CYCS-Related Thrombocytopenia

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Classifications

ICIMD (Inherited Metabolic Disorders)

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Mappings

MONDO

MONDO:0012775 thrombocytopenia 4

MONDO:0012775 is defined as thrombocytopenia caused by mutation in CYCS and carries the OMIM:612004 cross-reference for thrombocytopenia 4.

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Inheritance

1

Autosomal dominant inheritance HP:0000006

THC4 is caused by monoallelic heterozygous CYCS variants segregating with thrombocytopenia in affected pedigrees.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:38815995 SUPPORT Human Clinical

"Thrombocytopenia 4 (THC4) is an autosomal-dominant thrombocytopenia caused by mutations in CYCS"

Establishes autosomal-dominant inheritance for CYCS-related thrombocytopenia.

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Mechanistic Hypotheses

2

Variant-dependent caspase dysregulation impairs platelet biogenesis

cycs_caspase_platelet_model EMERGING

Altered apoptosome/caspase regulation may disrupt platelet production. Both increased and decreased readouts have been observed; the causal bridge remains unresolved.

Pathograph links

Altered Cytochrome c Conformation -> Altered Apoptosome Activation UNKNOWN Greater conformational flexibility correlates with enhanced apoptosome activation for the tested mature-protein G41S, Y48H and A51V variants. This proposed relation does not imply a universal direction for other alleles.

Altered Apoptosome Activation -> Dysregulated Megakaryocyte Platelet Release INDIRECT UNKNOWN INTERMEDIATES Altered caspase regulation is proposed to disturb platelet biogenesis, but neither the intermediate steps nor a universal direction of effect have been established.

Premature extravascular platelet release

cycs_marrow_release_model EMERGING

Cargeeg-family marrow observations support premature release outside vessels as a cause of low circulating platelets; applicability to other alleles is uncertain.

Pathograph links

Dysregulated Megakaryocyte Platelet Release -> Thrombocytopenia INDIRECT UNKNOWN INTERMEDIATES Premature extravascular release is proposed to reduce the number of mature platelets entering circulation in the Cargeeg family.

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Discussions and Knowledge Gaps

2

How do opposite caspase and respiratory responses converge on thrombocytopenia?

KNOWLEDGE GAP cycs_variant_and_model_dependence

Attached to

pathophysiology#Altered Apoptosome Activation pathophysiology#Altered Respiratory Electron Transfer pathophysiology#Enhanced Cytochrome c Peroxidase Activity

Thr20Ile megakaryoblasts differ from the older G41S/Y48H cell models. Variant identity, species, cell lineage and stimulation conditions may all matter. Purified-protein peroxidase enhancement is not sufficient evidence of a platelet-production mechanism. No universal respiratory-loss or apoptosis-gain pathway is established.

Show evidence (3 references)

PMID:33480393 SUPPORT In Vitro

"The role of cytochrome c in platelet formation, and the molecular mechanism underlying the association of cytochrome c mutations with thrombocytopenia remains unknown, although a gain-of-function is most likely."

The earlier mechanistic study explicitly identifies the unresolved disease link.

PMID:39191490 SUPPORT In Vitro

"Surprisingly, the variant abates caspase activation, contrasting with previously known effects of other CYCS variants."

The subsequent Thr20Ile data challenge a universal gain-of-apoptosis account.

PMID:31557440 SUPPORT BACKGROUND Model Organism

"Recent in vivo studies indicate that the enhanced peroxidase activity of the THC4-linked Cytc variants is unlikely the cause of THC4."

The introduction summarizes prior in-vivo studies; the current paper did not perform a new animal experiment. BACKGROUND distinguishes this evidence from its own biochemical results.

Why is proplatelet formation preserved in one patient-derived culture study but defective in preliminary registry observations?

KNOWLEDGE GAP cycs_proplatelet_context

Attached to

pathophysiology#Dysregulated Megakaryocyte Platelet Release

The Cargeeg study found normal proplatelet formation in culture. NCT07026578 describes preliminary progenitor cultures with preserved megakaryocyte maturation but defective proplatelets, and reduced cytochrome c with resistance to induced apoptosis in patient platelets. These registry observations are not posted trial results or a peer-reviewed replication. Variant and culture differences remain unresolved.

Show evidence (2 references)

clinicaltrials:NCT07026578 SUPPORT In Vitro

"Hematopoietic progenitors from 3 patients were differentiated in megakaryocytes. Maturation and differentiation were comparable between THC4 and healthy controls. Instead, their capability to form proplatelets was profoundly defective."

Preliminary sponsor observations differ from the Cargeeg cultures; the registry does not establish why.

clinicaltrials:NCT07026578 SUPPORT In Vitro

"Surprisingly, the expression of cytC was found reduced in platelets of all analyzed patients. Platelets showed no signs of early death. Instead, when stimulated with ABT-737, they showed inability to undergo apoptosis, suggesting that CYCS mutations confer resistance to apoptosis."

Preliminary ex-vivo platelet data, not a therapeutic ABT-737 trial.

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Pathophysiology

7

Heterozygous CYCS Sequence Alteration

Mechanism confidence: Established

Heterozygous CYCS missense substitutions and the in-frame Lys101 deletion segregate with thrombocytopenia. Different alleles need not have the same biochemical effect.

CYCS hgnc:19986

Downstream

Altered Cytochrome c Conformation Variant-dependent structural perturbations are supported by crystallography, biophysical measurements and molecular dynamics.

Reduced Cytochrome c Abundance Reduced abundance has been measured for Thr20Ile and for the yeast Lys101del model; it is not established for every allele.

Altered Respiratory Electron Transfer Respiratory effects depend on the allele and cellular system.

Altered Apoptosome Activation CYCS variants alter apoptosome-dependent caspase activation in biochemical and cellular assays.

Show evidence (2 references)

PMID:38815995 SUPPORT Human Clinical

"Thrombocytopenia 4 (THC4) is an autosomal-dominant thrombocytopenia caused by mutations in CYCS"

Establishes autosomal-dominant inheritance for CYCS-related thrombocytopenia.

PMID:30051457 SUPPORT Human Clinical

"This variant (c.301_303del:p.Lys101del) is located in the α-helix of the cytochrome c (CYCS) C-terminal domain."

The pathogenic allele spectrum includes an in-frame deletion, not only missense substitutions.

Altered Cytochrome c Conformation

Mechanism confidence: Provisional

Pathogenic cytochrome c substitutions alter local stability and conformational dynamics without necessarily disrupting the overall fold. Human G41S, Y48H and A51V show greater conformational flexibility associated with enhanced apoptosome activation. G41S does not produce the same mobility change in the mouse protein. Mature-protein G41S, Y48H and A51V correspond to initiator-inclusive Gly42Ser, Tyr49His and Ala52Val.

Variant-dependent caspase dysregulation impairs platelet biogenesis

CYCS hgnc:19986

Downstream

Altered Apoptosome Activation Greater conformational flexibility correlates with enhanced apoptosome activation for the tested mature-protein G41S, Y48H and A51V variants. This proposed relation does not imply a universal direction for other alleles.

Enhanced Cytochrome c Peroxidase Activity Several tested substitutions also increase purified-protein peroxidase activity, but this effect does not track native-state flexibility in the same way as apoptosome activation.

Show evidence (3 references)

PMID:33480393 SUPPORT Computational

"Molecular dynamics simulations of these variants, and two non-naturally occurring variants (G41A, G41T), indicate that increased apoptosome activation correlates with the increased overall flexibility of cytochrome c, particularly movement of the Ω loops."

Molecular dynamics supports a structure-activity association; induced-fit binding to Apaf-1 remains an interpretation.

PMID:31557440 SUPPORT In Vitro

"A 1.82 Å structure of the A51V variant shows only minor changes in tertiary structure relative to the wild-type (WT) protein."

Crystallography supports a local perturbation rather than gross unfolding.

PMID:38472487 SUPPORT Computational

"The G41S mutation increases main chain RSMD in human but not mouse cytochrome c (Fig. 2 B and D)."

The primary molecular-dynamics comparison demonstrates species-dependent structural effects; the source spells the metric RSMD in this sentence.

Reduced Cytochrome c Abundance

Mechanism confidence: Provisional

Thr20Ile reduces cytochrome c abundance in engineered MEG-01 clones and in platelets from one affected family member. Lys101del reduces cytochrome c abundance in a yeast model. These observations do not establish universal CYCS haploinsufficiency.

CYCS hgnc:19986

Experimental models

Thr20Ile knock-in MEG-01 megakaryoblasts CELL LINE Cytochrome c abundance is the measured facet of this mechanism.

Show evidence (3 references)

PMID:39191490 SUPPORT In Vitro

"Expression of CYCS was decreased in: (A) SC1 and SC3 MEG-01 p.(Thr20Ile) knock-in clones compared to wt"

Two engineered megakaryoblast clones had reduced cytochrome c abundance.

PMID:39191490 SUPPORT Human Clinical

"and was also reduced to 43% (p < 0.002) in platelets from thrombocytopenic patient IV-2 compared to healthy controls (Figure 3B)."

Patient IV-2 had reduced cytochrome c expression relative to healthy controls; this single-patient measurement is not a cohort-wide biomarker validation.

PMID:30051457 SUPPORT Model Organism

"Using the yeast model system, we clearly demonstrated that this one amino acid deletion (in-frame) resulted in significantly reduced cytochrome c protein expression and functional defects in the mitochondrial respiratory chain, indicating that the loss of function of cytochrome c underlies..."

The Lys101del yeast system supports reduced abundance and respiratory function, without proving a uniform effect across alleles.

Altered Respiratory Electron Transfer

Mechanism confidence: Provisional

Cytochrome c transfers electrons in the mitochondrial respiratory chain. G41S/Y48H models and Lys101del yeast show reduced respiratory function; by contrast, a Thr20Ile knock-in MEG-01 clone shows increased basal and maximal respiration. Cellular oxygen consumption measures the integrated respiratory phenotype and does not isolate the electron-transfer rate of each mutant protein. Respiratory abnormalities have not been established as a sufficient cause of thrombocytopenia.

CYCS hgnc:19986

respiratory electron transport chain GO:0022904 ⚠ ABNORMAL

electron transfer activity GO:0009055 ⚠ ABNORMAL

Experimental models

Thr20Ile knock-in MEG-01 megakaryoblasts CELL LINE Basal and maximal oxygen consumption is the measured facet of this mechanism.

G41S/Y48H-complemented mouse lung fibroblasts CELL LINE Cellular oxygen consumption is the measured facet of this mechanism.

