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PurposeDominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12.MethodsWe used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids.ResultsWe found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators' recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment.ConclusionOur study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.

Background: The proportion of females enrolling into medical schools has been growing steadily. However, the representation of female residents among individual specialties has shown considerable variation. The purpose of this study was to compare the trends of gender representation in Otolaryngology - Head and Neck Surgery (OTL-HNS) residency programs with other specialty training programs in Canada. In order to contextualize these findings, a second phase of analysis examined the success rate of applicants of different genders to OTL-HNS residency programs. Method: Anonymized data were obtained from the Canadian Residency Matching Service (CaRMS) and from the Canadian Post-M.D. Education Registry (CAPER) from 1988 to 2014. The differences in gender growth rates were compared to other subspecialty programs of varying size. Descriptive analysis was used to examine gender representation among OTL-HNS residents across years, and to compare these trends with other specialties. Bayesian hierarchical models were fit to analyze the growth in program rates in OTL-HNS based on gender. Results: CaRMS and CAPER data over a 27 year period demonstrated that OTL-HNS has doubled its female representation from 20% to 40% between 1990 and 1994 and 2010-2014. The difference in annual growth rate of female representation versus male representation in OTL-HNS over this time period was 2.7%, which was similar to other large specialty programs and surgical subspecialties. There was parity in success rates of female and male candidates ranking OTL-HNS as their first choice specialty for most years. Conclusions: Female representation in Canadian OTL-HNS residency programs is steadily increasing over the last 27 years. Large variation in female applicant acceptance rates was observed across Canadian universities, possibly attributable to differences in student body or applicant demographics. Factors influencing female medical student career selection to OTL-HNS require further study to mitigate disparities in gender representation and identify barriers to prospective female OTL-HNS applicants. [ABSTRACT FROM AUTHOR]