An exome-wide exploration of cases of primary ovarian insufficiency uncovers novel sequence variants and candidate genes.

Primary ovarian insufficiency (POI) implies the cessation of menstruation for several months in women before the age of 40 years and is a major cause of infertility. The study of the contribution of genetic factors to POI has been fueled by the use of whole exome sequencing (WES). Here, to uncover novel causative pathogenic variants and risk alleles, WES has been performed in 12 patients with familial POI (eight unrelated index cases and two pairs of sisters) and six women with early menopause and family history of POI (four index cases and one pair of sisters). Likely causative variants in NR5A1 and MCM9 genes were identified as well as a variant in INHA that requires further investigation. Moreover, we have identified more than one candidate variant in 3 out of 15 familial cases. Taken together, our results highlight the genetic heterogeneity of POI and early menopause and support the hypothesis of an oligogenic inheritance of such conditions, in addition to monogenic inheritance.

Educational tools support informed decision-making for genetic carrier screening in a heterogenic Israeli population.

Reproductive genetic carrier screening (RGCS) aims to provide couples with information to make informed decisions. Since 2013, the Israeli Carrier Screening Program has been offered routinely and free of charge to all Israelis of reproductive age, personalized based on religion, ethnicity, and village/tribe where a disorder is frequent. This study evaluated the impact of two educational tools on an informed choice on RGCS uptake and satisfaction with counselling within a heterogeneous population in northern Israel. Participants from diverse sociodemographic population groups were randomly assigned to watch an animated film, read a booklet conveying the same information, or receive no information before counselling for RGCS, and asked to complete pre- and post-counselling questionnaires. A higher informed-decision rate was demonstrated in the film (n=93/141, 66%) and booklet (n=88/131, 67%) groups vs. the non-intervention group (n=62/143, 43%) (P<0.001), assessed by the Multidimensional Measure of Informed Choice. Multivariate logistic regression analysis revealed that allocation to an intervention group, Jewish ethnicity and higher education level, best predicted informed choice. Most participants expressed high levels of satisfaction with the counselling process, regardless of group assignment. While only a minority of participants reported seeking information prior to visiting the clinic, the pre-counselling information interventions were well accepted. Pre-counselling self-learning educational tools should be promoted, easily available, and adjusted linguistically and culturally to targeted populations, to avoid unwanted "automatic" compliance of tested individuals and maximize the potential of informed decision-making. Our study can be applied to other countries where majority and minority ethnic groups access genetic services.