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 <i>CYCS</i>, the gene encoding cytochrome c. Although <i>CYCS</i>-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 <i>CYCS</i> p.Arg92Gly and inherited thrombocytopenia and provides clinically important data regarding antiplatelet therapy safety in this rare condition.