Show evidence (2 references)

PMID:24326104 SUPPORT In Vitro

"we found reduction of respiratory level and increased apoptotic rate, supporting the pathogenetic role of CYCS in thrombocytopenia."

The mammalian-cell component of the 2014 study supports reduced respiration in those models. The abstract also summarizes yeast experiments, but this item uses its cell-culture result.

PMID:39191490 SUPPORT In Vitro

"(A) Basal and maximal respiration were increased in MEG-01 p.(Thr20Ile) knock-in clone (solid lines) compared to wt (dashed lines)."

The opposite direction in a megakaryoblast model precludes a universal reduced-respiration mechanism.

Altered Apoptosome Activation

Mechanism confidence: Provisional

Cytochrome c activates the apoptosome and downstream caspases. Biochemical studies of mature-protein G41S, Y48H and A51V report enhanced apoptosome activation. Thr20Ile instead reduces caspase-3/7 activity in engineered MEG-01 cells and lysates. This downstream readout does not directly establish defective apoptosome assembly for Thr20Ile. The effect on platelet production is still a hypothesis.

Variant-dependent caspase dysregulation impairs platelet biogenesis

CYCS hgnc:19986

apoptosome GO:0043293

intrinsic apoptotic signaling pathway GO:0097193 ⚠ ABNORMAL

Experimental models

Thr20Ile knock-in MEG-01 megakaryoblasts CELL LINE Caspase-3/7 activity is the measured facet of this mechanism.

G41S/Y48H-complemented mouse lung fibroblasts CELL LINE Basal and staurosporine-induced apoptosis is the measured facet of this mechanism.

Downstream

Dysregulated Megakaryocyte Platelet Release Altered caspase regulation is proposed to disturb platelet biogenesis, but neither the intermediate steps nor a universal direction of effect have been established.

Show evidence (2 references)

PMID:33480393 SUPPORT In Vitro

"Three pathogenic variants (G41S, Y48H, A51V) cause an increase in apoptosome activation and peroxidase activity."

Purified-protein/cell assays support increased apoptosome activity for the three specified mature-protein variants.

PMID:39191490 SUPPORT In Vitro

"Surprisingly, the variant abates caspase activation, contrasting with previously known effects of other CYCS variants."

Thr20Ile decreases downstream caspase activation in engineered MEG-01 cells, demonstrating allele/model dependence.

Enhanced Cytochrome c Peroxidase Activity

Mechanism confidence: Provisional

Purified mature-protein G41S, Y48H and A51V have enhanced peroxidase activity. The A51V study used guaiacol oxidation with hydrogen peroxide; this does not directly demonstrate cardiolipin oxidation in patient platelets. Enhanced peroxidase activity is a biochemical property of these variants, not an established cause of thrombocytopenia.

CYCS hgnc:19986

peroxidase activity GO:0004601 ↑ INCREASED

Show evidence (3 references)

PMID:31557440 SUPPORT In Vitro

"Consistent with the greater accessibility of non-native conformers for the A51V variant, the kcat values for its peroxidase activity increase by 6- to 15-fold in the pH range of 5-8 versus those of the WT protein."

Purified A51V protein has enhanced peroxidase activity under the specified assay conditions.

PMID:33480393 SUPPORT In Vitro

"In contrast, peroxidase activity did not significantly correlate with protein dynamics."

This activity should not be conflated with the proposed flexibility-apoptosome relation.

PMID:31557440 SUPPORT In Vitro

"The formation of tetraguaiacol from guaiacol and H2O2 in the presence of Cytc was monitored at 470 nm."

The experimental method used guaiacol/H2O2, limiting inference about cardiolipin oxidation in patient platelets.

Dysregulated Megakaryocyte Platelet Release

Mechanism confidence: Provisional

In the G41S Cargeeg family, extravascular marrow contains platelet-like structures lacking the normal marginal microtubule coil. Premature release outside marrow vessels is proposed to reduce effective circulating platelet output. Patient-derived megakaryocytes can nevertheless form proplatelets normally in culture, implicating marrow context. These observations are not a proven universal mechanism for every CYCS allele.

Premature extravascular platelet release

megakaryocyte CL:0000556 platelet CL:0000233

platelet formation GO:0030220 ⚠ ABNORMAL

Experimental models

Cargeeg patient-derived megakaryocytes PRIMARY CELL CULTURE Proplatelet formation in culture is the measured facet of this mechanism.

Downstream

Thrombocytopenia Premature extravascular release is proposed to reduce the number of mature platelets entering circulation in the Cargeeg family.

Show evidence (2 references)

PMID:27861742 SUPPORT Human Clinical

"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."

Marrow observations support abnormal extravascular platelet-like release in the Cargeeg family.

PMID:27861742 SUPPORT Human Clinical

"the low platelet phenotype in Thrombocytopenia Cargeeg subjects is caused by premature release of platelets into non-vascular regions of the bone marrow."

The source proposes this mechanism specifically for the studied family, while the intracellular link remains unresolved.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

5

Thrombocytopenia Hematologic HP:0001873

Sequelae: Bruising susceptibility Petechiae Epistaxis Intracranial hemorrhage

Show evidence (3 references)

PMID:38815995 SUPPORT Human Clinical

"mild-to-moderate thrombocytopenia, normal platelet size, and function, low risk of bleeding, and no additional clinical phenotypes associated with reduced platelet count."

The 2024 six-family series supports the typical mild-to-moderate, largely nonsyndromic phenotype; this is not a claim that every CYCS family has normal platelet function.

PMID:35126455 SUPPORT Human Clinical

"The platelet counts of the patients were varied, ranging from 38 to 110 × 109/L (reference range: 150-450 x 109/L)."

A three-generation CYCS family documents reduced platelet counts in affected individuals.

PMID:39191490 SUPPORT Human Clinical

"Despite severe thrombocytopenia, bleeding episodes have rarely been reported."

The Thr20Ile daughter demonstrates that severe thrombocytopenia can coexist with limited bleeding.

Bruising susceptibility Hematologic HP:0000978

Show evidence (1 reference)

PMID:39191490 SUPPORT Human Clinical

"He suffered from larger haematomas after injuries."

The Thr20Ile proband had injury-related hematomas.

Petechiae Hematologic HP:0000967

Show evidence (1 reference)

PMID:41676885 SUPPORT Human Clinical

"One newborn presented with petechiae and grade 1 intracranial hemorrhage but recovered fully."

The Arg92Gly family includes a newborn with petechiae.

Epistaxis Hematologic HP:0000421

Show evidence (1 reference)

PMID:35126455 SUPPORT Human Clinical

"Most studied patients had mild bleeding of skin mucosa, except IV-5 with epistaxis, and the proband showed the spontaneous skin bleeding (Supplemental Table 1)."

The full text documents mucocutaneous bleeding and epistaxis despite the broader abstract wording.

Intracranial hemorrhage Hematologic HP:0002170

Show evidence (1 reference)

PMID:41676885 SUPPORT Human Clinical

"One newborn presented with petechiae and grade 1 intracranial hemorrhage but recovered fully."

Direct clinical observation supports this complication without estimating its population frequency.

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Genetic Associations

1

CYCS pathogenic variants causing thrombocytopenia 4

Gene: CYCS hgnc:19986

Autosomal dominant

Show evidence (2 references)

PMID:38815995 SUPPORT Human Clinical

"In this study, we describe six Italian families with five different heterozygous missense CYCS variants: p.Gly42Ser and p.Tyr49His previously associated with THC4, and three novel variants (p.Ala52Thr, p.Arg92Gly, and p.Leu99Val), which have been classified as pathogenic by bioinformatics and..."

The series extends the allele spectrum; biochemical support is not equivalent for every substitution.

PMID:33480393 SUPPORT In Vitro

"Three pathogenic variants (G41S, Y48H, A51V) cause an increase in apoptosome activation and peroxidase activity."

The mature-protein A51V allele is among the three pathogenic variants tested biochemically.

Variants (11)

CYCS p.Gly42Ser (mature protein G41S)

Gene: CYCS hgnc:19986

The original New Zealand family allele; mature-protein G41S is initiator-inclusive Gly42Ser. Enhanced apoptotic activity was measured in vitro.

Show evidence (1 reference)

PMID:18345000 SUPPORT Human Clinical

"Glycine 41, invariant throughout eukaryotes, is substituted by serine in a family with autosomal dominant thrombocytopenia caused by dysregulated platelet formation."

Identifies CYCS p.Gly41Ser as the original family variant associated with autosomal-dominant thrombocytopenia.

CYCS p.His27Tyr

Gene: CYCS hgnc:19986

A heterozygous CYCS missense variant reported in a large Chinese family with autosomal-dominant non-syndromic thrombocytopenia 4.

Show evidence (1 reference)

PMID:35126455 SUPPORT Human Clinical

"A novel heterozygous missense variant c.79C > T (p.His27Tyr) was identified in CYCS gene associated with autosomal dominant thrombocytopenia."

Identifies p.His27Tyr as a CYCS variant associated with autosomal-dominant thrombocytopenia in a three-generation family.

CYCS p.Thr20Ile

Gene: CYCS hgnc:19986

A likely pathogenic c.59C>T allele with reduced CYCS abundance, increased respiration and reduced caspase activation in MEG-01 models.

Show evidence (1 reference)

PMID:39191490 SUPPORT Human Clinical

"Here, we report a functional analysis of the novel CYCS variant NP_061820.1:p.(Thr20Ile) (NM_018947.6:c.59C>T), which segregates with thrombocytopenia in three generations of a Czech family."

The clinical report identifies this allele in familial CYCS-related thrombocytopenia.

CYCS p.Lys101del

Gene: CYCS hgnc:19986

An in-frame deletion associated with reduced protein abundance and respiratory function in yeast. Hemophilia A in the reported family is a separate disorder.

Show evidence (1 reference)

PMID:30051457 SUPPORT Human Clinical

"This variant (c.301_303del:p.Lys101del) is located in the α-helix of the cytochrome c (CYCS) C-terminal domain."

The clinical report identifies this allele in familial CYCS-related thrombocytopenia.

CYCS p.Asn71Thr

Gene: CYCS hgnc:19986

Reported with familial thrombocytopenia in a Japanese series.

Show evidence (1 reference)

PMID:41455048 SUPPORT Human Clinical

"Two were previously reported: c.274A > G,p.(Arg92Gly) and c.309C > T,p.(Thr103Ile); one was novel: c.212A > C,p.(Asn71Thr)."

The clinical report identifies this allele in familial CYCS-related thrombocytopenia.

CYCS p.Arg92Gly

Gene: CYCS hgnc:19986

Segregates in an additional multigenerational family. Structural modeling suggests local instability, but it is not a functional assay.

