Background Primary ovarian insufficiency (POI) affects 1% of women under 40 years and is a public health problem. The genetic causes of POI are highly heterogeneous with isolated or syndromic forms. Recently, variants in genes involved in DNA repair have been shown to cause POI. Notably, syndromic POI with Fanconi anaemia (FA) traits related to biallelic BRCA2 truncated variants has been reported. Here, we report a novel phenotype of isolated POI with a BRCA2 variant in a consanguineous Turkish family.
Methods Exome sequencing (ES) was performed in the patient. We also performed functional studies, including a homologous recombination (HR) test, cell proliferation, radiation-induced RAD51 foci formation assays and chromosome breakage studies in primary and lymphoblastoid immortalised cells. The expression of BRCA2 in human foetal ovaries was studied.
Results ES identified a homozygous missense c.8524C>T/p.R2842C-BRCA2 variant. BRCA2 defects induce cancer predisposition and FA. Remarkably, neither the patient nor her family exhibited somatic pathologies. The patient’s cells showed intermediate levels of chromosomal breaks, cell proliferation and radiation-induced RAD51 foci formation compared with controls and FA cells. R2842C-BRCA2 only partially complemented HR efficiency compared with wild type-BRCA2. BRCA2 is expressed in human foetal ovaries in pachytene stage oocytes, when meiotic HR occurs.
Conclusion We describe the functional assessment of a homozygous hypomorphic BRCA2 variant in a patient with POI without cancer or FA trait. Our findings extend the phenotype of BRCA2 biallelic alterations to fully isolated POI. This study has a major impact on the management and genetic counselling of patients with POI.
- primary ovarian insufficiency
- BRCA2 exome
- cancer Fanconi anemia
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SC, AH and ED are joint first authors.
Contributors MM, BSL and GL designed research studies. ED, AH, ST and SM conducted experiments. SC, ED, AH, GL, BSL and MM acquired and analysed data. AH, HC and ML collected clinical data and biological samples of the patient and their parents. MM, BSL, SC, AH and GL wrote the manuscript.
Funding This study was supported by Université Paris Diderot (SC), Université Paris Sud-Paris Saclay (ED, AH and MM), by the Agence Nationale de Biomédecine (AH and MM) and by Institut Universitaire de France (GL). BSL was supported by the Ligue Nationale contre le cancer 'Equipe labellisée 2017', Agence Nationale de la Recherche (ANR-16-CE12-0011-02 and ANR-16-CE18-0012-02), AFM-Téléthon and Institut National du Cancer (INCa-PLBIO18-232).
Competing interests None declared.
Patient consent for publication Obtained.
Ethics approval The study was approved by all the institutions involved and by the Agence de Biomedecine (reference number PFS12-002).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. Data supporting the claims made in this paper are available upon request after its publication.
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