Autosomal dominant thrombocytopenia associated with the CYCS p.Arg92Gly variant: clinical characterization of an additional family and observation of antiplatelet tolerance

Thrombocytopenia 4 (THC4) is a rare autosomal dominant inherited thrombocytopenia caused by pathogenic variants in CYCS, the gene encoding cytochrome c. Although CYCS-related thrombocytopenia is well characterized as a mild, non-syndromic quantitative platelet disorder, few families have been described worldwide. Recently, the missense variant c.274A > G (p.Arg92Gly) was reported in a single family. Here, we describe an additional multi-generational family from the Middle East carrying the same variant, thereby providing independent confirmation of pathogenicity and expanding the available phenotypic data. Seven affected individuals exhibited stable, moderate thrombocytopenia (55–88 × 109/L) with normal platelet size and morphology, normal platelet aggregation responses, and no syndromic features. One newborn presented with petechiae and grade 1 intracranial hemorrhage but recovered fully. Whole-exome sequencing identified p.Arg92Gly as the only variant segregating with disease; Sanger sequencing confirmed heterozygosity in all affected members. Structural modeling demonstrated loss of stabilizing hydrogen bonds involving a highly conserved residue within the C-terminal helical region of cytochrome c, likely impairing local structural stability. Importantly, one affected individual tolerated long-term aspirin and clopidogrel therapy following an ischemic stroke without bleeding complications—an observation not previously reported in THC4. This Brief Report strengthens the association between CYCS p.Arg92Gly and inherited thrombocytopenia and provides clinically important data regarding antiplatelet therapy safety in this rare condition.