Novel/Recurrent Variants in Pakistani Glanzmann Thrombasthenia and Glanzmann-like Bleeding Diathesis: Insights from...

Glanzmann thrombasthenia (GT) and GT-like phenotype represent inherited platelet disorders caused by defects in platelet glycoprotein αIIbβ3 (encoded by ITGA2B and ITGB3) or RASGRP2- and FERMT3-mediated platelet intracellular signaling, respectively. While globally rare, prevalence of these bleeding phenotypes is notably higher in regions with high consanguinity, including Pakistan, with limited data on GT-associated variants. Compared with traditional diagnostic approaches, next-generation sequencing (NGS) offers comprehensive detection of known and novel variants, enhancing diagnostic accuracy in genetically heterogeneous disorders like GT.

This study investigated the mutational spectrum of GT and GT-like phenotype in 67 patients from 55 unrelated Pakistani families using a targeted gene panel. Variant annotation and pathogenicity assessments were performed using established guidelines. Structural modeling and molecular dynamics simulations were used to predict the functional consequences of select novel variants.

A total of 21 distinct variants were identified (15 in ITGA2B and 6 in ITGB3), achieving an 87.3% diagnostic yield. In all, 10 were novel, including missense, frameshift, splice-site, and copy number variants (CNVs). Two recurrent ITGA2B frameshift variants suggested possible founder effect. Analysis of RASGRP2 revealed two novel homozygous variants in GT-like cases. A genotype-phenotype association analyses suggested a severe bleeding diathesis in GT patients harboring truncating mutations in an age-dependent manner, and clinical diversity among GT patients with same genetic variant.

This study expands the mutational spectrum of GT and GT-like bleeding diathesis in Pakistani population, identifying novel and recurrent mutations, which highlights the diagnostic value of NGS.