Autosomal dominant thrombocytopenia caused by a heterozygous CYCS variant: a new family and literature review.

BACKGROUND

CYCS variants cause a rare autosomal dominant nonsyndromic thrombocytopenia: thrombocytopenia 4 (THC4).

OBJECTIVES

This study aimed to determine the genetic basis of thrombocytopenia in a Chinese family and to summarize the clinical spectrum of CYCS-related thrombocytopenia.

METHODS

Clinical data and laboratory findings, including complete blood counts, thromboelastography, platelet aggregation, and surface glycoprotein expression, were collected. Whole-exome sequencing followed by Sanger sequencing was performed to identify disease-associated variants. In silico pathogenicity prediction analyses were conducted. A systematic literature review of previously reported CYCS-related thrombocytopenia was also performed.

RESULTS

Four affected individuals presented with isolated mild-to-moderate thrombocytopenia (platelet counts ranging from 54 to 83 × 109/L) with normal platelet size and morphology. Thromboelastography revealed decreased maximum amplitude. Mildly reduced responses to ADP, arachidonic acid, collagen, and ristocetin were observed in patients I-1 and II-2. Surface glycoprotein expression was normal. A heterozygous CYCS missense variant, c.292T>C (p.Y98H), cosegregated with thrombocytopenia across 3 generations. Structural prediction suggested protein destabilization. Individuals harboring variants within the central Ω-loop of cytochrome c had significantly higher platelet counts than those carrying variants in other domains.

CONCLUSION

This study reports a Chinese pedigree with CYCS-associated thrombocytopenia, adding detailed clinical and laboratory data to the rare CYCS p.Y98H variant and expanding the known phenotypic and geographic spectrum of THC4. Domain-specific genotype-phenotype correlations in CYCS-related thrombocytopenia suggest a potential structural influence of mutation location on disease severity. Intrafamilial heterogeneity underscores the potential role of secondary genetic modifiers in modulating individual phenotypic traits, which warrants further scrutiny.