{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:36:10Z","timestamp":1790660170068,"version":"4.1.0"},"reference-count":62,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T00:00:00Z","timestamp":1732060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CNRS","award":["PFS12-002"],"award-info":[{"award-number":["PFS12-002"]}]},{"name":"Universit\u00e9 Paris-Saclay","award":["PFS12-002"],"award-info":[{"award-number":["PFS12-002"]}]},{"name":"Hopitaux Universitaires Paris-Saclay","award":["PFS12-002"],"award-info":[{"award-number":["PFS12-002"]}]},{"name":"Agence Nationale de Biom\u00e9decine","award":["PFS12-002"],"award-info":[{"award-number":["PFS12-002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The use of next-generation sequencing (NGS) has recently enabled the discovery of genetic causes of primary ovarian insufficiency (POI) with high genetic heterogeneity. In contrast, the causes of diminished ovarian reserve (DOR) remain poorly understood. Here, we identified by NGS and whole exome sequencing (WES) the cause of isolated DOR in a 14-year-old patient. Two frameshift mutations in BRCA1 (NM_007294.4) were found: in exon 8 (c.470_471del; p.Ser157Ter) and in exon 11 (c.791_794del, p.Ser264MetfsTer33). Unexpectedly, the patient presented no signs of Fanconi anemia (FA), i.e., no developmental abnormalities or indications of bone marrow failure. However, high chromosomal fragility was found in the patient\u2019s cells, consistent with an FA diagnosis. RT-PCR and Western-blot analysis support the fact that the c. 791_794del BRCA1 allele is transcribed and translated into a shorter protein (del11q), while no expression of the full-length BRCA1 protein was found. DNA damage response (DDR) studies after genotoxic agents demonstrate normal activation of the early stages of the DDR and FANC\/BRCA pathway. This is consistent with the maintenance of residual repair activity for the del11q BRCA1 isoform. Our observation is the first implication of bi-allelic BRCA1 mutations in isolated ovarian dysfunction or infertility in humans, without clinical signs of FA, and highlights the importance of BRCA1 in ovarian development and function.<\/jats:p>","DOI":"10.3390\/ijms252212460","type":"journal-article","created":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T07:02:58Z","timestamp":1732086178000},"page":"12460","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Biallelic Germline BRCA1 Frameshift Mutations Associated with Isolated Diminished Ovarian Reserve"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2686-2798","authenticated-orcid":false,"given":"Anne","family":"Helbling-Leclerc","sequence":"first","affiliation":[{"name":"Genome Integrity and Cancer, CNRS UMR9019, Universit\u00e9 Paris-Saclay, Gustave Roussy, 94805 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Falampin","sequence":"additional","affiliation":[{"name":"Service d\u2019Endocrinologie, Gyn\u00e9cologie et Diab\u00e9tologie P\u00e9diatrique, APHP H\u00f4pital Universitaire Necker Enfants Malades, 75743 Paris, France"},{"name":"Centre de R\u00e9f\u00e9rence Maladies Rares-CRMR des Pathologies Gyn\u00e9cologiques Rares, 75743 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1966-5462","authenticated-orcid":false,"given":"Abdelkader","family":"Heddar","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de G\u00e9n\u00e9tique Mol\u00e9culaire des Maladies M\u00e9taboliques et de la Reproduction, Laboratoire de R\u00e9f\u00e9rence Pour les Infertilit\u00e9s G\u00e9n\u00e9tiques, APHP H\u00f4pitaux Universitaires Paris-Saclay, Facult\u00e9 de M\u00e9decine Paris Saclay, H\u00f4pital Bic\u00eatre, 94275 Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e9a","family":"Guerrini-Rousseau","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Canc\u00e9rologie de L\u2019enfant et de L\u2019adolescent, Gustave Roussy, Universit\u00e9 Paris Saclay, 94805 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maud","family":"Marchand","sequence":"additional","affiliation":[{"name":"Service d\u2019Endocrinologie, Gyn\u00e9cologie et Diab\u00e9tologie P\u00e9diatrique, APHP H\u00f4pital Universitaire Necker Enfants Malades, 75743 Paris, France"},{"name":"Centre de R\u00e9f\u00e9rence Maladies Rares-CRMR des Pathologies Gyn\u00e9cologiques Rares, 75743 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4599-4729","authenticated-orcid":false,"given":"Iphigenie","family":"Cavadias","sequence":"additional","affiliation":[{"name":"Service d\u2019Endocrinologie, Gyn\u00e9cologie et Diab\u00e9tologie P\u00e9diatrique, APHP H\u00f4pital Universitaire Necker Enfants Malades, 75743 Paris, France"},{"name":"Centre de R\u00e9f\u00e9rence Maladies Rares-CRMR des Pathologies Gyn\u00e9cologiques Rares, 75743 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9744-4470","authenticated-orcid":false,"given":"Nathalie","family":"Auger","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Biologie et de Pathologie M\u00e9dicales, Gustave Roussy, 94805 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0245-8608","authenticated-orcid":false,"given":"Brigitte","family":"Bressac-de Paillerets","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Biologie et Pathologies M\u00e9dicales et U1279 INSERM, Gustave Roussy, Universit\u00e9 Paris-Saclay, 94805 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7798-6651","authenticated-orcid":false,"given":"Laurence","family":"Brugieres","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Canc\u00e9rologie de L\u2019enfant et de L\u2019adolescent, Gustave Roussy, Universit\u00e9 Paris Saclay, 94805 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard S.","family":"Lopez","sequence":"additional","affiliation":[{"name":"Faculte de Medecine, INSERM 1016, UMR 80104 CNRS, Institut Cochin, Universit\u00e9 de Paris-Cit\u00e9, 24 Rue du Faubourg ST Jacques, 75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Polak","sequence":"additional","affiliation":[{"name":"Service d\u2019Endocrinologie, Gyn\u00e9cologie et Diab\u00e9tologie P\u00e9diatrique, APHP H\u00f4pital Universitaire Necker Enfants Malades, 75743 Paris, France"},{"name":"Centre de R\u00e9f\u00e9rence Maladies Rares-CRMR des Pathologies Gyn\u00e9cologiques Rares, 75743 Paris, France"},{"name":"Facult\u00e9 de Sant\u00e9, Universit\u00e9 de Paris, 75006 Paris, France"},{"name":"Groupement de Coop\u00e9ration Sanitaire-GCS SeqOIA, R\u00e9f\u00e9rent Clinicien Pr\u00e9indication Insuffisance Ovarienne Primitive and Plan France M\u00e9decine G\u00e9nomique 2025, 78 rue du G\u00e9n\u00e9ral Leclerc, 94270 Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1080-5745","authenticated-orcid":false,"given":"Filippo","family":"Rosselli","sequence":"additional","affiliation":[{"name":"Genome Integrity and Cancer, CNRS UMR9019, Universit\u00e9 Paris-Saclay, Gustave Roussy, 94805 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5379-8859","authenticated-orcid":false,"given":"Micheline","family":"Misrahi","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de G\u00e9n\u00e9tique Mol\u00e9culaire des Maladies M\u00e9taboliques et de la Reproduction, Laboratoire de R\u00e9f\u00e9rence Pour les Infertilit\u00e9s G\u00e9n\u00e9tiques, APHP H\u00f4pitaux Universitaires Paris-Saclay, Facult\u00e9 de M\u00e9decine Paris Saclay, H\u00f4pital Bic\u00eatre, 94275 Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,20]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2023). 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