PB1439 - Diversity of Hereditary Protein C Deficiency in North France: a Genotype-Phenotype Correlation

Tuesday, June 27, 2023

18:30 – 19:30 ET

Room: Exhibition

Co-Author(s)

MD

Maximilien Desvages

PharmD
Lille University, CHU, Department of Haematology, Lille, France
Lille, Nord-Pas-de-Calais, France
Melanie Daniel, MD

MD
Hematology Transfusion, Lille Hospital University, 59000, Lille, France
Lille, Nord-Pas-de-Calais, France
Caroline Kitel, PharmD

Pharmacy resident
Lille University Hospital, Hematology Transfusion, 59000, Lille, France
Lille, Nord-Pas-de-Calais, France
AB

Anne Bauters

PharmD
Hematologie Biologique, CHU Lille, France
Lille, Nord-Pas-de-Calais, France
NT

Nathalie Trillot

MD
Lille University, CHU, Department of Haematology and Clinical Haemostasis Unit, Lille, France
Lille, Nord-Pas-de-Calais, France
Laetitia Mauge, PharmD PhD

PharmD, PhD
Service d’Hématologie biologique, AP-HP, Hôpital européen Georges-Pompidou, F-75015, Université Paris Cité, Inserm, PARCC, F-75015 Paris, France
Paris, Ile-de-France, France
SG

Sophie Gandrille

PharmD, PhD
Service d’Hématologie biologique, AP-HP, Hôpital européen Georges-Pompidou, F-75015, Université Paris Cité, Inserm U1140, F-75006 Paris, France
Paris, Ile-de-France, France
JO

Justine Onraed

PharmD
Service d’Hématologie biologique, Centre Hospitalier de Valenciennes, Valenciennes, France.
Valenciennes, Nord-Pas-de-Calais, France
PM

Pierre-Emmanuel Morange, MD, PhD

MD, PhD
Aix-Marseille Univ, INSERM, INRAE, C2VN, Laboratory of Haematology, Hôpitaux de Marseille, Marseille, France
Marseille, Provence-Alpes-Cote d'Azur, France
Sophie Susen, MD, PhD (she/her/hers)

MD, PhD
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France
Lille, Nord-Pas-de-Calais, France

Presenting Author(s)

CZ

Christophe Zawadzki, PharmD PhD

PharmD, PhD
Lille University, CHU, Department of Haematology, Lille, France
Lille, Nord-Pas-de-Calais, France

Background: Protein C is a major regulator of coagulation in association with protein S. Its hereditary deficiency increases the risk of venous thromboembolism (VTE). Numerous genetic variations of the PROC gene are associated with quantitative (type I) or qualitative deficiencies (decreased anticoagulant and chromogenic activities in type IIa and only decreased anticoagulant activity in type IIb).

Aims: We compared genotype and phenotype of probands belonging to 149 different families of North France with protein C deficiency (protein C anticoagulant activity < 70%), followed in the Clinical Haemostasis Unit of Lille University Hospital.

Methods: All patients were genotyped using NGS or Sanger sequencing and their chromogenic and antigen protein C levels were measured.

Results: Patients were 48+/-23 years old (average+/-SD) with sex ratio 63M/86F. The percentage of VTE was 91.3% (n=136) and 4% (n=6) with additional arterial events. Major risk factors of VTE were found in 59.7% of patients (n=89). Type I deficiency was the most frequent (81.9%,n=122), then type IIb (9.4%,n=14) and type IIa (8.7%,n=13). We detected 65 different variants and 11 were never described (ACMG score ≥ 3). Most of them are located in the catalytic domain of the protein. Nine of them were found in 75 patients especially with a type I deficiency and a founder effect can be suspected for the most frequent (p.(Leu265Phe) n=29, p.(Arg220Gln) n=10 and p.(Arg272Cys) n=9). Missense variants were the most frequent (84.6%,n=55), then nonsense (7.7%,n=5), splice (4.6%,n=3) and frameshift (3.1%,n=2). All type II deficiencies were explained by a missense variation. Six patients were heterozygous compound for 2 variants with significantly lower levels of protein C.

Conclusion(s): A significant number of different variants are associated with hereditary protein C deficiency in North France, emphazising its genetic diversity. Moreover a founder effect could explain the most frequent of them.