Obstetric and gynaecological features in females carrying variants in the skeletal muscle ryanodine receptor type 1 (RYR1) gene: a questionnaire study

Mutations in the ryanodine receptor type 1 (RYR1) gene are amongst the most common causes of early-onset, non-dystrophic neuromuscular disorders. RYR1 mutations have also anecdotally been implicated in non-skeletal muscle symptoms such as an increased bleeding tendency particularly prominent in females, but the prevalence of these features is currently unknown. In this questionnaire-based study, we aimed to evaluate smooth muscle function, bleeding, obstetric, and gynaecological outcomes in RYR1-variant carrying females. Questions were developed using a modified version of the MCMDM-1VWD questionnaire, and the NHS-heavy periods self-assessment tool. Obstetric and gynaecological symptoms explored included pregnancy-related complications, gestation length, parturition duration, post-partum haemorrhage and offspring birthweight. Recruitment was online via the RYR1-Foundation patient support group and covered countries across the world. We identified 66 RYR1-variant carrying females and 88 non-mutated controls including unaffected relatives and the general healthy population. Women with RYR1 variants exhibited a higher incidence of pathological bleeding scores (p < 0.0001), severe menstrual bleeding, complications during pregnancy (preeclampsia and placenta praevia), frequent planned Caesarean sections, offspring with lower birthweight, and gastrointestinal symptoms, compared to controls. Considering their population frequency in otherwise pauci-symptomatic individuals, RYR1 variants ought to be considered as a cause of unexplained menorrhagia and other gynaecological and obstetric manifestations.