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Molecular analysis of inherited bleeding disorders in North Indian cohort

1PGIMER Chandigarh, Chandigarh, Chandigarh, India, 2Post Graduate Institute of Medical Education and Research, Chandigarh, India, Chandigarh, Chandigarh, India, 3Postgraduate Institute of Medical Education and Research, Chandigarh, India, Chandigarh, Chandigarh, India, 4Postgraduate Institute of Medical Education and Research, Chandigarh, India., Chandigarh, Chandigarh, India

Abstract Number: PB1157

Meeting: ISTH 2022 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Clinical

Background: Inherited bleeding disorders (IBDs), a heterogeneous group of disorders characterized by lifelong bleeding episodes. Diagnosis includes assessment of bleeding phenotype, laboratory investigations followed by genetic analysis.

Aims: We aimed to determine the genetic spectrum of IBDs using various DNA-based techniques.

Methods: A total of 588 families (635 cases) of IBDs were recruited, including 400 Hemophilia A (HA), 90 Hemophilia B (HB), 40 von Willebrand Disease (VWD), 35 FVII deficiency, 16 FXIII deficiency, and 7 Glanzmann Thrombasthenia (GT) based on laboratory investigations. Genetic workup for HA included intron 22 (INV22) and intron 1 inversion (INV1), conformation sensitive gel electrophoresis (CSGE) followed by targeted Next-generation sequencing (NGS). Molecular characterization of HB cases was done using Sanger sequencing. HaloPlexHS Target Enrichment System for Illumina and AmpliSeq Custom Panel for Illumina were used for library preparation. SureCall, Local Run Manager, and Variant Interpreter were used for data analysis. Pathogenicity of shortlisted variants was predicted and validated by Sanger sequencing.

Results: In HA cases, 35.5% had INV22, INV1 was in 2.3%, and in 5.2% cases, large deletions were found. The molecular characterization using CSGE, targeted NGS, and Sanger sequencing in 153 HA cases revealed probably pathogenic variants in 73.8%. Targeted NGS detected the variants in 87.5% VWD, 68.8% of FXIII deficiency, 74.3% FVII deficiency, 100% in GT and HB (using Sanger sequencing). Hot spots of genetic variants were found in F8, F9, F7, F13A1, and VWF genes. Overall 54% missense, 20.7% frameshift, 15.3% nonsense and 9.5% was splice site variants. Fifty-six variants were novel.

Conclusion(s): This is the largest cohort of IBDs diagnosed using targeted NGS from north India. Multiple DNA-based techniques were able to determine pathogenic variants in 74.5% of cases. Hot spot variants can be screened as the first step for genetic diagnosis. This molecular analysis has helped us in genetic counseling, carrier screening, and prenatal testing.

To cite this abstract in AMA style:

Sharma R, Jamwal M, Senee H, Hans C, Bansal D, Trehan A, Malhotra P, Kumar N, Ahluwalia J, Das R. Molecular analysis of inherited bleeding disorders in North Indian cohort [abstract]. https://abstracts.isth.org/abstract/molecular-analysis-of-inherited-bleeding-disorders-in-north-indian-cohort/. Accessed October 2, 2023.

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