PB0704 - Hemizygous FGG p.Ala108Gly in a hypofibrinogenemic patient with a heterozygous 14.8 Mb deletion encompassing the entire fibrinogen gene cluster

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

Alexander J. Couzens, MSt

PhD student
University of Geneva, Geneva, Switzerland
Geneva, Geneve, Switzerland

Co-Author(s)

AL

Aurélien Lebreton

MD
Service d’hématologie, CHU Clermont-Ferrand, Hôpital Estaing
Clermont Ferrand, Auvergne, France
FM

Frédéric Masclaux

Bioinformation
Medical Genetics Service, University Hospitals of Geneva, Geneva, Switzerland
Geneva, Geneve, Switzerland
MG

Michel Guipponi

Diagnostic Test Manager
Medical Genetics Service, University Hospitals of Geneva, Geneva, Switzerland
Geneva, Geneve, Switzerland
CP

Céline Pebrel-Richard

Hospital Practitioner
Service de cytogénétique médicale, CHU Clermont-Ferrand, Clermont-Ferrand, France
Clermont-Ferrand, Rhone-Alpes, France
FL

Fanny Laffargue

Hospital Practitioner
Service de génétique médicale, CHU Clermont-Ferrand, Clermont-Ferrand, France
Clermont-Ferrand, Rhone-Alpes, France
PG

Piotr Gembara

Paediatrician
Service d’hématologie biologique, CHU Clermont-Ferrand, Clermont-Ferrand, France
Clermont-Ferrand, Rhone-Alpes, France
AC

Alessandro Casini

MD
Division of angiology and hemostasis, University Hospitals of Geneva, Faculty of Medicine, Geneva, Switzerland
Geneva, Geneve, Switzerland
MN

Marguerite Neerman-Arbez

Professor
UNIGE
Geneva, Geneve, Switzerland

Background: Congenital hypofibrinogenemia is a quantitative congenital fibrinogen disorder (CFD) characterised by concordantly low levels of antigenic and functional fibrinogen. Most cases are due to heterozygous variants which in homozygosity would lead to afibrinogenemia (no detectable fibrinogen). Here we present the case of a patient with severe hypofibrinogenemia (antigenic fibrinogen 0.6 g/l; functional fibrinogen 0.5-0.7 g/l Clauss) and developmental delay. CGH array and FISH analysis identified an interstitial de novo 14.8 Mb deletion on chromosome 4, causing the loss of one copy of the entire fibrinogen cluster (genes, FGA, FGB and FGG).

Aims: The fibrinogen levels observed appeared too low to be explained by the large deletion alone. We investigated the hypothesis that a second mutation was present using whole exome sequencing (WES).

Methods: WES was performed at the Health 2030 Genome Centre, Geneva using IDT reagents and protocols. WES read mapping, variant calling and copy number variation detection was performed using an in-house read depth-based algorithm. This study was performed with institutional review board approval and written informed consent from all participants (Declaration of Helsinki).

Results: We identified variant rs148685782 (FGG exon 4 c.323C>G p.Ala108Gly) on the non-deleted allele which has previously been associated with hypofibrinogenemia and predicted to destabilise fibrinogen assembly. Due to the hemizygosity of FGG in this patient the effect of the variant is ` homozygous-like` but does not result in afibrinogenemia. Sanger sequencing revealed that the patient’s asymptomatic mother with a fibrinogen concentration of 2.2 g/l (Clauss) was heterozygous for the FGG p.Ala108Gly variant.

Conclusion(s): We identified a patient with a large de novo deletion of the entire fibrinogen gene cluster and a hemizygous variant in FGG that results in a severe hypoﬁbrinogenemia phenotype. This case emphasizes the value of further probing cases for which the fibrinogen levels appear too low to be explained by a single mutation.