PB0566 - Understanding the burden of clinically actionable yet severe pathogenic variants of F13A1 (FXIII deficiency): From Detection to Variant Interpretation

Monday, June 24, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

Amit Sharma, MSc PhD

Research Associate
Department of Hematology, All India Institute for Medical Sciences
GHAZIABAD, Uttar Pradesh, India

Co-Author(s)

SS

Sneha Singh, PhD

Post Doctoral Scientist
Institute for Experimental Hematology and Transfusion Medicine, University Hospital of Bonn
Bonn, Nordrhein-Westfalen, Germany
Ravi Ranjan, MSc PhD

Scientist
All India Institute of Medical Sciences
New Delhi, Delhi, India
Samhitha Urs Ramaraje Urs, M.Sc

PhD Student
Institute for Experimental Hematology and Transfusion Medicine, University Hospital Bonn
Bonn, Nordrhein-Westfalen, Germany
JD

Jasmita Dass, MD, DM

Associate Professor of Hematopathology
All India Institute of Medical Sciences, New Delhi
New Delhi, Delhi, India
MA

Mukul Aggarwal

Assistant Professor
All India Institute of Medical Sciences, New Delhi
Delhi, Delhi, India
GV

Ganesh Kumar Viswanathan

Associate Professor
All India Institute of Medical Sciences, New Delhi
New Delhi, Delhi, India
Johannes Oldenburg, MD

Professor, Chairman and Director
University Clinic Bonn AöR, Institute of Experimental Haematology and Transfusion Medicine
Bonn, Nordrhein-Westfalen, Germany
AB

Arijit Biswas

PD
Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn
Bonn, Nordrhein-Westfalen, Germany
MM

Manoranjan Mahapatra

Professor and Head
All India institute of Medical Sciences, New Delhi
New Delhi, Delhi, India

Background: Molecular defects of Coagulation Factor XIII (FXIII) lead to autosomal-inherited, rare bleeding phenotypes termed FXIII deficiency, where defects in genes F13A1 and F13B are accountable. Since this rare deficiency can have fatal-to-mild bleeding consequences, a proper diagnosis relies on accurate detection and interpretation of the genetic defect

Aims: To screen mutations in the F13 and explore their effects on protein structure and function

Methods: Ten Patients (M: F=5:5) with clinical and laboratory features of FXIII deficiency were collected and confirmed by Clot-solubility assay. Whole blood-derived gDNA was subjected to Next-generation sequencing on a MiSeq platform. Detected variants were tested in silico for their possible effects on protein

Results: The commonest bleeding symptom was umbilical cord bleeding observed in 70% of cases followed by intracranial and intra-abdominal hemorrhage (20%), hemarthroses, and Ecchymoses (20%). A total of 12 pathogenic variants were detected, out of which 8 were non-synonymous missense and 4 were novel variants (R409L, I235F, large deletion of exon 4-10, and K679del) as shown in Table. In silico assessment revealed that K679del affects stability and gives quantitative impairment by losing the two H-bonds formed in the barrel 2 domain (Figure). I235F lies on the periphery of the helix and substitution to Phenylalanine introduces a bulky group and hence clashes within the sensitive region. The variant R409L affects the hydrogen bonding network by staying in close vicinity of Calcium binding site III, and interfering with catalytic diad (His 342, Glu 401, Figure)

Conclusion(s): Our study shows heterogeneity in terms of molecular defects and the missense mutations are the most frequent. All novel/reported mutations were detected only in the F13A1 gene. All Novel variants lie in the functionally conserved region they lead to severe functional/quantitative phenotype by altering the structural makeup and disrupting the activation mechanics of the enzyme