Show evidence (1 reference)

PMID:41676885 SUPPORT Human Clinical

"Whole-exome sequencing identified p.Arg92Gly as the only variant segregating with disease; Sanger sequencing confirmed heterozygosity in all affected members."

The clinical report identifies this allele in familial CYCS-related thrombocytopenia.

CYCS p.Thr103Ile

Gene: CYCS hgnc:19986

A previously reported allele also identified in the Japanese family series.

Show evidence (1 reference)

PMID:41455048 SUPPORT Human Clinical

"Two were previously reported: c.274A > G,p.(Arg92Gly) and c.309C > T,p.(Thr103Ile); one was novel: c.212A > C,p.(Asn71Thr)."

The clinical report identifies this allele in familial CYCS-related thrombocytopenia.

CYCS p.Tyr49His (mature protein Y48H)

Gene: CYCS hgnc:19986

Reported in the Italian family series. The strength and type of functional evidence differ among alleles.

Show evidence (1 reference)

PMID:38815995 SUPPORT Human Clinical

"In this study, we describe six Italian families with five different heterozygous missense CYCS variants: p.Gly42Ser and p.Tyr49His previously associated with THC4, and three novel variants (p.Ala52Thr, p.Arg92Gly, and p.Leu99Val), which have been classified as pathogenic by bioinformatics and..."

The series extends the allele spectrum; biochemical support is not equivalent for every substitution.

CYCS p.Ala52Thr

Gene: CYCS hgnc:19986

Reported in the Italian family series. The strength and type of functional evidence differ among alleles.

Show evidence (1 reference)

PMID:38815995 SUPPORT Human Clinical

"In this study, we describe six Italian families with five different heterozygous missense CYCS variants: p.Gly42Ser and p.Tyr49His previously associated with THC4, and three novel variants (p.Ala52Thr, p.Arg92Gly, and p.Leu99Val), which have been classified as pathogenic by bioinformatics and..."

The series extends the allele spectrum; biochemical support is not equivalent for every substitution.

CYCS p.Leu99Val

Gene: CYCS hgnc:19986

Reported in the Italian family series. The strength and type of functional evidence differ among alleles.

Show evidence (1 reference)

PMID:38815995 SUPPORT Human Clinical

"In this study, we describe six Italian families with five different heterozygous missense CYCS variants: p.Gly42Ser and p.Tyr49His previously associated with THC4, and three novel variants (p.Ala52Thr, p.Arg92Gly, and p.Leu99Val), which have been classified as pathogenic by bioinformatics and..."

The series extends the allele spectrum; biochemical support is not equivalent for every substitution.

CYCS p.Ala52Val (mature protein A51V)

Gene: CYCS hgnc:19986

A thrombocytopenia-associated substitution studied in purified-protein structure, stability, apoptosome and peroxidase assays.

Show evidence (1 reference)

PMID:33480393 SUPPORT In Vitro

"Three pathogenic variants (G41S, Y48H, A51V) cause an increase in apoptosome activation and peroxidase activity."

The mature-protein A51V allele is among the three pathogenic variants tested biochemically.

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External Assertions

1

Orphanet CYCS disease-gene record

Orphanet disease gene record ORPHA:168629

Orphanet identifies ORPHA:168629 as autosomal isolated thrombocytopenia with normal platelet size and links CYCS as a disease-causing germline gene.

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Medical Actions

2

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counseling for autosomal-dominant transmission and family testing where a pathogenic CYCS variant has been identified.

Show evidence (1 reference)

PMID:27479822 SUPPORT Human Clinical

"All results following platelet function testing and WES were reported back to the referring hematology consultants to aid in genetic counselling and disease management."

A broader inherited-thrombocytopenia cohort supports using molecular findings for counseling; it is not a CYCS-specific treatment trial.

Clinical observation for limited bleeding

Published Thr20Ile cases were followed without thrombocytopenia-directed medication when bleeding was limited. This is case-based management evidence, not a universal recommendation or a validated surveillance schedule.

Show evidence (2 references)

PMID:39191490 SUPPORT Human Clinical

"There was no pathology in white blood count, and no other bleeding episodes. Thus, the proband was without medication."

The proband was observed without medication despite persistent thrombocytopenia.

PMID:39191490 SUPPORT Human Clinical

"She was followed from 2012 to 2021 without requiring any medication."

The affected daughter initially required no medication; later treatment addressed concurrent autoimmune disease.

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Diagnosis

2

Blood count and platelet morphology

Persistent isolated thrombocytopenia with generally normal platelet size and morphology, especially with affected relatives, supports an inherited platelet disorder. Normal morphology does not exclude CYCS-related disease.

Show evidence (1 reference)

PMID:41455048 SUPPORT Human Clinical

"Patients showed no or mild bleeding tendency, with preserved platelet size and morphology, and without other abnormalities in blood cell lineages."

The Japanese series describes the characteristic hematologic findings.

CYCS sequencing and familial segregation

A congenital thrombocytopenia panel or exome sequencing can identify a CYCS variant; segregation and variant-level evidence inform interpretation. Familial disease can be misdiagnosed as immune thrombocytopenia.

Show evidence (2 references)

PMID:41455048 SUPPORT Human Clinical

"Genetic testing should be considered in unexplained familial thrombocytopenia."

The clinical series supports molecular testing in this setting.

PMID:39191490 SUPPORT Human Clinical

"His condition was initially misdiagnosed as idiopathic thrombocytopenic purpura."

The full case description documents initial misclassification before recognition of familial thrombocytopenia.

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Prevalence

1

Reported CYCS families

Cases In Literature Ultra Rare

The literature describes a rare familial disorder; reported family series do not establish a population prevalence. Overlapping reports should not be summed as independent cases.

Show evidence (1 reference)

PMID:38815995 SUPPORT Human Clinical

"THC4 is considered an extremely rare condition since only a few patients have been reported so far."

The authors describe rarity from the limited reported families, rather than a measured population prevalence.

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Clinical Trials

1

NCT07026578 NOT_APPLICABLE ACTIVE_NOT_RECRUITING

Observational mechanistic study of cytochrome c abundance, apoptosis and platelet biogenesis in THC4. The registry describes preliminary patient-cell observations, not therapeutic efficacy results.

Show evidence (3 references)

clinicaltrials:NCT07026578 SUPPORT Human Clinical

"Since thrombocytopenia is the only phenotypic manifestation of CYCS mutations, the investigators believe that THC4 represents a unique model for deciphering the role of Cytc and apoptosis in megakaryopoiesis and platelet biogenesis."

The registry specifies a mechanistic observational rationale, not a treatment study.

url:https://clinicaltrials.gov/api/v2/studies/NCT07026578 SUPPORT Other

""statusModule": {"statusVerifiedDate": "2025-04", "overallStatus": "ACTIVE_NOT_RECRUITING", "expandedAccessInfo": {"hasExpandedAccess": false}, "startDateStruct": {"date": "2024-06-18", "type": "ACTUAL"}, "primaryCompletionDateStruct": {"date": "2026-06-30", "type": "ESTIMATED"},..."

Registry metadata verifies the recorded recruitment status, update date and estimated completion; it does not establish that completion occurred.

url:https://clinicaltrials.gov/api/v2/studies/NCT07026578 SUPPORT Other

""studyType": "OBSERVATIONAL", "patientRegistry": false, "designInfo": {"observationalModel": "CASE_CONTROL", "timePerspective": "PROSPECTIVE"}, "bioSpec": {"retention": "SAMPLES_WITH_DNA", "description": "25 mL of peripheral whole blood anticoagulated with ACD for platelet isolation and for..."

The official design metadata identifies an observational study, so a therapeutic trial phase is not applicable.

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Experimental Models

3

Thr20Ile knock-in MEG-01 megakaryoblasts CELL_LINE

CRISPR/Cas9-engineered MEG-01 clones carrying Thr20Ile model reduced CYCS abundance, increased respiration and decreased caspase activation. These assays did not directly establish a proplatelet-output defect.

Cell source

Human MEG-01 megakaryoblastic cell line

Pathograph links

Reduced Cytochrome c Abundance measures fidelity: unknown observes: cellular Cytochrome c abundance is the measured facet of this mechanism.

Limitations: Engineered megakaryoblast line; does not directly establish platelet-output effects in patient marrow.

Readouts

Cytochrome c abundance

Direction: DECREASED

Show evidence (1 reference)

PMID:39191490 SUPPORT In Vitro

"Expression of CYCS was decreased in: (A) SC1 and SC3 MEG-01 p.(Thr20Ile) knock-in clones compared to wt"

Two engineered megakaryoblast clones had reduced cytochrome c abundance.

Show evidence (1 reference)

PMID:39191490 SUPPORT In Vitro

"Expression of CYCS was decreased in: (A) SC1 and SC3 MEG-01 p.(Thr20Ile) knock-in clones compared to wt"

Two engineered megakaryoblast clones had reduced cytochrome c abundance.

Altered Respiratory Electron Transfer measures fidelity: unknown observes: cellular Basal and maximal oxygen consumption is the measured facet of this mechanism.

Limitations: Engineered megakaryoblast line; does not directly establish platelet-output effects in patient marrow.

Readouts

Basal and maximal oxygen consumption

Direction: INCREASED

Show evidence (1 reference)

PMID:39191490 SUPPORT In Vitro

"(A) Basal and maximal respiration were increased in MEG-01 p.(Thr20Ile) knock-in clone (solid lines) compared to wt (dashed lines)."

The opposite direction in a megakaryoblast model precludes a universal reduced-respiration mechanism.

Show evidence (1 reference)

PMID:39191490 SUPPORT In Vitro

"(A) Basal and maximal respiration were increased in MEG-01 p.(Thr20Ile) knock-in clone (solid lines) compared to wt (dashed lines)."

The opposite direction in a megakaryoblast model precludes a universal reduced-respiration mechanism.

Altered Apoptosome Activation measures fidelity: unknown observes: cellular Caspase-3/7 activity is the measured facet of this mechanism.

Limitations: Engineered megakaryoblast line; does not directly establish platelet-output effects in patient marrow.

Readouts

Caspase-3/7 activity

Direction: DECREASED

Show evidence (1 reference)

PMID:39191490 SUPPORT In Vitro

"Surprisingly, the variant abates caspase activation, contrasting with previously known effects of other CYCS variants."

Thr20Ile decreases downstream caspase activation in engineered MEG-01 cells, demonstrating allele/model dependence.

Show evidence (1 reference)

PMID:39191490 SUPPORT In Vitro

"Surprisingly, the variant abates caspase activation, contrasting with previously known effects of other CYCS variants."

