Whole Exome Sequencing Reveals Candidate Variants in Ion Channel Genes for Pelvic Muscle Dysfunction in Young Females...

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.