Evaluation of DSD training schools organized by cost action BM1303 "DSDnet"

Abstract Background The Differences of Sex Development network (DSDnet) aims to establish interactive relationships between clinicians, scientists, support groups and people with a difference of sex development (DSD) to improve the overall care for people affected by such condition. DSDnet has hosted three Training Schools (TSs) in Ghent, Bologna and Budapest between 2015 and 2017 with the primary purpose of providing multidisciplinary training to young professionals and encouraging ongoing activity in the field of DSD. The aim of our study was to evaluate the success and long-term effect effectiveness of these three TSs. Methods and results Eighty-seven trainees (70 women, 17 men) attended one of three TSs. The distribution of trainees according to their professional field was: 47 (54.0%) from Pediatrics/Endocrinology, 13 (14.9%) from Biology/Genetics, 12 (13.8%) from Psychology/Psychiatry and 15 (17.2%) from Surgical Professions. All trainees were asked to complete an evaluation form on the last day of the TS to gain feedback on how to improve the next one. A further survey was sent at the end of 2017 to provide information about the overall long-term impact of the TSs. Seventy-eight (89.7%) trainees completed evaluation forms at the end of the respective TSs. Replies to the subsequent survey were received from 76 (87.4%) of trainees. A total of 72/76 (94.7%) responders reported that they continue to be active in the field of DSD. The vast majority (64/68, 94.1%) reported that the TSs had enlarged their professional networks. Among the 76 respondent trainees, 11.8% (n = 9) had applied for a research grant and 10.5% (n = 8) had received a fellowship related to DSD since their TS attendance. Conclusions According to our results, the majority of TS participants continue to be active in the field of DSD and have enlarged their professional networks following participation at the TS. These findings indicate the need of this type of educational program and justify ongoing efforts to provide postgraduate multidisciplinary training in rare diseases such as DSD

Pathogenic mosaic variants in congenital hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder resulting in absent puberty and infertility. The genetic architecture is complex with multiple loci involved, variable expressivity, and incomplete penetrance. The majority of cases are sporadic, consistent with a disease affecting fertility. The current study aims to investigate mosaicism as a genetic mechanism for CHH, focusing on de novo rare variants in CHH genes. We evaluated 60 trios for de novo rare sequencing variants (RSV) in known CHH genes using exome sequencing. Potential mosaicism was suspected among RSVs with altered allelic ratios and confirmed using customized ultradeep sequencing (UDS) in multiple tissues. Among the 60 trios, 10 probands harbored de novo pathogenic variants in CHH genes. Custom UDS demonstrated that three of these de novo variants were in fact postzygotic mosaicism-two in FGFR1 (p.Leu630Pro and p.Gly348Arg), and one in CHD7 (p.Arg2428*). Statistically significant variation across multiple tissues (DNA from blood, buccal, hair follicle, urine) confirmed their mosaic nature. We identified a significant number of de novo pathogenic variants in CHH of which a notable number (3/10) exhibited mosaicism. This report of postzygotic mosaicism in CHH patients provides valuable information for accurate genetic counseling