Thr20Ile decreases downstream caspase activation in engineered MEG-01 cells, demonstrating allele/model dependence.

Findings

Cytochrome c abundance was reduced in two knock-in clones.

Basal and maximal respiration were increased in the tested clone.

Caspase-3/7 activity was reduced in lysates and intact cells.

CD9 expression increased, while ploidy, adhesion, shape, size, CD41 and CD61 did not change.

Show evidence (4 references)

PMID:39191490 SUPPORT In Vitro

"CRISPR/Cas9-mediated gene editing was used to introduce the new CYCS gene variant into a megakaryoblast cell line (MEG-01)."

The model is an engineered cell line, not direct patient megakaryocytes.

PMID:39191490 SUPPORT In Vitro

"Interestingly, the variant decreases the expression of CYCS while increasing mitochondrial respiration and the expression of CD9 cell surface antigen."

The measured expression and respiratory phenotype differs from older models.

PMID:39191490 SUPPORT In Vitro

"Surprisingly, the variant abates caspase activation, contrasting with previously known effects of other CYCS variants."

The caspase readout is reduced.

+ 1 more reference

G41S/Y48H-complemented mouse lung fibroblasts CELL_LINE

Immortalized mouse lung fibroblasts lacking both somatic and testis cytochrome c were complemented with wild-type or mutant murine cDNA. The G41S/Y48H constructs reduced respiration and enhanced basal and staurosporine-induced apoptosis. These are in-vitro fibroblast models rather than in-vivo mouse thrombocytopenia experiments.

Cell source

Cycs/Cyct double-knockout immortalized mouse lung fibroblasts

Pathograph links

Altered Respiratory Electron Transfer measures fidelity: unknown observes: cellular Cellular oxygen consumption is the measured facet of this mechanism.

Limitations: Murine fibroblasts expressing complemented cytochrome c; lineage, species and expression context differ from human megakaryocytes.

Readouts

Cellular oxygen consumption

Direction: DECREASED

Show evidence (1 reference)

PMID:24326104 SUPPORT In Vitro

"we found reduction of respiratory level and increased apoptotic rate, supporting the pathogenetic role of CYCS in thrombocytopenia."

The abstract summarizes the respiratory and apoptotic changes in the experimental models.

Show evidence (1 reference)

PMID:24326104 SUPPORT In Vitro

"we found reduction of respiratory level and increased apoptotic rate, supporting the pathogenetic role of CYCS in thrombocytopenia."

The abstract summarizes the respiratory and apoptotic changes in the experimental models.

Altered Apoptosome Activation measures fidelity: unknown observes: cellular Basal and staurosporine-induced apoptosis is the measured facet of this mechanism.

Limitations: Murine fibroblasts expressing complemented cytochrome c; lineage, species and expression context differ from human megakaryocytes.

Readouts

Basal and staurosporine-induced apoptosis

Direction: INCREASED

Show evidence (1 reference)

PMID:24326104 SUPPORT In Vitro

"we found reduction of respiratory level and increased apoptotic rate, supporting the pathogenetic role of CYCS in thrombocytopenia."

The abstract summarizes the respiratory and apoptotic changes in the experimental models.

Show evidence (1 reference)

PMID:24326104 SUPPORT In Vitro

"we found reduction of respiratory level and increased apoptotic rate, supporting the pathogenetic role of CYCS in thrombocytopenia."

The abstract summarizes the respiratory and apoptotic changes in the experimental models.

Show evidence (2 references)

url:https://www.iris.unict.it/bitstream/20.500.11769/55250/1/Cytochr%20C%20BiochBiophysActa14.pdf SUPPORT In Vitro

"Mouse lung ﬁbroblasts, where both somatic and testis cytochromec isoforms were deleted (Cycs −/−/Cyct−/− MLF)"

The methods of De Rocco et al. identify the mouse lung fibroblast double-knockout background, which is not specified in the PMID abstract. This URL is the self-archived full text of the same paper, not an independent study.

PMID:24326104 SUPPORT In Vitro

"we found reduction of respiratory level and increased apoptotic rate, supporting the pathogenetic role of CYCS in thrombocytopenia."

The abstract summarizes the respiratory and apoptotic changes in the experimental models.

Cargeeg patient-derived megakaryocytes PRIMARY_CELL_CULTURE

Megakaryocytes derived from peripheral blood of G41S Cargeeg subjects show preserved proplatelet formation in vitro despite abnormal platelet-like structures in extravascular marrow. The culture does not fully reproduce the proposed marrow-dependent release defect.

Cell source

Peripheral blood-derived patient megakaryocytes

Pathograph links

Dysregulated Megakaryocyte Platelet Release fails to recapitulate fidelity: low observes: cellular Proplatelet formation in culture is the measured facet of this mechanism.

Limitations: Peripheral blood-derived culture lacks the marrow environment and does not reproduce premature extravascular platelet-like release.

Readouts

Proplatelet formation in culture

Direction: UNCHANGED

Show evidence (1 reference)

PMID:27861742 SUPPORT In Vitro

"Circulating platelets have a normal marginal microtubule coil, and cultured megakaryocytes derived from peripheral blood cells of Thrombocytopenia Cargeeg subjects form proplatelets normally and release platelets containing a marginal microtubule coil, consistent with effective platelet release..."

Preserved culture output limits a cell-autonomous interpretation of the marrow observation.

Show evidence (1 reference)

PMID:27861742 SUPPORT In Vitro

"Circulating platelets have a normal marginal microtubule coil, and cultured megakaryocytes derived from peripheral blood cells of Thrombocytopenia Cargeeg subjects form proplatelets normally and release platelets containing a marginal microtubule coil, consistent with effective platelet release..."

Preserved culture output limits a cell-autonomous interpretation of the marrow observation.

Show evidence (1 reference)

PMID:27861742 SUPPORT In Vitro

"Circulating platelets have a normal marginal microtubule coil, and cultured megakaryocytes derived from peripheral blood cells of Thrombocytopenia Cargeeg subjects form proplatelets normally and release platelets containing a marginal microtubule coil, consistent with effective platelet release..."

Preserved culture output limits a cell-autonomous interpretation of the marrow observation.

