombocytopenia 4 (THC4): Six novel families with mutations of the cytochrome c gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thrombocytopenia 4 (THC4) is an autosomal-dominant thrombocytopenia caused by mutations in CYCS, the gene encoding cytochrome c (CYCS), a small haeme protein essential for electron transport in mitochondria and cell apoptosis."
    explanation: Identifies CYCS as the causal gene and cytochrome c as an electron-transfer and apoptosis protein.
  downstream:
  - target: Reduced Respiration and Increased Apoptotic Activity
    causal_link_type: DIRECT
    description: >-
      CYCS variants alter both electron-transfer/bioenergetic behavior and
      apoptotic activity of cytochrome c.
- name: Reduced Respiration and Increased Apoptotic Activity
  role: central_effector
  description: >-
    Functional studies of thrombocytopenia-associated CYCS variants show reduced
    respiratory performance alongside increased apoptotic activity. This
    distinguishes CYCS-related thrombocytopenia from classic Complex IV
    assembly deficiency: cytochrome c is affected, but patients generally do not
    show a syndromic cytochrome c oxidase deficiency phenotype.
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  biological_processes:
  - preferred_term: respiratory electron transport chain
    term:
      id: GO:0022904
      label: respiratory electron transport chain
    modifier: DECREASED
  - preferred_term: positive regulation of apoptotic process
    term:
      id: GO:0043065
      label: positive regulation of apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:24326104
    reference_title: "Mutations of cytochrome c identified in patients with thrombocytopenia THC4 affect both apoptosis and cellular bioenergetics."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we found reduction of respiratory level and increased apoptotic rate, supporting the pathogenetic role of CYCS in thrombocytopenia."
    explanation: Yeast and mouse cellular models directly support reduced respiration and increased apoptosis downstream of thrombocytopenia-associated CYCS variants.
  - reference: PMID:18345000
    reference_title: "A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The mutation yields a cytochrome c variant with enhanced apoptotic activity in vitro."
    explanation: The original CYCS G41S study supports enhanced apoptotic activity as a variant effect.
  downstream:
  - target: Dysregulated Megakaryocyte Platelet Release
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered cytochrome c respiratory function
    - enhanced intrinsic apoptotic signaling
    description: >-
      Altered cytochrome c function perturbs megakaryocyte platelet-release
      behavior, with premature platelet-like release in the marrow space.
- name: Dysregulated Megakaryocyte Platelet Release
  role: central_effector
  description: >-
    Patient studies indicate that circulating proplatelet formation can remain
    effective, but CYCS-mutant megakaryocytes also release platelet-like
    structures prematurely into extravascular bone marrow regions. Platelet-like
    structures released outside the vascular space lack a normal marginal
    microtubule coil, making them ineffective contributors to the circulating
    platelet pool.
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: platelet formation
    term:
      id: GO:0030220
      label: platelet formation
  evidence:
  - reference: PMID:27861742
    reference_title: "Megakaryocytes from CYCS mutation-associated thrombocytopenia release platelets by both proplatelet-dependent and -independent processes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the low platelet phenotype in Thrombocytopenia Cargeeg subjects is caused by premature release of platelets into non-vascular regions of the bone marrow."
    explanation: Patient marrow observations support premature extravascular platelet release as a mechanism for low circulating platelet count.
  - reference: PMID:27861742
    reference_title: "Megakaryocytes from CYCS mutation-associated thrombocytopenia release platelets by both proplatelet-dependent and -independent processes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "platelet-like structures within the extravascular bone marrow space have the dimensions of platelets but lack the marginal microtubule coil, suggesting abnormal proplatelet-independent platelet release."
    explanation: The abnormal extravascular platelet-like structures provide a tissue-level link from CYCS-mutant megakaryocytes to reduced effective platelet production.
  downstream:
  - target: Thrombocytopenia
    causal_link_type: DIRECT
    description: >-
      Premature or misplaced platelet-like release reduces the number of mature
      platelets reaching the circulation.
phenotypes:
- name: Thrombocytopenia
  category: Hematologic
  description: >-
    Mild-to-moderate isolated thrombocytopenia with normal platelet size and
    generally low bleeding risk.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:38815995
    reference_title: "Thrombocytopenia 4 (THC4): Six novel families with mutations of the cytochrome c gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild-to-moderate thrombocytopenia, normal platelet size, and function, low risk of bleeding, and no additional clinical phenotypes associated with reduced platelet count."
    explanation: The largest reported THC4 cohort defines the characteristic platelet phenotype.
