PB0211 - The utilities of multiple genetic analyses for rare coagulation deficiencies and rare bleeding disorders

Sunday, June 25, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

Yuri Uchiyama, MD, PhD

Assistant professor
Department Rare Disease Genomics, Yokohama City University Hospital
Yokohama, Kanagawa, Japan

Co-Author(s)

Yoshiyuki Ogawa, MD, PhD

Senior Assistant Professor
Department of Hematology, Gunma University Graduate School of Medicine, Maebashi, Japan
Maebashi, Gumma, Japan
KY

Kunio Yanagisawa

Assistant Professor
Infection Control and Prevention Center, Gunma University Hospital
Maebashi, Gumma, Japan
Akira Matsumoto, MD (he/him/his)

Physician
Department of Hematology, Gunma University Graduate School of Medicine, Maebashi, Japan
Maebashi, Gumma, Japan
TM

Takeshi Mizuguchi

associate professor
Department of Human Genetics, Yokohama City University Graduate School of Medicine
Yokohama, Kanagawa, Japan
HU

Hideki Uchiumi

Physician
Department of Hematology, Gunma University Graduate School of Medicine, Maebashi, Japan
Maebashi, Gumma, Japan
HH

Hiroshi Handa

Associate Professor
Department of Hematology, Gunma University Graduate School of Medicine
Maebashi, Gumma, Japan
NM

Naomichi Matsumoto

Professor
Department of Human Genetics, Yokohama City University Graduate School of Medicine
Yokohama, Kanagawa, Japan

Background: Coagulation tests are useful in diagnosing rare coagulation factor deficiencies (RCDs) and rare bleeding disorders (RBDs), but their additional genetic tests may provide us with much more comprehensive knowledge.

Aims: To identify the genetic variants in patients with RCDs and RBDs, we performed exome and/or genome sequencing (ES and GS). Our precise aims are: (1) to identify pathogenic variants and (2) to re-evaluate the clinical diagnosis by considering ES and GS data.

Methods: A total of 12 families with RCDs and RBDs were recruited to this study: 3 factor V deficiency, 1 factor VII deficiency, 1 combined factor V and VIII deficiency, 1 factor XI deficiency, 2 factor XII deficiency, 1 prekallikrein deficiency, and 3 undiagnosed bleeding disorder (UBD) without platelet dysfunction families. All families (either child-onset or adult-onset) have been clinically evaluated and diagnosed by coagulation tests, and acquired coagulation disorders have been denied. Proband-based ES analysis was first conducted to evaluated both single nucleotide variants (SNVs) and copy number variations (CNVs), and 8 cases were solved. Subsequent genome analysis was done on the remaining 4 cases.

Results: ES analyses identified causal variants in either F11, F5, LMAN1, F12, ENG, or KLKB1 in eight families (8/12, 66.7%): four novel and four reported SNVs and one novel CNV. A patient with UBD was found to have a pathogenic variant in ENG, leading to the diagnosis of hereditary hemorrhagic telangiectasia. GS analysis detected two novel candidate variants in the deep intronic regions of F5 and F7, possibly associated with aberrant splicing.

Conclusion(s): Our comprehensive genetic analyses targeting SNVs, CNVs, and structural variation analyses using ES and GS, and these multiple genetic analyses potentially identified 10 pathogenic and/or strong candidate variants in 10 of 12 patients (83.3%). These results support the diagnosis of RCDs and RBDs and their potential treatments.