PB0210 - Heterozygous structural variation mimicking homozygous substitution in MCFD2 in a French patient with combined Factor V and Factor VIII deficiency.

Sunday, June 25, 2023

18:30 – 19:30 ET

Room: Exhibition

Co-Author(s)

YJ

Yohann Jourdy

PharmD, phD
Hospices Civils de Lyon, Groupe Hospitalier Est, Service d’hématologie biologique, Bron, France
LYON, Rhone-Alpes, France
PC

Pierre Chamouni

MD
Haemophilia Treatment Centre, University Hospital, Rouen, France
Rouen, Haute-Normandie, France
MF

Mathilde Fretigny

PharmD
Hospices Civils de Lyon, Groupe Hospitalier Est, Service d’hématologie biologique, Bron, France
LYON, Rhone-Alpes, France
VB

Virginie Barbay

MD
Haemophilia Treatment Centre, University Hospital, Rouen, France
Rouen, Haute-Normandie, France
Véronique Le Cam Duchez, MD PhD (she/her/hers)

Head of Hematology Laboratory
Rouen University Hospital
ROUEN, Haute-Normandie, France
VB

Victor Bobee

Dr
CHU de Rouen, Hôpital Charles Nicolle, Service d’hématologie biologique, Rouen, France
ROUEN, Haute-Normandie, France
SL

Simon Lanne

Biologist
Laboratoire Defrance, Le Petit Quevilly, France
Le Petit Quevilly, Haute-Normandie, France
PS

Pascale Schneider

Professor
Hôpital Charles-Nicolle, Service d'hémato-oncologie pédiatrie, Rouen, France
Rouen, Haute-Normandie, France

Presenting Author(s)

Christine Vinciguerra, PharmD, phD

Professor
Hospices Civils de Lyon, Groupe Hospitalier Est, Service d’hématologie biologique, Bron, France
LYON, Rhone-Alpes, France

Background: Combined deficiency of coagulation Factor (F) V and FVIIII (F5F8D) is a rare autosomal recessive bleeding disorder characterized by deficiency of both FV and FVIII. F5F8D is caused by genetic variation involving LMAN1 or MCFD2. To date, at least 20 pathogenic variations of the MCFD2 have been reported. Most of them are nucleotide substitutions.

Aims: Here, we report the case of a French patient with F5F8D which is compound heterozygous for two variations in MCFD2 including a large deletion.

Methods: The sequencing of the LMAN1 and MCFD2 coding regions, intron/exon boundaries, and both the 3’ and 5’UTR has been performed using Next generation sequencing (NGS). All candidate variants were confirmed by either Sanger sequencing for or qPCR.

Results: A non-consanguineous one-year old boy was referred to the haematology unit of the Rouen university Hospital for exploration of abnormalities of routine coagulation tests in a context of persistent nail bleeding (>36h). A F5F8D was suspected because his FV and FVIII coagulant activities were 12% and 4.5%, respectively. NGS analysis identified the c.149+5G>A variation in MCFD2 at the homozygous state. Because the c.149+5G>A has been previously reported in several cases of F5F8D, it is considered as pathogenic. Surprisingly, familial investigations found the c.149+5G>A at heterozygous state in the father only. A depth-of-coverage analysis of NGS data performed in the propositus suggested the presence of a large deletion encompassing the exons 2 to 4 of MCFD2 at heterozygous state. This deletion was confirmed by qPCR in the propositus and in his mother. This last result indicated that the propositus is carrier for the c.149+5G>A at hemizygous state (or pseudohomozygous).

Conclusion(s): This case highlighted the usefulness of segregation studies in the context of recessive disorders in order to support the sequencing data. Such investigations should be performed systematically in order to improve the genetic counselling.