Type-3 von Willebrand disease in India-Clinical spectrum and molecular profile

Area of Science:

• Genetics
• Hematology
• Molecular Biology

Background:

• Type 3 von Willebrand disease (VWD) is a rare, severe bleeding disorder caused by near-complete deficiency of von Willebrand factor (VWF).
• Understanding the molecular basis of type 3 VWD is crucial for diagnosis and potential therapeutic strategies.

Purpose of the Study:

• To comprehensively evaluate the molecular pathology of type 3 VWD in an Indian cohort.
• To identify novel mutations and characterize the spectrum of VWF gene variants in Indian patients with type 3 VWD.

Main Methods:

• Phenotypic data and bleeding scores were collected from 102 patients across 90 families.
• VWF antigen levels were measured to diagnose type 3 VWD (undetectable).
• VWF gene sequencing, structural modeling, and in vitro expression studies were performed for identified mutations.

Main Results:

• Mutations were identified in 91% of patients (93/102), revealing 55 distinct VWF gene variants, 34 of which were novel.
• A significant cluster of mutations (23.5%) was found in the VWF propeptide region.
• Structural and functional studies suggested that missense mutations impair VWF secretion.

Conclusions:

• This study represents one of the largest series defining the molecular basis of type 3 VWD.
• The findings expand the knowledge of VWF mutations and their impact on VWF secretion in type 3 VWD patients.