Phenotype description and response to thrombopoietin receptor agonist in DIAPH1-related disorder

The heritable thrombocytopenias (HTs) are genetically heterogeneous rare disorders in which
reduced circulating platelet levels may be associated with nonhematological features. Among
recently discovered HTs, DIAPH1-related disorder (D-RD; OMIM #124900) was initially reported in
pedigrees with macrothrombocytopenia and hearing loss. This phenotype segregated with a
heterozygous p.R1213* variant in DIAPH1, which encodes the cytoskeletal regulator diaphanous
homolog 1 (DIAPH1). This predicted truncation of the DIAPH1 C terminus diaphanous autoregulatory domain (DAD) and was proposed to confer gain-of-function, resulting in megakaryocyte (MK) cytoskeletal dysregulation and impaired proplatelet formation. Macrothrombocytopenia and hearing loss have subsequently been reported in further isolated pedigrees with DAD DIAPH1 variants,4-6 suggesting that D-RD is a distinct syndromic HT. However, other descriptions of similar DIAPH1 variants include hearing loss but not hematological findings. To provide a full phenotypic description of D-RD and the relationship with different DIAPH1 variants, we report detailed hematological findings from 5 D-RD pedigrees, including the in vitro response and clinical outcome of treatment with the thrombopoietin (TPO) receptor agonist
eltrombopag.