Sadakierska-Chudy Anna, Szymanowski Paweł, Szepieniec Wioletta Katarzyna, Boniewska-Bernacka Ewa, Pollak Agnieszka
Department of Genetics, Faculty of Medicine, Collegium Medicum, Andrzej Frycz Modrzewski Krakow University, Gustawa Herlinga-Grudzinskiego 1, 30-705, Krakow, Poland.
Department of Gynecology and Urogynecology, Faculty of Medicine, Collegium Medicum, Andrzej Frycz Modrzewski Krakow University, Gustawa Herlinga-Grudzinskiego 1, 30-705, Krakow, Poland.
Int Urogynecol J. 2025 Feb;36(2):457-468. doi: 10.1007/s00192-025-06048-7. Epub 2025 Jan 20.
Pelvic floor dysfunction usually results in pelvic organ prolapse (POP) and/or urinary incontinence. In women, several factors, including pregnancy and vaginal delivery, can affect pelvic muscle conditions. The aim of the study was to perform a genetic analysis in young women with a family history of pelvic floor dysfunction to find potentially harmful variants or variants that increase the risk of developing pelvic floor disorders.
We employed whole exome sequencing to test ten young women with pelvic floor muscle dysfunction (along with their parents) and a family history. The average age of symptoms was 29.1 (± 3.98) years old, soon after their first delivery.
In five out of ten patients, trio-based WES analysis revealed potentially pathogenic, causative nonsense variants in ion channel genes, including ATP1A4, CLCN1, GRIN2C, and ORAI1, as well as missense variants in PIEZO1 and RYR1. Additionally, some of these patients had variants in genes related to muscle function (MUSK) and connective tissue disorder (FKBP14, p.Glu122ArgfsTer7). The variants found in this study, such as CLCN1 (p.Arg894Ter) and MUSK (p.Val790Met), have already been associated with neuromuscular channelopathy and severe muscle weakness.
The identified candidate genes encode mainly proteins involved in electrical action potential and mechanical muscle contraction. The results suggest that the identified genetic variants may result in skeletal muscle ion channelopathies that affect muscle function, gradually leading to muscle hypotonia and weakness.
盆底功能障碍通常会导致盆腔器官脱垂（POP）和/或尿失禁。在女性中，包括怀孕和阴道分娩在内的多种因素会影响盆底肌肉状况。本研究的目的是对有盆底功能障碍家族史的年轻女性进行基因分析，以发现潜在有害变异或增加患盆底疾病风险的变异。
我们采用全外显子组测序对10名有盆底肌肉功能障碍（及其父母）且有家族史的年轻女性进行检测。症状出现的平均年龄为29.1（±3.98）岁，在她们首次分娩后不久。
在10名患者中的5名中，基于三联体的全外显子组测序分析在离子通道基因中发现了潜在致病、导致无义突变的变异，包括ATP1A4、CLCN1、GRIN2C和ORAI1，以及PIEZO1和RYR1中的错义变异。此外，其中一些患者在与肌肉功能相关的基因（MUSK）和结缔组织疾病相关的基因（FKBP14，p.Glu122ArgfsTer7）中存在变异。本研究中发现的变异，如CLCN1（p.Arg894Ter）和MUSK（p.Val790Met），已与神经肌肉通道病和严重肌无力相关。
鉴定出的候选基因主要编码参与电动作电位和肌肉机械收缩的蛋白质。结果表明，鉴定出的基因变异可能导致影响肌肉功能的骨骼肌离子通道病，逐渐导致肌张力减退和肌无力。