{ }

Source YAML

click to show

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 platelet
  disorder caused by heterozygous CYCS variants, including missense substitutions and an in-frame
  deletion. Most reported families have isolated mild-to-moderate thrombocytopenia with normal platelet
  size and little bleeding, although severe platelet-count reduction and neonatal intracranial hemorrhage
  have been reported. Cytochrome c participates in mitochondrial electron transfer and apoptosome
  activation. Functional effects differ by variant and experimental system: several variants reduce
  respiration or enhance apoptosis, whereas Thr20Ile increases respiration and reduces caspase activation
  in engineered megakaryoblasts. How these effects disrupt platelet production remains incompletely
  resolved.
classifications:
  icimd_category:
  - classification_value: cytochrome_c
    notes: >-
      CYCS encodes the soluble electron carrier cytochrome c rather than a cytochrome c oxidase structural
      subunit or assembly factor. The clinical entity is thrombocytopenia 4 (MONDO:0012775; OMIM:612004),
      distinct from mitochondrial Complex IV deficiency.
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: >-
    The literature describes a rare familial disorder; reported family series do not establish a
    population prevalence. Overlapping reports should not be summed as independent cases.
  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 authors describe rarity from the limited reported families, rather than a measured population
      prevalence.
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: Heterozygous CYCS Sequence Alteration
  role: trigger
  description: >-
    Heterozygous CYCS missense substitutions and the in-frame Lys101 deletion segregate with thrombocytopenia.
    Different alleles need not have the same biochemical effect.
  biological_scale: MOLECULAR
  gene:
    preferred_term: CYCS
    term:
      id: hgnc:19986
      label: CYCS
  mechanism_confidence: ESTABLISHED
  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.
  - reference: PMID:30051457
    reference_title: >-
      A novel CYCS mutation in the α-helix of the CYCS C-terminal domain causes non-syndromic thrombocytopenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This variant (c.301_303del:p.Lys101del) is located in the α-helix of the cytochrome c (CYCS)
      C-terminal domain.
    explanation: >-
      The pathogenic allele spectrum includes an in-frame deletion, not only missense substitutions.
  downstream:
  - target: Altered Cytochrome c Conformation
    description: >-
      Variant-dependent structural perturbations are supported by crystallography, biophysical measurements
      and molecular dynamics.
    causal_link_type: DIRECT
  - target: Reduced Cytochrome c Abundance
    description: >-
      Reduced abundance has been measured for Thr20Ile and for the yeast Lys101del model; it is not
      established for every allele.
    causal_link_type: DIRECT
  - target: Altered Respiratory Electron Transfer
    description: Respiratory effects depend on the allele and cellular system.
    causal_link_type: DIRECT
  - target: Altered Apoptosome Activation
    description: >-
      CYCS variants alter apoptosome-dependent caspase activation in biochemical and cellular assays.
    causal_link_type: DIRECT
- name: Altered Cytochrome c Conformation
  role: central_effector
  description: >-
    Pathogenic cytochrome c substitutions alter local stability and conformational dynamics without
    necessarily disrupting the overall fold. Human G41S, Y48H and A51V show greater conformational
    flexibility associated with enhanced apoptosome activation. G41S does not produce the same mobility
    change in the mouse protein. Mature-protein G41S, Y48H and A51V correspond to initiator-inclusive
    Gly42Ser, Tyr49His and Ala52Val.
  biological_scale: MOLECULAR
  gene:
    preferred_term: CYCS
    term:
      id: hgnc:19986
      label: CYCS
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:33480393
    reference_title: >-
      Altered structure and dynamics of pathogenic cytochrome c variants correlate with increased
      apoptotic activity.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Molecular dynamics simulations of these variants, and two non-naturally occurring variants
      (G41A, G41T), indicate that increased apoptosome activation correlates with the increased overall
      flexibility of cytochrome c, particularly movement of the Ω loops.
    explanation: >-
      Molecular dynamics supports a structure-activity association; induced-fit binding to Apaf-1
      remains an interpretation.
  - reference: PMID:31557440
    reference_title: >-
      Naturally Occurring A51V Variant of Human Cytochrome c Destabilizes the Native State and Enhances
      Peroxidase Activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A 1.82 Å structure of the A51V variant shows only minor changes in tertiary structure relative
      to the wild-type (WT) protein.
    explanation: Crystallography supports a local perturbation rather than gross unfolding.
  - reference: PMID:38472487
    reference_title: >-
      Altered conformational dynamics contribute to species-specific effects of cytochrome c mutations
      on caspase activation.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The G41S mutation increases main chain RSMD in human but not mouse cytochrome c (Fig. 2 B and
      D).
    explanation: >-
      The primary molecular-dynamics comparison demonstrates species-dependent structural effects;
      the source spells the metric RSMD in this sentence.
  downstream:
  - target: Altered Apoptosome Activation
    description: >-
      Greater conformational flexibility correlates with enhanced apoptosome activation for the tested
      mature-protein G41S, Y48H and A51V variants. This proposed relation does not imply a universal
      direction for other alleles.
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - cycs_caspase_platelet_model
  - target: Enhanced Cytochrome c Peroxidase Activity
    description: >-
      Several tested substitutions also increase purified-protein peroxidase activity, but this effect
      does not track native-state flexibility in the same way as apoptosome activation.
    causal_link_type: UNKNOWN
- name: Reduced Cytochrome c Abundance
  role: central_effector
  description: >-
    Thr20Ile reduces cytochrome c abundance in engineered MEG-01 clones and in platelets from one
    affected family member. Lys101del reduces cytochrome c abundance in a yeast model. These observations
    do not establish universal CYCS haploinsufficiency.
  biological_scale: MOLECULAR
  gene:
    preferred_term: CYCS
    term:
      id: hgnc:19986
      label: CYCS
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:39191490
    reference_title: >-
      A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
      study.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Expression of CYCS was decreased in: (A) SC1 and SC3 MEG-01 p.(Thr20Ile) knock-in clones compared
      to wt
    explanation: Two engineered megakaryoblast clones had reduced cytochrome c abundance.
  - reference: PMID:39191490
    reference_title: >-
      A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
      study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      and was also reduced to 43% (p < 0.002) in platelets from thrombocytopenic patient IV-2 compared
      to healthy controls (Figure 3B).
    explanation: >-
      Patient IV-2 had reduced cytochrome c expression relative to healthy controls; this single-patient
      measurement is not a cohort-wide biomarker validation.
  - reference: PMID:30051457
    reference_title: >-
      A novel CYCS mutation in the α-helix of the CYCS C-terminal domain causes non-syndromic thrombocytopenia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using the yeast model system, we clearly demonstrated that this one amino acid deletion (in-frame)
      resulted in significantly reduced cytochrome c protein expression and functional defects in
      the mitochondrial respiratory chain, indicating that the loss of function of cytochrome c underlies
      thrombocytopenia.
    explanation: >-
      The Lys101del yeast system supports reduced abundance and respiratory function, without proving
      a uniform effect across alleles.
- name: Altered Respiratory Electron Transfer
  role: central_effector
  description: >-
    Cytochrome c transfers electrons in the mitochondrial respiratory chain. G41S/Y48H models and
    Lys101del yeast show reduced respiratory function; by contrast, a Thr20Ile knock-in MEG-01 clone
    shows increased basal and maximal respiration. Cellular oxygen consumption measures the integrated
    respiratory phenotype and does not isolate the electron-transfer rate of each mutant protein.
    Respiratory abnormalities have not been established as a sufficient cause of thrombocytopenia.
  biological_scale: CELLULAR
  genes:
  - preferred_term: CYCS
    term:
      id: hgnc:19986
      label: CYCS
  molecular_functions:
  - preferred_term: electron transfer activity
    term:
      id: GO:0009055
      label: electron transfer activity
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: respiratory electron transport chain
    term:
      id: GO:0022904
      label: respiratory electron transport chain
    modifier: ABNORMAL
  mechanism_confidence: PROVISIONAL
  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: >-
      The mammalian-cell component of the 2014 study supports reduced respiration in those models.
      The abstract also summarizes yeast experiments, but this item uses its cell-culture result.
  - reference: PMID:39191490
    reference_title: >-
      A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
      study.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      (A) Basal and maximal respiration were increased in MEG-01 p.(Thr20Ile) knock-in clone (solid
      lines) compared to wt (dashed lines).
    explanation: >-
      The opposite direction in a megakaryoblast model precludes a universal reduced-respiration
      mechanism.
- name: Altered Apoptosome Activation
  role: central_effector
  description: >-
    Cytochrome c activates the apoptosome and downstream caspases. Biochemical studies of mature-protein
    G41S, Y48H and A51V report enhanced apoptosome activation. Thr20Ile instead reduces caspase-3/7
    activity in engineered MEG-01 cells and lysates. This downstream readout does not directly establish
    defective apoptosome assembly for Thr20Ile. The effect on platelet production is still a hypothesis.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CYCS
    term:
      id: hgnc:19986
      label: CYCS
  protein_complexes:
  - preferred_term: apoptosome
    term:
      id: GO:0043293
      label: apoptosome
  biological_processes:
  - preferred_term: intrinsic apoptotic signaling pathway
    term:
      id: GO:0097193
      label: intrinsic apoptotic signaling pathway
    modifier: ABNORMAL
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:33480393
    reference_title: >-
      Altered structure and dynamics of pathogenic cytochrome c variants correlate with increased
      apoptotic activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Three pathogenic variants (G41S, Y48H, A51V) cause an increase in apoptosome activation and
      peroxidase activity.
    explanation: >-
      Purified-protein/cell assays support increased apoptosome activity for the three specified
      mature-protein variants.
  - reference: PMID:39191490
    reference_title: >-
      A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
      study.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Surprisingly, the variant abates caspase activation, contrasting with previously known effects
      of other CYCS variants.
    explanation: >-
      Thr20Ile decreases downstream caspase activation in engineered MEG-01 cells, demonstrating
      allele/model dependence.
  downstream:
  - target: Dysregulated Megakaryocyte Platelet Release
    description: >-
      Altered caspase regulation is proposed to disturb platelet biogenesis, but neither the intermediate
      steps nor a universal direction of effect have been established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - cycs_caspase_platelet_model
    evidence:
    - reference: PMID:39191490
      reference_title: >-
        A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
        study.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Some reports indicate that caspases may be involved in thrombopoiesis; thus, the observed
        dysregulation of caspase activity might contribute to thrombocytopenia.
      explanation: >-
        The authors explicitly present the link as a possible contribution, not a demonstrated pathway.
- name: Enhanced Cytochrome c Peroxidase Activity
  role: central_effector
  description: >-
    Purified mature-protein G41S, Y48H and A51V have enhanced peroxidase activity. The A51V study
    used guaiacol oxidation with hydrogen peroxide; this does not directly demonstrate cardiolipin
    oxidation in patient platelets. Enhanced peroxidase activity is a biochemical property of these
    variants, not an established cause of thrombocytopenia.
  biological_scale: MOLECULAR
  gene:
    preferred_term: CYCS
    term:
      id: hgnc:19986
      label: CYCS
  molecular_functions:
  - preferred_term: peroxidase activity
    term:
      id: GO:0004601
      label: peroxidase activity
    modifier: INCREASED
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:31557440
    reference_title: >-
      Naturally Occurring A51V Variant of Human Cytochrome c Destabilizes the Native State and Enhances
      Peroxidase Activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consistent with the greater accessibility of non-native conformers for the A51V variant, the
      kcat values for its peroxidase activity increase by 6- to 15-fold in the pH range of 5-8 versus
      those of the WT protein.
    explanation: >-
      Purified A51V protein has enhanced peroxidase activity under the specified assay conditions.
  - reference: PMID:33480393
    reference_title: >-
      Altered structure and dynamics of pathogenic cytochrome c variants correlate with increased
