OC 75.1 - First US Rare Bleeding Disorder Genotype-Phenotype Registry (ATHN 10) Discovers Many Individuals with Both Novel and Multiple Variants Using a Customized 30-Gene Next-Generation Sequencing Panel

Wednesday, June 28, 2023

10:15 – 10:30 ET

Room: 510

Session Available As: On-Demand

Presenting Author(s)

Diane Nugent, MD (she/her/hers)

Director Pediatric Hematology
CHOC Childrens and Center for Inherited Blood Disorders
Orange, California, United States

Co-Author(s)

SW

Shirley Williams

Senior Scientist
CHOC Childrens Hospital and UC Irvine
Orange, California, United States
CA

Christina Ashburner

Clinical Research Associate
Center for Inherited Blood Disorder
Orange, California, United States
NC

Nicole Crook

Director Clinical Research Administration
Center for Inherited Blood Disorders
Orange, California, United States
HM

Haduwa Momoh

Clinical Project Manager
American Thrombosis and Hemostasis Network
Rochester, New York, United States
Michael Recht, MD, PhD, MBA (he/him/his)

Chief Medical and Scientific Officer
National Hemophilia Foundation
New York, New York, United States
MC

Martin Chandler

Data Scientist
American Thrombosis Hemostasis Network
Rochester, New York, United States
AS

Amy Shapiro

Medical Director
Indiana Hemophilia & Thrombosis Center, Indianapolis, IN, USA
Indianapolis, Indiana, United States

Background: The United States’ population of ~340 million individuals is comprised of highly diverse racial and ethnic backgrounds. The incidence of ultra-rare bleeding disorders is unknown, but is critically important to understand the need for specialized health care services, linkage of individuals to centers for further genetic sequencing and counseling, and eventual care.

Aims: To better understand the nature and frequency of ultra-rare bleeding disorders in the US, the American Thrombosis and Hemostasis Network (ATHN) initiated ATHN 10, a collaborative effort within its network of 140 affiliated treatment centers, to perform whole gene sequencing and collection of detailed phenotypic data, including bleeding scores on enrolled patients with one of 30 identified ultra-rare bleeding disorders.

Methods: Participants gave informed consent for data collection and genetic testing. Whole gene sequencing (exons, introns, and 1500 nucleotides both up and down stream) for 30 genes known to cause ultra-rare factor deficiency or platelet dysfunction was performed on each participant. This next-generation sequencing (NGS) panel captured not only missense variants but was also very effective in detecting large deletions, splice site variants, copy number variants, and early stop codon mutations.

Results: Since August 2020, 643 individuals with an established ultra-rare bleeding disorder have been sequenced for their factor deficiency along with the 29 other clotting disorder genes, resulting in 19,290 genes for analysis. On the gene panel, 95% of participants analyzed had identified variants within the gene associated with the previous clinical diagnosis, 20% being novel. Importantly, 24% of participants had more than one gene identified with a previously reported pathological variant causative for a bleeding disorder. Only 5% had no identified pathologic variant.

Conclusion(s): ATHN 10 provides important opportunities for clinicians and researchers to understand the pathophysiology of the evaluated disorders and to optimize treatment options and genetic counseling for each individual.

Learning Objectives:

recognize the benefit of whole gene sequencing in identifying pathologic variants in rare clotting protein disorders.
consider the possibility of a secondary , pathologic variant when the bleeding phenotype does not match predicted pattern based on clotting protein activity measured in the clinical laboratory
understand the power of large scale, rare blood disorder registries where clinical data can be alligned with gene sequencing to broaden our understanding of the pathophysiology of novel variants, their association with a broad spectrum of races and nationalities, and determination of optimal therapeutic options.