Deletion of five residues from the coiled coil of fibrinogen (Bβ Asn167_Glu171del) associated with bleeding and hypodysfibrinogenemia

Genotype:phenotype correlation in dysfibrinogenemia remains unpredictable, and so additions to clinical data are valuable. In this report, the authors identify a novel mutation resulting in loss of 5 amino acids from the fibrinogen B‚ chain and causing hypodysfibrinogenemia. The mutation is associated with bleeding in this family but caution is counseled in attributing this directly or entirely to the abnormal fibrinogen

Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1/SF-1 variants of sex developmentResearch in context

Summary: Background: Steroidogenic factor 1 (SF-1/NR5A1) is essential for human sex development. Heterozygous NR5A1/SF-1 variants manifest with a broad range of phenotypes of differences of sex development (DSD), which remain unexplained. Methods: We conducted a retrospective analysis on the so far largest international cohort of individuals with NR5A1/SF-1 variants, identified through the I-DSD registry and a research network. Findings: Among 197 individuals with NR5A1/SF-1 variants, we confirmed diverse phenotypes. Over 70% of 46, XY individuals had a severe DSD phenotype, while 90% of 46, XX individuals had female-typical sex development. Close to 100 different novel and known NR5A1/SF-1 variants were identified, without specific hot spots. Additionally, likely disease-associated variants in other genes were reported in 32 individuals out of 128 tested (25%), particularly in those with severe or opposite sex DSD phenotypes. Interestingly, 48% of these variants were found in known DSD or SF-1 interacting genes, but no frequent gene-clusters were identified. Sex registration at birth varied, with <10% undergoing reassignment. Gonadectomy was performed in 30% and genital surgery in 58%. Associated organ anomalies were observed in 27% of individuals with a DSD, mainly concerning the spleen. Intrafamilial phenotypes also varied considerably. Interpretation: The observed phenotypic variability in individuals and families with NR5A1/SF-1 variants is large and remains unpredictable. It may often not be solely explained by the monogenic pathogenicity of the NR5A1/SF-1 variants but is likely influenced by additional genetic variants and as-yet-unknown factors. Funding: Swiss National Science Foundation (320030-197725) and Boveri Foundation Zürich, Switzerland