Molecular Testing in the Diagnosis of Inherited Bleeding Disorders – Insights and Advances

Abstract

Inherited bleeding disorders represent a diverse group of conditions characterized by an increased bleeding tendency that is most often caused by defects in platelets or coagulation factors. The clinical and genetic heterogeneity of these disorders entails significant diagnostic challenges, as traditional approaches based on clinical evaluation, family history and specialized laboratory assays often lack both sensitivity and specificity, especially for rare or atypical presentations. Recent advances in molecular genetics, particularly high throughput sequencing (HTS), have transformed the diagnostic landscape of inherited bleeding disorders. HTS enables the simultaneous analysis of multiple genes, facilitating the identification of causative DNA variants in an increasing number of patients. Targeted gene panels, whole exome sequencing, and whole genome sequencing each offer unique advantages in terms of coverage, depth, and the ability to detect a broad spectrum of genetic alterations. The implementation of multigene panels has led to a significantly increased diagnostic yield and reduced diagnostic delays. Despite these advances, important challenges remain, particularly regarding the interpretation of variants of uncertain significance, detection of complex rearrangements, and the management of incidental findings. In this review, we describe recent insights and advances in the application of HTS for the diagnosis of inherited bleeding disorders and discuss the implications for clinical practice.