      apoptotic activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In contrast, peroxidase activity did not significantly correlate with protein dynamics.
    explanation: This activity should not be conflated with the proposed flexibility-apoptosome relation.
  - reference: PMID:31557440
    reference_title: >-
      Naturally Occurring A51V Variant of Human Cytochrome c Destabilizes the Native State and Enhances
      Peroxidase Activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The formation of tetraguaiacol from guaiacol and H2O2 in the presence of Cytc was monitored
      at 470 nm.
    explanation: >-
      The experimental method used guaiacol/H2O2, limiting inference about cardiolipin oxidation
      in patient platelets.
- name: Dysregulated Megakaryocyte Platelet Release
  role: central_effector
  description: >-
    In the G41S Cargeeg family, extravascular marrow contains platelet-like structures lacking the
    normal marginal microtubule coil. Premature release outside marrow vessels is proposed to reduce
    effective circulating platelet output. Patient-derived megakaryocytes can nevertheless form proplatelets
    normally in culture, implicating marrow context. These observations are not a proven universal
    mechanism for every CYCS allele.
  biological_scale: CELLULAR
  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
    modifier: ABNORMAL
  mechanism_confidence: PROVISIONAL
  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: >-
      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: >-
      Marrow observations support abnormal extravascular platelet-like release in the Cargeeg family.
  - 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: >-
      The source proposes this mechanism specifically for the studied family, while the intracellular
      link remains unresolved.
  downstream:
  - target: Thrombocytopenia
    description: >-
      Premature extravascular release is proposed to reduce the number of mature platelets entering
      circulation in the Cargeeg family.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - cycs_marrow_release_model
phenotypes:
- name: Thrombocytopenia
  category: Hematologic
  description: >-
    Persistent isolated thrombocytopenia is usually mild to moderate, but severe reduction also occurs.
    Platelet size and morphology are generally preserved. Bleeding tendency varies and is often mild.
  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 2024 six-family series supports the typical mild-to-moderate, largely nonsyndromic phenotype;
      this is not a claim that every CYCS family has normal platelet function.
  - 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.
  - reference: PMID:39191490
    reference_title: >-
      A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
      study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Despite severe thrombocytopenia, bleeding episodes have rarely been reported.
    explanation: >-
      The Thr20Ile daughter demonstrates that severe thrombocytopenia can coexist with limited bleeding.
  sequelae:
  - target: Bruising susceptibility
    description: >-
      Reduced platelet number can contribute to this bleeding manifestation; severity is not determined
      by platelet count alone.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Petechiae
    description: >-
      Reduced platelet number can contribute to this bleeding manifestation; severity is not determined
      by platelet count alone.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Epistaxis
    description: >-
      Reduced platelet number can contribute to this bleeding manifestation; severity is not determined
      by platelet count alone.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intracranial hemorrhage
    description: >-
      Reduced platelet number can contribute to this bleeding manifestation; severity is not determined
      by platelet count alone.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Bruising susceptibility
  category: Hematologic
  description: Trauma-related hematomas and mild spontaneous skin bleeding occur in some families.
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:39191490
    reference_title: >-
      A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
      study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He suffered from larger haematomas after injuries.
    explanation: The Thr20Ile proband had injury-related hematomas.
- name: Petechiae
  category: Hematologic
  description: Petechiae have been reported in childhood and in a newborn carrying Arg92Gly.
  phenotype_term:
    preferred_term: Petechiae
    term:
      id: HP:0000967
      label: Petechiae
  evidence:
  - reference: PMID:41676885
    reference_title: >-
      Autosomal dominant thrombocytopenia associated with the CYCS p.Arg92Gly variant: clinical characterization
      of an additional family and observation of antiplatelet tolerance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One newborn presented with petechiae and grade 1 intracranial hemorrhage but recovered fully.
    explanation: The Arg92Gly family includes a newborn with petechiae.
- name: Epistaxis
  category: Hematologic
  description: >-
    Epistaxis was reported in an affected member of the His27Tyr family; the full clinical report
    qualifies the abstract claim of no bleeding abnormality.
  phenotype_term:
    preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
  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: >-
      Most studied patients had mild bleeding of skin mucosa, except IV-5 with epistaxis, and the
      proband showed the spontaneous skin bleeding (Supplemental Table 1).
    explanation: >-
      The full text documents mucocutaneous bleeding and epistaxis despite the broader abstract wording.
- name: Intracranial hemorrhage
  category: Hematologic
  description: >-
    Neonatal intracranial hemorrhage is a reported complication, rather than the usual presentation.
    The Arg92Gly newborn had a grade 1 hemorrhage and recovered.
  phenotype_term:
    preferred_term: Intracranial hemorrhage
    term:
      id: HP:0002170
      label: Intracranial hemorrhage
  evidence:
  - reference: PMID:41676885
    reference_title: >-
      Autosomal dominant thrombocytopenia associated with the CYCS p.Arg92Gly variant: clinical characterization
      of an additional family and observation of antiplatelet tolerance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One newborn presented with petechiae and grade 1 intracranial hemorrhage but recovered fully.
    explanation: >-
      Direct clinical observation supports this complication without estimating its population frequency.
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.Gly42Ser (mature protein G41S)
    description: >-
      The original New Zealand family allele; mature-protein G41S is initiator-inclusive Gly42Ser.
      Enhanced apoptotic activity was measured 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.
  - name: CYCS p.Thr20Ile
    description: >-
      A likely pathogenic c.59C>T allele with reduced CYCS abundance, increased respiration and reduced
      caspase activation in MEG-01 models.
    gene:
      preferred_term: CYCS
      term:
        id: hgnc:19986
        label: CYCS
    evidence:
    - reference: PMID:39191490
      reference_title: >-
        A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
        study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here, we report a functional analysis of the novel CYCS variant NP_061820.1:p.(Thr20Ile)
        (NM_018947.6:c.59C>T), which segregates with thrombocytopenia in three generations of a Czech
        family.
      explanation: The clinical report identifies this allele in familial CYCS-related thrombocytopenia.
  - name: CYCS p.Lys101del
    description: >-
      An in-frame deletion associated with reduced protein abundance and respiratory function in
      yeast. Hemophilia A in the reported family is a separate disorder.
    gene:
      preferred_term: CYCS
      term:
        id: hgnc:19986
        label: CYCS
    evidence:
    - reference: PMID:30051457
      reference_title: >-
        A novel CYCS mutation in the α-helix of the CYCS C-terminal domain causes non-syndromic thrombocytopenia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This variant (c.301_303del:p.Lys101del) is located in the α-helix of the cytochrome c (CYCS)
        C-terminal domain.
      explanation: The clinical report identifies this allele in familial CYCS-related thrombocytopenia.
  - name: CYCS p.Asn71Thr
    description: Reported with familial thrombocytopenia in a Japanese series.
    gene:
      preferred_term: CYCS
      term:
        id: hgnc:19986
        label: CYCS
    evidence:
    - reference: PMID:41455048
      reference_title: >-
        CYCS-related thrombocytopenia in three Japanese families with a novel variant in one family.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Two were previously reported: c.274A > G,p.(Arg92Gly) and c.309C > T,p.(Thr103Ile); one was
        novel: c.212A > C,p.(Asn71Thr).
      explanation: The clinical report identifies this allele in familial CYCS-related thrombocytopenia.
  - name: CYCS p.Arg92Gly
    description: >-
      Segregates in an additional multigenerational family. Structural modeling suggests local instability,
      but it is not a functional assay.
    gene:
      preferred_term: CYCS
      term:
        id: hgnc:19986
        label: CYCS
    evidence:
    - reference: PMID:41676885
      reference_title: >-
        Autosomal dominant thrombocytopenia associated with the CYCS p.Arg92Gly variant: clinical
        characterization of an additional family and observation of antiplatelet tolerance.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Whole-exome sequencing identified p.Arg92Gly as the only variant segregating with disease;
        Sanger sequencing confirmed heterozygosity in all affected members.
      explanation: The clinical report identifies this allele in familial CYCS-related thrombocytopenia.
  - name: CYCS p.Thr103Ile
    description: A previously reported allele also identified in the Japanese family series.
    gene:
      preferred_term: CYCS
      term:
        id: hgnc:19986
        label: CYCS
    evidence:
    - reference: PMID:41455048
      reference_title: >-
        CYCS-related thrombocytopenia in three Japanese families with a novel variant in one family.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Two were previously reported: c.274A > G,p.(Arg92Gly) and c.309C > T,p.(Thr103Ile); one was
        novel: c.212A > C,p.(Asn71Thr).
      explanation: The clinical report identifies this allele in familial CYCS-related thrombocytopenia.
  - name: CYCS p.Tyr49His (mature protein Y48H)
    gene:
      preferred_term: CYCS
      term:
        id: hgnc:19986
        label: CYCS
    description: >-
      Reported in the Italian family series. The strength and type of functional evidence differ
      among alleles.
    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: >-
        In this study, we describe six Italian families with five different heterozygous missense
        CYCS variants: p.Gly42Ser and p.Tyr49His previously associated with THC4, and three novel
        variants (p.Ala52Thr, p.Arg92Gly, and p.Leu99Val), which have been classified as pathogenic
        by bioinformatics and segregation analyses.
      explanation: >-
        The series extends the allele spectrum; biochemical support is not equivalent for every substitution.
  - name: CYCS p.Ala52Thr
    gene:
      preferred_term: CYCS
      term:
        id: hgnc:19986
        label: CYCS
    description: >-
      Reported in the Italian family series. The strength and type of functional evidence differ
      among alleles.
    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: >-
        In this study, we describe six Italian families with five different heterozygous missense
        CYCS variants: p.Gly42Ser and p.Tyr49His previously associated with THC4, and three novel
        variants (p.Ala52Thr, p.Arg92Gly, and p.Leu99Val), which have been classified as pathogenic
        by bioinformatics and segregation analyses.
      explanation: >-
        The series extends the allele spectrum; biochemical support is not equivalent for every substitution.
  - name: CYCS p.Leu99Val
    gene:
      preferred_term: CYCS
      term:
        id: hgnc:19986
        label: CYCS
    description: >-
      Reported in the Italian family series. The strength and type of functional evidence differ
      among alleles.
    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: >-
        In this study, we describe six Italian families with five different heterozygous missense
        CYCS variants: p.Gly42Ser and p.Tyr49His previously associated with THC4, and three novel
        variants (p.Ala52Thr, p.Arg92Gly, and p.Leu99Val), which have been classified as pathogenic
        by bioinformatics and segregation analyses.
      explanation: >-
        The series extends the allele spectrum; biochemical support is not equivalent for every substitution.
  - name: CYCS p.Ala52Val (mature protein A51V)
    gene:
      preferred_term: CYCS
      term:
        id: hgnc:19986
        label: CYCS
    description: >-
      A thrombocytopenia-associated substitution studied in purified-protein structure, stability,
      apoptosome and peroxidase assays.
    evidence:
    - reference: PMID:33480393
      reference_title: >-
        Altered structure and dynamics of pathogenic cytochrome c variants correlate with increased
        apoptotic activity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Three pathogenic variants (G41S, Y48H, A51V) cause an increase in apoptosome activation and
        peroxidase activity.
      explanation: >-
        The mature-protein A51V allele is among the three pathogenic variants tested biochemically.
  features: >-
    Reported alleles include missense substitutions and the in-frame Lys101del. Segregation and functional
    support vary among alleles; neither complete penetrance nor a single gain- or loss-of-function
    mechanism has been established across all families. Mature-protein G41S/Y48H/A51V in biochemical
