Sadakierska-Chudy Anna, Szymanowski Paweł, Szepieniec Wioletta Katarzyna, Bartosiewicz Angelika, Lebioda Arleta, Płoski Rafał, Pollak Agnieszka
Department of Andrzej Frycz Modrzewski Krakow University, Krakow, Poland.
Department of Gynecology and Urogynecology, Faculty of Medicine, Collegium Medicum, Andrzej Frycz Modrzewski Krakow University, Krakow, Poland.
Am J Obstet Gynecol. 2025 Mar 27. doi: 10.1016/j.ajog.2025.03.029.
Pelvic organ prolapse is a common condition usually affecting postmenopausal women, but it is also seen in about 10% of women aged 20 to 39 years. In young females, genetic factors seem to be of particular interest.
This study aimed to identify inherited and de novo variants relevant to pelvic organ prolapse in young females without a family history.
A total of 25 women aged ≤40 years with parity ≤2 and Pelvic Organ Prolapse Quantification stage ≥II were included in the study. Moreover, females had no history of pelvic organ prolapse and any previous history of urogynecological surgery. A trio-based exome analysis was performed on patients and both their parents. Bioinformatic analysis of raw whole exome sequencing data and genetic variant 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 Sorting Intolerant From Tolerant, PolyPhen2, MutPred2, Phyre2, and SNPeffect 4.0. To determine the molecular interaction network of the proteins, Search Tool for the Retrieval of Interacting Genes database was applied.
The mean age of women was 33.50 (±3.07) years, the mean body mass index 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. Whole exome sequencing analysis identified 76 de novo variants, but only 19 were missense and 2 were nonsense variants. Three genetic variants in CSPG4, ITGA7, and MT-CO3 genes appear potentially relevant to pelvic organ prolapse. Interestingly, paternally inherited variants in SGCG, CYP24A1, and TK2 genes likely related to pelvic organ prolapse 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.
盆腔器官脱垂是一种常见病症，通常影响绝经后女性，但在20至39岁的女性中也有大约10%会出现。在年轻女性中，遗传因素似乎特别值得关注。
本研究旨在识别无家族病史的年轻女性中与盆腔器官脱垂相关的遗传和新生变异。
共有25名年龄≤40岁、产次≤2且盆腔器官脱垂定量分期≥II期的女性纳入本研究。此外，这些女性无盆腔器官脱垂病史及任何既往泌尿妇科手术史。对患者及其父母进行了基于三联体的外显子组分析。使用内部生物信息学流程对原始全外显子组测序数据进行生物信息学分析并对遗传变异进行优先级排序。利用ClinVar数据库、GeneCard和人类蛋白质图谱来确定遗传变异的临床意义、疾病关联及相关表型。使用包括从耐受中筛选不耐受、PolyPhen2、MutPred2、Phyre2和SNPeffect 4.0等多种预测工具评估致病遗传变异对蛋白质结构和功能的影响。为确定蛋白质的分子相互作用网络，应用了检索相互作用基因的搜索工具数据库。
女性的平均年龄为33.50（±3.07）岁，平均体重指数值为21.80（±2.07），产次为1.76（±0.44）。在研究组中，25名女性中有18名需要手术治疗。全外显子组测序分析鉴定出76个新生变异，但只有19个是错义变异，2个是无义变异。CSPG4、ITGA7和MT - CO3基因中的三个遗传变异似乎与盆腔器官脱垂潜在相关。有趣的是，在新的新生变异携带者中发现了SGCG、CYP24A1和TK2基因中可能与盆腔器官脱垂相关的父系遗传变异。
在本研究中，女性组未发现常见的遗传变异。在与细胞外基质、线粒体或骨骼肌状况相关的基因中发现了潜在的致病患者特异性变异。所发现的遗传变异可能破坏肌肉和线粒体的功能，进而可能导致年轻女性盆底功能障碍。
