TY - JOUR
T1 - Biallelic Germline BRCA1 Frameshift Mutations Associated with Isolated Diminished Ovarian Reserve
AU - Helbling-Leclerc, Anne
AU - Falampin, Marie
AU - Heddar, Abdelkader
AU - Guerrini-Rousseau, Léa
AU - Marchand, Maud
AU - Cavadias, Iphigenie
AU - Auger, Nathalie
AU - Bressac-de Paillerets, Brigitte
AU - Brugieres, Laurence
AU - Lopez, Bernard S.
AU - Polak, Michel
AU - Rosselli, Filippo
AU - Misrahi, Micheline
N1 - Publisher Copyright:
© 2024 by the authors.
PY - 2024/11/1
Y1 - 2024/11/1
N2 - 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’s 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.
AB - 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’s 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.
KW - BRCA1 mutation
KW - DNA repair
KW - Fanconi anemia
KW - diminished ovarian reserve
KW - genetic counseling
KW - meiosis
KW - primary ovarian insufficiency
UR - http://www.scopus.com/inward/record.url?scp=85210592932&partnerID=8YFLogxK
U2 - 10.3390/ijms252212460
DO - 10.3390/ijms252212460
M3 - Article
C2 - 39596525
AN - SCOPUS:85210592932
SN - 1661-6596
VL - 25
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 22
M1 - 12460
ER -