    papers correspond to initiator-inclusive Gly42Ser/Tyr49His/Ala52Val. Additional reported substitutions
    include Tyr49His (mature Y48H), Ala52Val (mature A51V), Ala52Thr and Leu99Val.
  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: >-
      In this study, we describe six Italian families with five different heterozygous missense CYCS
      variants: p.Gly42Ser and p.Tyr49His previously associated with THC4, and three novel variants
      (p.Ala52Thr, p.Arg92Gly, and p.Leu99Val), which have been classified as pathogenic by bioinformatics
      and segregation analyses.
    explanation: >-
      The series extends the allele spectrum; biochemical support is not equivalent for every substitution.
  - reference: PMID:33480393
    reference_title: >-
      Altered structure and dynamics of pathogenic cytochrome c variants correlate with increased
      apoptotic activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Three pathogenic variants (G41S, Y48H, A51V) cause an increase in apoptosome activation and
      peroxidase activity.
    explanation: >-
      The mature-protein A51V allele is among the three pathogenic variants tested biochemically.
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: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:27479822
    reference_title: >-
      Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary
      qualitative function defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All results following platelet function testing and WES were reported back to the referring
      hematology consultants to aid in genetic counselling and disease management.
    explanation: >-
      A broader inherited-thrombocytopenia cohort supports using molecular findings for counseling;
      it is not a CYCS-specific treatment trial.
- name: Clinical observation for limited bleeding
  description: >-
    Published Thr20Ile cases were followed without thrombocytopenia-directed medication when bleeding
    was limited. This is case-based management evidence, not a universal recommendation or a validated
    surveillance schedule.
  evidence:
  - reference: PMID:39191490
    reference_title: >-
      A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
      study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was no pathology in white blood count, and no other bleeding episodes. Thus, the proband
      was without medication.
    explanation: The proband was observed without medication despite persistent thrombocytopenia.
  - reference: PMID:39191490
    reference_title: >-
      A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
      study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She was followed from 2012 to 2021 without requiring any medication.
    explanation: >-
      The affected daughter initially required no medication; later treatment addressed concurrent
      autoimmune disease.
notes: >-
  CYCS encodes cytochrome c, a soluble respiratory electron carrier with apoptotic functions; THC4
  should not be conflated with cytochrome c oxidase assembly deficiency. Clinical reports generally
  describe a nonsyndromic platelet disorder. Concurrent hemophilia, autoimmune disease or infection
  in individual families does not establish these as CYCS manifestations. Tolerance of aspirin and
  clopidogrel after stroke in one reported carrier is not evidence that antiplatelet drugs treat
  THC4 or are uniformly safe in it.
diagnosis:
- name: Blood count and platelet morphology
  description: >-
    Persistent isolated thrombocytopenia with generally normal platelet size and morphology, especially
    with affected relatives, supports an inherited platelet disorder. Normal morphology does not
    exclude CYCS-related disease.
  evidence:
  - reference: PMID:41455048
    reference_title: >-
      CYCS-related thrombocytopenia in three Japanese families with a novel variant in one family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients showed no or mild bleeding tendency, with preserved platelet size and morphology,
      and without other abnormalities in blood cell lineages.
    explanation: The Japanese series describes the characteristic hematologic findings.
- name: CYCS sequencing and familial segregation
  description: >-
    A congenital thrombocytopenia panel or exome sequencing can identify a CYCS variant; segregation
    and variant-level evidence inform interpretation. Familial disease can be misdiagnosed as immune
    thrombocytopenia.
  evidence:
  - reference: PMID:41455048
    reference_title: >-
      CYCS-related thrombocytopenia in three Japanese families with a novel variant in one family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genetic testing should be considered in unexplained familial thrombocytopenia.
    explanation: The clinical series supports molecular testing in this setting.
  - reference: PMID:39191490
    reference_title: >-
      A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
      study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His condition was initially misdiagnosed as idiopathic thrombocytopenic purpura.
    explanation: >-
      The full case description documents initial misclassification before recognition of familial
      thrombocytopenia.
experimental_models:
- name: Thr20Ile knock-in MEG-01 megakaryoblasts
  experimental_model_type: CELL_LINE
  description: >-
    CRISPR/Cas9-engineered MEG-01 clones carrying Thr20Ile model reduced CYCS abundance, increased
    respiration and decreased caspase activation. These assays did not directly establish a proplatelet-output
    defect.
  cell_source: Human MEG-01 megakaryoblastic cell line
  modeled_mechanisms:
  - target: Reduced Cytochrome c Abundance
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    description: Cytochrome c abundance is the measured facet of this mechanism.
    limitations: >-
      Engineered megakaryoblast line; does not directly establish platelet-output effects in patient
      marrow.
    evidence:
    - reference: PMID:39191490
      reference_title: >-
        A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
        study.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Expression of CYCS was decreased in: (A) SC1 and SC3 MEG-01 p.(Thr20Ile) knock-in clones
        compared to wt
      explanation: Two engineered megakaryoblast clones had reduced cytochrome c abundance.
    readouts:
    - name: Cytochrome c abundance
      direction: DECREASED
      evidence:
      - reference: PMID:39191490
        reference_title: >-
          A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
          study.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Expression of CYCS was decreased in: (A) SC1 and SC3 MEG-01 p.(Thr20Ile) knock-in clones
          compared to wt
        explanation: Two engineered megakaryoblast clones had reduced cytochrome c abundance.
      target: Reduced Cytochrome c Abundance
  - target: Altered Respiratory Electron Transfer
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    description: Basal and maximal oxygen consumption is the measured facet of this mechanism.
    limitations: >-
      Engineered megakaryoblast line; does not directly establish platelet-output effects in patient
      marrow.
    evidence:
    - reference: PMID:39191490
      reference_title: >-
        A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
        study.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        (A) Basal and maximal respiration were increased in MEG-01 p.(Thr20Ile) knock-in clone (solid
        lines) compared to wt (dashed lines).
      explanation: >-
        The opposite direction in a megakaryoblast model precludes a universal reduced-respiration
        mechanism.
    readouts:
    - name: Basal and maximal oxygen consumption
      direction: INCREASED
      evidence:
      - reference: PMID:39191490
        reference_title: >-
          A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
          study.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          (A) Basal and maximal respiration were increased in MEG-01 p.(Thr20Ile) knock-in clone
          (solid lines) compared to wt (dashed lines).
        explanation: >-
          The opposite direction in a megakaryoblast model precludes a universal reduced-respiration
          mechanism.
      target: Altered Respiratory Electron Transfer
  - target: Altered Apoptosome Activation
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    description: Caspase-3/7 activity is the measured facet of this mechanism.
    limitations: >-
      Engineered megakaryoblast line; does not directly establish platelet-output effects in patient
      marrow.
    evidence:
    - reference: PMID:39191490
      reference_title: >-
        A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
        study.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Surprisingly, the variant abates caspase activation, contrasting with previously known effects
        of other CYCS variants.
      explanation: >-
        Thr20Ile decreases downstream caspase activation in engineered MEG-01 cells, demonstrating
        allele/model dependence.
    readouts:
    - name: Caspase-3/7 activity
      direction: DECREASED
      evidence:
      - reference: PMID:39191490
        reference_title: >-
          A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
          study.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Surprisingly, the variant abates caspase activation, contrasting with previously known
          effects of other CYCS variants.
        explanation: >-
          Thr20Ile decreases downstream caspase activation in engineered MEG-01 cells, demonstrating
          allele/model dependence.
      target: Altered Apoptosome Activation
  findings:
  - statement: Cytochrome c abundance was reduced in two knock-in clones.
  - statement: Basal and maximal respiration were increased in the tested clone.
  - statement: Caspase-3/7 activity was reduced in lysates and intact cells.
  - statement: >-
      CD9 expression increased, while ploidy, adhesion, shape, size, CD41 and CD61 did not change.
  evidence:
  - reference: PMID:39191490
    reference_title: >-
      A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
      study.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      CRISPR/Cas9-mediated gene editing was used to introduce the new CYCS gene variant into a megakaryoblast
      cell line (MEG-01).
    explanation: The model is an engineered cell line, not direct patient megakaryocytes.
  - reference: PMID:39191490
    reference_title: >-
      A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
      study.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Interestingly, the variant decreases the expression of CYCS while increasing mitochondrial
      respiration and the expression of CD9 cell surface antigen.
    explanation: The measured expression and respiratory phenotype differs from older models.
  - reference: PMID:39191490
    reference_title: >-
      A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
      study.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Surprisingly, the variant abates caspase activation, contrasting with previously known effects
      of other CYCS variants.
    explanation: The caspase readout is reduced.
  - reference: PMID:39191490
    reference_title: >-
      A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
      study.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The effects of the variant p.(Thr20Ile) on markers of blood cell differentiation were studied
      in MEG‐01 p.(Thr20Ile) knock‐in clones. The variant did not affect: (1) adhesion, shape and
      size assessed by regular light microscope inspection; (2) ploidy and CD41 and CD61 cell surface
      antigen expression assessed by flow cytometry (Figures S2 and S3). Out of the analysed surface
      markers, only CD9 expression was increased by 40% in SC1 (p = 0.003) and by 31% in SC3 (p =
      0.022) MEG‐01 p.(Thr20Ile) knock‐in clones compared to wt (Figure S3). The platelet immunophenotype
      of patient IV‐2 was normal (data not shown).
    explanation: >-
      The full results distinguish increased CD9 from unchanged differentiation and morphology readouts;
      the patient platelet immunophenotype was normal.
- name: G41S/Y48H-complemented mouse lung fibroblasts
  experimental_model_type: CELL_LINE
  description: >-
    Immortalized mouse lung fibroblasts lacking both somatic and testis cytochrome c were complemented
    with wild-type or mutant murine cDNA. The G41S/Y48H constructs reduced respiration and enhanced
    basal and staurosporine-induced apoptosis. These are in-vitro fibroblast models rather than in-vivo
    mouse thrombocytopenia experiments.
  cell_source: Cycs/Cyct double-knockout immortalized mouse lung fibroblasts
  modeled_mechanisms:
  - target: Altered Respiratory Electron Transfer
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    description: Cellular oxygen consumption is the measured facet of this mechanism.
    limitations: >-
      Murine fibroblasts expressing complemented cytochrome c; lineage, species and expression context
      differ from human megakaryocytes.
    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: The abstract summarizes the respiratory and apoptotic changes in the experimental models.
    readouts:
    - name: Cellular oxygen consumption
      direction: DECREASED
      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: The abstract summarizes the respiratory and apoptotic changes in the experimental models.
      target: Altered Respiratory Electron Transfer
  - target: Altered Apoptosome Activation
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    description: Basal and staurosporine-induced apoptosis is the measured facet of this mechanism.
    limitations: >-
      Murine fibroblasts expressing complemented cytochrome c; lineage, species and expression context
      differ from human megakaryocytes.
    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: The abstract summarizes the respiratory and apoptotic changes in the experimental models.
    readouts:
    - name: Basal and staurosporine-induced apoptosis