  - reference: PMID:35126455
    reference_title: "A Novel Heterozygous Pathogenic Variation in CYCS Gene Cause Autosomal Dominant Non-Syndromic Thrombocytopenia 4 in a Large Chinese Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The platelet counts of the patients were varied, ranging from 38 to 110 × 109/L (reference range: 150-450 x 109/L)."
    explanation: A three-generation CYCS family documents reduced platelet counts in affected individuals.
genetic:
- name: CYCS pathogenic variants causing thrombocytopenia 4
  gene_term:
    preferred_term: CYCS
    term:
      id: hgnc:19986
      label: CYCS
  inheritance:
  - name: Autosomal dominant
    evidence:
    - reference: PMID:35126455
      reference_title: "A Novel Heterozygous Pathogenic Variation in CYCS Gene Cause Autosomal Dominant Non-Syndromic Thrombocytopenia 4 in a Large Chinese Family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A novel heterozygous missense variant c.79C > T (p.His27Tyr) was identified in CYCS gene associated with autosomal dominant thrombocytopenia."
      explanation: A heterozygous CYCS missense variant segregated with autosomal-dominant thrombocytopenia in a three-generation family.
  variants:
  - name: CYCS p.Gly41Ser
    description: >-
      The original New Zealand family variant; it alters cytochrome c and
      enhances intrinsic apoptotic activity in vitro.
    gene:
      preferred_term: CYCS
      term:
        id: hgnc:19986
        label: CYCS
    evidence:
    - reference: PMID:18345000
      reference_title: "A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Glycine 41, invariant throughout eukaryotes, is substituted by serine in a family with autosomal dominant thrombocytopenia caused by dysregulated platelet formation."
      explanation: Identifies CYCS p.Gly41Ser as the original family variant associated with autosomal-dominant thrombocytopenia.
  - name: CYCS p.His27Tyr
    description: >-
      A heterozygous CYCS missense variant reported in a large Chinese family
      with autosomal-dominant non-syndromic thrombocytopenia 4.
    gene:
      preferred_term: CYCS
      term:
        id: hgnc:19986
        label: CYCS
    evidence:
    - reference: PMID:35126455
      reference_title: "A Novel Heterozygous Pathogenic Variation in CYCS Gene Cause Autosomal Dominant Non-Syndromic Thrombocytopenia 4 in a Large Chinese Family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A novel heterozygous missense variant c.79C > T (p.His27Tyr) was identified in CYCS gene associated with autosomal dominant thrombocytopenia."
      explanation: Identifies p.His27Tyr as a CYCS variant associated with autosomal-dominant thrombocytopenia in a three-generation family.
  features: >-
    Heterozygous CYCS missense variants cause autosomal-dominant
    thrombocytopenia 4. Reported pathogenic variants cluster in regions that
    affect cytochrome c functions in apoptosis and mitochondrial respiration,
    with variable severity of platelet count reduction.
treatments:
- name: Genetic Counseling
  description: >-
    Counseling for autosomal-dominant transmission and family testing where a
    pathogenic CYCS variant has been identified.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
notes: >-
  The seed label "mitochondrial cytochrome c deficiency" was not used as the
  disease name because independent MONDO, OMIM, Orphanet, and PubMed evidence
  identify OMIM:612004 / ORPHA:168629 as CYCS-related thrombocytopenia 4. This
  entry therefore models the CYCS/cytochrome c mechanism leading to
  thrombocytopenia and intentionally does not add CYCS to the mitochondrial
  Complex IV deficiency grouping.