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Homozygous hypomorphic variant in primary ovarian insufficiency without cancer or Fanconi anaemia trait. | LitMetric

AI Article Synopsis

  • Primary ovarian insufficiency (POI) affects around 1% of women under 40, and genetic causes, including DNA repair variants, have been linked to this condition, with a case of isolated POI reported in a Turkish family.
  • Exome sequencing revealed a specific BRCA2 variant in the patient, and various functional tests indicated that this variant affects genetic repair processes, although no cancer or syndromic traits were evident.
  • The study broadens the understanding of BRCA2 mutations by linking a specific variant to isolated POI, which can influence patient management and genetic counseling strategies for those affected.

Article Abstract

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 truncated variants has been reported. Here, we report a novel phenotype of isolated POI with 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 in human foetal ovaries was studied.

Results: ES identified a homozygous missense c.8524C>T/p.R2842C 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 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.

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Source
http://dx.doi.org/10.1136/jmedgenet-2019-106672DOI Listing

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