      direction: 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: The abstract summarizes the respiratory and apoptotic changes in the experimental models.
      target: Altered Apoptosome Activation
  evidence:
  - reference: url:https://www.iris.unict.it/bitstream/20.500.11769/55250/1/Cytochr%20C%20BiochBiophysActa14.pdf
    reference_title: https://www.iris.unict.it/bitstream/20.500.11769/55250/1/Cytochr%20C%20BiochBiophysActa14.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mouse lung ﬁbroblasts, where both somatic and testis cytochromec isoforms were deleted (Cycs
      −/−/Cyct−/− MLF)
    explanation: >-
      The methods of De Rocco et al. identify the mouse lung fibroblast double-knockout background,
      which is not specified in the PMID abstract. This URL is the self-archived full text of the
      same paper, not an independent study.
  - 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: The abstract summarizes the respiratory and apoptotic changes in the experimental models.
- name: Cargeeg patient-derived megakaryocytes
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Megakaryocytes derived from peripheral blood of G41S Cargeeg subjects show preserved proplatelet
    formation in vitro despite abnormal platelet-like structures in extravascular marrow. The culture
    does not fully reproduce the proposed marrow-dependent release defect.
  cell_source: Peripheral blood-derived patient megakaryocytes
  cell_types:
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  modeled_mechanisms:
  - target: Dysregulated Megakaryocyte Platelet Release
    relationship: FAILS_TO_RECAPITULATE
    model_scale: CELLULAR
    fidelity: LOW
    description: Proplatelet formation in culture is the measured facet of this mechanism.
    limitations: >-
      Peripheral blood-derived culture lacks the marrow environment and does not reproduce premature
      extravascular platelet-like release.
    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: IN_VITRO
      snippet: >-
        Circulating platelets have a normal marginal microtubule coil, and cultured megakaryocytes
        derived from peripheral blood cells of Thrombocytopenia Cargeeg subjects form proplatelets
        normally and release platelets containing a marginal microtubule coil, consistent with effective
        platelet release via the proplatelet mechanism.
      explanation: >-
        Preserved culture output limits a cell-autonomous interpretation of the marrow observation.
    readouts:
    - name: Proplatelet formation in culture
      direction: UNCHANGED
      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: IN_VITRO
        snippet: >-
          Circulating platelets have a normal marginal microtubule coil, and cultured megakaryocytes
          derived from peripheral blood cells of Thrombocytopenia Cargeeg subjects form proplatelets
          normally and release platelets containing a marginal microtubule coil, consistent with
          effective platelet release via the proplatelet mechanism.
        explanation: >-
          Preserved culture output limits a cell-autonomous interpretation of the marrow observation.
      target: Dysregulated Megakaryocyte Platelet Release
  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: IN_VITRO
    snippet: >-
      Circulating platelets have a normal marginal microtubule coil, and cultured megakaryocytes
      derived from peripheral blood cells of Thrombocytopenia Cargeeg subjects form proplatelets
      normally and release platelets containing a marginal microtubule coil, consistent with effective
      platelet release via the proplatelet mechanism.
    explanation: >-
      Preserved culture output limits a cell-autonomous interpretation of the marrow observation.
clinical_trials:
- name: NCT07026578
  phase: NOT_APPLICABLE
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Observational mechanistic study of cytochrome c abundance, apoptosis and platelet biogenesis
    in THC4. The registry describes preliminary patient-cell observations, not therapeutic efficacy
    results.
  notes: >-
    The registry status was last verified in April 2025 and last updated in June 2025. The estimated
    June 2026 completion date is not evidence of actual completion. No results are posted in the
    cached registry record.
  evidence:
  - reference: clinicaltrials:NCT07026578
    reference_title: >-
      Unravelling the Role of Apoptosis in Platelets Biogenesis Through the Study of the CYCS Mut-associated
      Thrombocytopenia THC4
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Since thrombocytopenia is the only phenotypic manifestation of CYCS mutations, the investigators
      believe that THC4 represents a unique model for deciphering the role of Cytc and apoptosis
      in megakaryopoiesis and platelet biogenesis.
    explanation: The registry specifies a mechanistic observational rationale, not a treatment study.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07026578
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT07026578
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "statusModule": {"statusVerifiedDate": "2025-04", "overallStatus": "ACTIVE_NOT_RECRUITING",
      "expandedAccessInfo": {"hasExpandedAccess": false}, "startDateStruct": {"date": "2024-06-18",
      "type": "ACTUAL"}, "primaryCompletionDateStruct": {"date": "2026-06-30", "type": "ESTIMATED"},
      "completionDateStruct": {"date": "2026-06-30", "type": "ESTIMATED"}, "studyFirstSubmitDate":
      "2025-03-13", "studyFirstSubmitQcDate": "2025-06-10", "studyFirstPostDateStruct": {"date":
      "2025-06-18", "type": "ACTUAL"}, "lastUpdateSubmitDate": "2025-06-10", "lastUpdatePostDateStruct":
      {"date": "2025-06-18", "type": "ACTUAL"}}
    explanation: >-
      Registry metadata verifies the recorded recruitment status, update date and estimated completion;
      it does not establish that completion occurred.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07026578
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT07026578
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "studyType": "OBSERVATIONAL", "patientRegistry": false, "designInfo": {"observationalModel":
      "CASE_CONTROL", "timePerspective": "PROSPECTIVE"}, "bioSpec": {"retention": "SAMPLES_WITH_DNA",
      "description": "25 mL of peripheral whole blood anticoagulated with ACD for platelet isolation
      and for separation of hematopoietic progenitors to differentiate megakaryocytes"}
    explanation: >-
      The official design metadata identifies an observational study, so a therapeutic trial phase
      is not applicable.
mechanistic_hypotheses:
- hypothesis_group_id: cycs_caspase_platelet_model
  hypothesis_label: Variant-dependent caspase dysregulation impairs platelet biogenesis
  status: EMERGING
  description: >-
    Altered apoptosome/caspase regulation may disrupt platelet production. Both increased and decreased
    readouts have been observed; the causal bridge remains unresolved.
- hypothesis_group_id: cycs_marrow_release_model
  hypothesis_label: Premature extravascular platelet release
  status: EMERGING
  description: >-
    Cargeeg-family marrow observations support premature release outside vessels as a cause of low
    circulating platelets; applicability to other alleles is uncertain.
discussions:
- discussion_id: cycs_variant_and_model_dependence
  kind: KNOWLEDGE_GAP
  prompt: How do opposite caspase and respiratory responses converge on thrombocytopenia?
  attaches_to:
  - pathophysiology#Altered Apoptosome Activation
  - pathophysiology#Altered Respiratory Electron Transfer
  - pathophysiology#Enhanced Cytochrome c Peroxidase Activity
  rationale: >-
    Thr20Ile megakaryoblasts differ from the older G41S/Y48H cell models. Variant identity, species,
    cell lineage and stimulation conditions may all matter. Purified-protein peroxidase enhancement
    is not sufficient evidence of a platelet-production mechanism. No universal respiratory-loss
    or apoptosis-gain pathway is established.
  evidence:
  - reference: PMID:33480393
    reference_title: >-
      Altered structure and dynamics of pathogenic cytochrome c variants correlate with increased
      apoptotic activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The role of cytochrome c in platelet formation, and the molecular mechanism underlying the
      association of cytochrome c mutations with thrombocytopenia remains unknown, although a gain-of-function
      is most likely.
    explanation: The earlier mechanistic study explicitly identifies the unresolved disease link.
  - reference: PMID:39191490
    reference_title: >-
      A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
      study.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Surprisingly, the variant abates caspase activation, contrasting with previously known effects
      of other CYCS variants.
    explanation: The subsequent Thr20Ile data challenge a universal gain-of-apoptosis account.
  - reference: PMID:31557440
    reference_title: >-
      Naturally Occurring A51V Variant of Human Cytochrome c Destabilizes the Native State and Enhances
      Peroxidase Activity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Recent in vivo studies indicate that the enhanced peroxidase activity of the THC4-linked Cytc
      variants is unlikely the cause of THC4.
    explanation: >-
      The introduction summarizes prior in-vivo studies; the current paper did not perform a new
      animal experiment. BACKGROUND distinguishes this evidence from its own biochemical results.
    quote_role: BACKGROUND
- discussion_id: cycs_proplatelet_context
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why is proplatelet formation preserved in one patient-derived culture study but defective in
    preliminary registry observations?
  attaches_to:
  - pathophysiology#Dysregulated Megakaryocyte Platelet Release
  rationale: >-
    The Cargeeg study found normal proplatelet formation in culture. NCT07026578 describes preliminary
    progenitor cultures with preserved megakaryocyte maturation but defective proplatelets, and reduced
    cytochrome c with resistance to induced apoptosis in patient platelets. These registry observations
    are not posted trial results or a peer-reviewed replication. Variant and culture differences
    remain unresolved.
  evidence:
  - reference: clinicaltrials:NCT07026578
    reference_title: >-
      Unravelling the Role of Apoptosis in Platelets Biogenesis Through the Study of the CYCS Mut-associated
      Thrombocytopenia THC4
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Hematopoietic progenitors from 3 patients were differentiated in megakaryocytes. Maturation
      and differentiation were comparable between THC4 and healthy controls. Instead, their capability
      to form proplatelets was profoundly defective.
    explanation: >-
      Preliminary sponsor observations differ from the Cargeeg cultures; the registry does not establish
      why.
  - reference: clinicaltrials:NCT07026578
    reference_title: >-
      Unravelling the Role of Apoptosis in Platelets Biogenesis Through the Study of the CYCS Mut-associated
      Thrombocytopenia THC4
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Surprisingly, the expression of cytC was found reduced in platelets of all analyzed patients.
      Platelets showed no signs of early death. Instead, when stimulated with ABT-737, they showed
      inability to undergo apoptosis, suggesting that CYCS mutations confer resistance to apoptosis.
    explanation: Preliminary ex-vivo platelet data, not a therapeutic ABT-737 trial.
references:
- reference: PMID:18345000
  title: >-
    A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia.
- reference: PMID:24326104
  title: >-
    Mutations of cytochrome c identified in patients with thrombocytopenia THC4 affect both apoptosis
    and cellular bioenergetics.
- reference: PMID:27479822
  title: >-
    Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary
    qualitative function defects.
- reference: PMID:27861742
  title: >-
    Megakaryocytes from CYCS mutation-associated thrombocytopenia release platelets by both proplatelet-dependent
    and -independent processes.
- reference: PMID:30051457
  title: >-
    A novel CYCS mutation in the α-helix of the CYCS C-terminal domain causes non-syndromic thrombocytopenia.
- reference: PMID:31557440
  title: >-
    Naturally Occurring A51V Variant of Human Cytochrome c Destabilizes the Native State and Enhances
    Peroxidase Activity.
- reference: PMID:33480393
  title: >-
    Altered structure and dynamics of pathogenic cytochrome c variants correlate with increased apoptotic
    activity.
- reference: PMID:35126455
  title: >-
    A Novel Heterozygous Pathogenic Variation in CYCS Gene Cause Autosomal Dominant Non-Syndromic
    Thrombocytopenia 4 in a Large Chinese Family.
- reference: PMID:38472487
  title: >-
    Altered conformational dynamics contribute to species-specific effects of cytochrome c mutations
    on caspase activation.
- reference: PMID:38815995
  title: 'Thrombocytopenia 4 (THC4): Six novel families with mutations of the cytochrome c gene.'
- reference: PMID:39191490
  title: >-
    A novel thrombocytopenia-4-causing CYCS gene variant decreases caspase activity: Three-generation
    study.
- reference: PMID:41455048
  title: >-
    CYCS-related thrombocytopenia in three Japanese families with a novel variant in one family.
- reference: PMID:41676885
  title: >-
    Autosomal dominant thrombocytopenia associated with the CYCS p.Arg92Gly variant: clinical characterization
    of an additional family and observation of antiplatelet tolerance.
- reference: clinicaltrials:NCT07026578
  title: >-
    Unravelling the Role of Apoptosis in Platelets Biogenesis Through the Study of the CYCS Mut-associated
    Thrombocytopenia THC4
- reference: url:https://www.iris.unict.it/bitstream/20.500.11769/55250/1/Cytochr%20C%20BiochBiophysActa14.pdf
  title: https://www.iris.unict.it/bitstream/20.500.11769/55250/1/Cytochr%20C%20BiochBiophysActa14.pdf
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07026578
  title: https://clinicaltrials.gov/api/v2/studies/NCT07026578

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References & Deep Research

References

16

PMID:18345000

A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia.