PB0169 - Unearthing the genotype-inhibitor phenotype association in severe hemophilia A: a north Indian cohort study

Sunday, June 25, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

Debadrita Ray, DM (she/her/hers)

Senior Resident
PGIMER, Chandigarh
CHANDIGARH, Chandigarh, India

Co-Author(s)

NK

Narender Kumar, Doctor of Philosophy

Postdoctoral Fellow
LSUHSC
New Orleans, Louisiana, United States
CH

Chander Hans

Tutor Technician
Dept . of Hematology ,PGIMER, Chandigarh
Chandigarh, Chandigarh, India
AK

Anita Kler

Senior technician
Dept. of Hematology ,PGIMER, Chandigarh
Chandigarh, Chandigarh, India
Ritika Sharma, 82.6%

Research Scholar
PGIMER, Chandigarh
Chandigarh, Chandigarh, India
MJ

Manu Jamwal

Research Scholar
PGIMER, Chandigarh
Chandigarh, Chandigarh, India
HK

Hari Kishan Sene

Senior technician
PGIMER, Chandigarh
Chandigarh, Chandigarh, India
RT

Rozy Thakur

Research Scholar
PGIMER, Chandigarh
Chandigarh, Chandigarh, India
MS

Meenu Singh

Assistant Professor
PGIMER, Chandigarh
chandigarh, Chandigarh, India
PB

Prateek Bhatia

Doctor
PGIMER, Chandigarh
Chandigarh, Chandigarh, India
DB

Deepak Bansal

Professor
PGIMER, Chandigarh
Chandigarh, Chandigarh, India
AJ

Arihant Jain

Associate Professor
Department of Clinical Hematology and Medical Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Chandigarh, Chandigarh, India
Pankaj Malhotra, MD

Professor
Department of Clinical Hematology and Medical Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Chandigarh, Chandigarh, India
Jasmina Ahluwalia, MD (she/her/hers)

Professor
Department of Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Chandigarh, Chandigarh, India
RD

Reena Das

Professor
PGIMER, Chandigarh
Chandigarh, Chandigarh, India

Background: Various risk factors for inhibitor development in Hemophilia A (HA) have been described but Indian data remains scanty.

Aims: We aimed to evaluate the genetic changes in Indian HA patients that are associated with the development of inhibitors.

Methods: All HA patients with inhibitors who availed coagulation-laboratory services from January-2015 till December-2021 and had their samples preserved for DNA extraction were included in this study. An equal number of severity-matched HA patients without inhibitors were also included as controls. Intron 22 and intron 1 inversions in Factor VIII gene were identified using inverse-shifting PCR. Inversion-negative patients were further assessed by NGS and MLPA.

Results: Thirty HA patients with inhibitors (high titre: 83.3%; low titre: 16.7%) were identified. All had severe HA. Thirty severe HA patients without inhibitors were also included as controls. Causative variants were identified in all the 60 patients. Overall, intron 22 inversion (65%), large deletions (15%) and nonsense variants (8.3%) were the commonest variants identified. There was no difference in genetic variants in patient with low and high titre inhibitors. A3, A2 and C2 were the most common domains involved in inversion-negative patients with inhibitors (Figure 1). All patients with multidomain involvement had inhibitors. However, there was no significant difference in domain involvement among inversion negative patients with and without inhibitors. Exon 14 was the most common exon involved by point mutation or copy number variants. Seven novel variants were identified including 3 large deletions, 1 large duplication and 2 nonsense variants in inhibitor positive patients, and one frameshift variant in inhibitor negative patient. After adjusting for clinical risk factors, large deletions were independently associated with the presence of inhibitors [aOR:6.1 (1.41-56.3)].

Conclusion(s): Intron 22 inversions are the commonest variant in Indian patients with severe HA. Large deletions predispose to inhibitor development independent of clinical risk factors.