PB0074 - Experience of interpretating F8 missense variants using F8-specific variant interpretation guidelines published by the ClinGen Coagulation Factor Deficiency Expert Panel

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

YJ

Yohann Jourdy, PharmD, phD

PharmD PhD
Hospices civils de Lyon, laboratoire d'hématologie biologique, Lyon, France
Lyon, Rhone-Alpes, France

Co-Author(s)

MF

Mathilde Fretigny

Biologist
Réseau national des laboratoires réalisant les caractéristiques génétiques des maladies constitutionnelles de l’hémostase (Génostase), France
Lyon, Rhone-Alpes, France
CZ

Christophe Zawadzki

PharmD
CHU Lille, Service d'Hemostase et Transfusion - Lille FRANCE
Lille, Nord-Pas-de-Calais, France
CB

Cyril Burin Des Roziers

Biologist
Réseau national des laboratoires réalisant les caractéristiques génétiques des maladies constitutionnelles de l’hémostase (Génostase), France
Paris, Ile-de-France, France
PB

Pierre Boisseau

Biologist
Réseau national des laboratoires réalisant les caractéristiques génétiques des maladies constitutionnelles de l’hémostase (Génostase), France
NANTES, Pays de la Loire, France
CV

Christine Vinciguerra

PharmD PhD
Service d’hématologie Biologique, Groupe Hospitalier Est, Hospices Civils de Lyon, Bron, France, Université Claude Bernard Lyon 1, UR 4609 Hémostase et thrombose, Lyon, France
Lyon, Rhone-Alpes, France

Background: Despite the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, the clinical interpretation of F8 missense variations could be discordant between interpreters. To address these discrepancies, the ClinGen Coagulation Factor Deficiency Expert Panel has recently proposed F8-specific variant interpretation guidelines.

Aims: To reassess F8 missense variations found in patients with haemophilia A patients explored in our laboratory using F8-specific guidelines.

Methods: Minor allele frequency was referenced from GnomAD V4. The F8 locus specific database (F8-db) of the European Association for Haemophilia and Allied Disorders (EAHAD) was used for literature search.

Results: 523 F8 missense variations from 1616 unrelated families were studied. Using the F8-specific guidelines, 129 (24%) were classified as pathogenic, 379 (72 %) as variant of uncertain significances (VUS) and 25 (4%) as benign/likely benign. The PS4_PVS (variants previously found in ≥8 probands) was the main criterion to classify a variant as pathogenic (criterion used for n=87/129 variants classified as pathogenic). Due to the reduction in number of rules for combining criteria compared to the original ACMG guidelines, it was difficult to class a missense variant as HA-causing in the absence of PS4_PVS. However, most of F8 missense variant associated with severe phenotype in our cohort (n = 93) did not presented the PS4_PVS requirement. Consequently, only 15 (16%) of these variants were classified as pathogenic and the remaining 78 (84%) variants were VUS.

Conclusion(s): The new F8-specific guidelines gave clarifications of ACMG criteria, which were essential for the harmonization of practices. However, these guidelines were restrictive leading to the reassessment of three quarters of F8 missense variants as VUS. The reintroducing of some rules for combining criteria initially present in the ACMG guidelines could lead to F8-specific guidelines more consistent with the routine diagnosis practices.