ECE2020 Audio ePoster Presentations Hot topics (including COVID-19) (110 abstracts)
A homozygous hypomorphic BRCA2 variant in primary ovarian insufficiency without cancer or Fanconi anemia trait
Abdelkader Heddar 1 , Caburet Sandrine 2 , Dardillac Elodie 3 , Creux Héléne 4 , Lambert Marie 4 , Livera Gabriel 5 , Bernard S Lopez 3 & Micheline Misrahi 1
1Le Kremlin-Bicêtre, Faculté de Médecine, Université –Paris-Saclay, Le Kremlin-Bicêtre, France; 2Université de Paris, Institut Jacques Monod, Paris, France; 3Institut Cochin, Université de Paris, Institut Cochin, Paris, France; 4CHU de Bordeaux, Service de Gynécologie et Médecine de la Reproduction, Bordeaux, France; 5Université de Paris, Université Paris-Saclay,, UMR Stabilité Génétique, Cellules Souches et Radiations, Fontenay-aux-Roses, France
BRCA2, is a gene with a critical role in DNA repair and homologous recombination in somatic cells. Patients with BRCA2 biallelic mutations develop Fanconi Anemia (FA), a severe life-threatening condition characterized by pancytopenia and multiple malformations and malignancies, while women with monoallelic alteration are at high risk to develop breast or ovarian cancer (up to 60%). Primary Ovarian insufficiency (POI) affects 1% of women under forty and is a public health problem. The genetic causes of POI are highly heterogeneous with isolated or syndromic forms. Recently, mutations in genes involved in DNA repair have been shown to cause POI. Here, using exome sequencing, we surprisingly uncovered a homozygous pathogenic variant of BRCA2 in a patient with isolated POI but without cancer or FA in all her family. The homozygous missense c.8524C > T/p.R2842C BRCA2 variantchanges a strictly conserved residuelocated in BRCA2 DNA-binding domain. We demonstrated that this alteration only mildly altered the function of the protein usingseveral in vitro functional assays in primary and lymphoblastoid immortalized cells. Hence, the patient’s cells showed intermediate levels of chromosomal breaks, cell proliferation and radiation-induced RAD51 foci formation compared to controls and FA cells. R2842C-BRCA2 only partially (~30%) complemented HR efficiency compared to WT-BRCA2. We show that BRCA2 is expressed in the fetal ovary in meiotic germinal cells which undergoing a high level of DNA breaks and subsequently repair. Our findings extend the phenotype of BRCA2 bi-allelic alterations to fully-isolated POI. This study has a major impact on the management of patients with POI and the genetic counsellingthat should now be addressed while keeping in mind a possible defect in a major DNA repair gene such as BRCA2.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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