Genetic reanalysis of patients with a difference of sex development carrying the NR5A1/SF-1 variant p.Gly146Ala has discovered other likely disease-causing variations.

NR5A1/SF-1 (Steroidogenic factor-1) variants may cause mild to severe differences of sex development (DSD) or may be found in healthy carriers. The NR5A1/SF-1 c.437G>C/p.Gly146Ala variant is common in individuals with a DSD and has been suggested to act as a susceptibility factor for adrenal disease or cryptorchidism. Since the allele frequency is high in the general population, and the functional testing of the p.Gly146Ala variant revealed inconclusive results, the disease-causing effect of this variant has been questioned. However, a role as a disease modifier is still possible given that oligogenic inheritance has been described in patients with NR5A1/SF-1 variants. Therefore, we performed next generation sequencing (NGS) in 13 DSD individuals harboring the NR5A1/SF-1 p.Gly146Ala variant to search for other DSD-causing variants and clarify the function of this variant for the phenotype of the carriers. Panel and whole-exome sequencing was performed, and data were analyzed with a filtering algorithm for detecting variants in NR5A1- and DSD-related genes. The phenotype of the studied individuals ranged from scrotal hypospadias and ambiguous genitalia in 46,XY DSD to opposite sex in both 46,XY and 46,XX. In nine subjects we identified either a clearly pathogenic DSD gene variant (e.g. in AR) or one to four potentially deleterious variants that likely explain the observed phenotype alone (e.g. in FGFR3, CHD7). Our study shows that most individuals carrying the NR5A1/SF-1 p.Gly146Ala variant, harbor at least one other deleterious gene variant which can explain the DSD phenotype. This finding confirms that the NR5A1/SF-1 p.Gly146Ala variant may not contribute to the pathogenesis of DSD and qualifies as a benign polymorphism. Thus, individuals, in whom the NR5A1/SF-1 p.Gly146Ala gene variant has been identified as the underlying genetic cause for their DSD in the past, should be re-evaluated with a NGS method to reveal the real genetic diagnosis.

Impact of COVID-19 lockdown on glycemic control in patients with type 1 diabetes.

INTRODUCTION: The COVID-19 pandemic has forced governments to take exceptional measures to minimize its spread, imposing lockdown policies. The aim of this study was to evaluate the impact of lockdown on type 1 diabetes (T1D) glycemic control. MATERIAL AND METHODS: People with T1D using flash glucose monitoring were included. Data from the 14 days before lockdown were compared with data from the last 14 days after 8 weeks of lockdown. RESULTS: A total of 307 patients were included (age 45.8 ± 12.6 years, 50.2% male, diabetes duration 21.1 ± 12.3 years). Only one patient had COVID-19 infection. Mean glucose decreased from 166.89 ± 29.4 to 158.0 ± 29.0 mg/dL and estimated HbA1c declined from 7.4 ± 1.0 to 7.1 ± 1.0% (54 ± 10.9 vs 57 ± 10.9 mmol/mol; p < 0.001). Time in range increased from 57.8 ± 15.8 to 62.46 ± 16.1%. Time in hyperglycemia > 180 mg/dL and >250 mg/dL decreased from 37.3 ± 1.9% to 32.0 ± 17.1% and from 13.0 ± 11.3 to 10.3 ± 10.6%, respectively; (p < 0.001). Time in hypoglycaemia <70 mg/dL increased from 4.9 ± 4.0% to 5.5 ± 4.4% (p < 0.001). No differences in time <54 mg/dl, coefficient of variation (CV%) or number of scans per day were found. CONCLUSION: Despite the limitations of lockdown, glycemic control improved in patients with T1D. These results suggest that having more time for self-management may help improve glycemic control in the short term.