Inherited primary hemostasis disorders (IPHD) comprise a clinically and genetically heterogeneous spectrum, including inherited platelet disorders (IPD), heritable disorders of connective tissue (HDCT) associated with bleeding, and bleeding disorders of unknown cause (BDUC). Their phenotypic overlap and limited access to specific functional testing make genetic analysis essential for accurate diagnosis. This study aimed to investigate the genetic basis of patients with IPHD through Whole-exome sequencing (WES), providing genotype-phenotype correlations to guide clinical management. A total of 170 probands were included: 114 with IPD (67%), 28 with HDCT (16%), and 28 with BDUC (16%). Definitive genotype-phenotype correlation was achieved in 83 probands (49%), identifying 98 unique candidate variants across 48 genes. Notably, 19 patients carried variants in different genes that can contribute to the phenotype. A partial genotype-phenotype correlation was achieved in 19 probands (11%), while no variants were identified in the remaining 68 (40%), especially in the BDUC group. This multicenter study represents the first integrated analysis using a single workflow for patients with IPHD, encompassing not only IPD and BDUC but also HDCT. The high rate of genotype-phenotype correlations achieved, the identification of 68 previously undescribed variants, and the evidence of a shared and overlapped genetic and phenotypic profile among IPHD patients demonstrate the clinical value of WES. The study advocates for a paradigm shift in the clinical diagnosis of IPHD, from traditional phenotype-driven assesment to genotype-informed strategies, positioning WES as a first-line tool together with basic laboratory tests, allowing faster and more accurate diagnosis and personalized patient care.
Bandini et al. (Wed,) studied this question.