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American journal of obstetrics and gynecologyMar 2025 DOI:
10.1016/j.ajog.2025.03.029

Inherited and de novo variants in young females potentially associated with pelvic organ prolapse

Sadakierska-Chudy, Anna; Szymanowski, Paweł; Szepieniec, Wioletta Katarzyna; Bartosiewicz, Angelika; Lebioda, Arleta; Płoski, Rafał; Pollak, Agnieszka
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Variant Libraries
Abstract
Pelvic organ prolapse (POP) is a common condition usually affecting postmenopausal women, but it is also seen in about 10% of women aged 20-39. In young females, genetic factors seem to be of particular interest.This study aimed to identify inherited and de novo variants relevant to POP in young females, without a family history.A total of 25 women aged ≤ 40 years, with parity ≤ 2 and POP-Q stage ≥ II were included in the study. Moreover, females had no history of POP and any previous history of urogynecological surgery. A trio-based exome analysis was performed on patients and both their parents. Bioinformatic analysis of raw WES data and genetic variants prioritization were performed using in-house bioinformatic pipeline. The ClinVar database, GeneCard, and the Human Protein Atlas were used to determine clinical significance, disease associations, and linked phenotypes of the genetic variants. The impact of causative genetic variants on protein structure and function was assessed using various prediction tools including SIFT, PolyPhen2, MutPred2, Phyre2, and SNPeffect 4.0. To determine the molecular interaction network of the proteins STRING database was applied.The mean age of women was 33.50 (±3.07), the mean BMI value was 21.80 (± 2.07), and the number of parity was 1.76 (±0.44). In the study group, 18 of 25 women required surgical treatment. WES analysis identified 76 de novo variants, but only 19 were missense and two were nonsense variants. Three genetic variants in CSPG4, ITGA7, and MT-CO3 genes appear potentially relevant to POP. Interestingly, paternally inherited variants in SGCG, CYP24A1, and TK2 genes likely related to POP were found in carriers of new de novo variants.In this study, no common genetic variants were found in the female group. Potentially causative patient-specific variants were found in genes related to extracellular matrix, mitochondria, or skeletal muscle conditions. The uncovered genetic variants presumably disrupt the functioning of muscles and mitochondria, which may consequently lead to pelvic floor dysfunction in young women.
Product Used
Variant Libraries

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