No abstract

Sex determination in mammals is governed by antagonistic interactions of two genetic pathways, imbalance in which may lead to disorders/differences of sex development (DSD) in human. Among 46,XX individuals with testicular DSD (TDSD) or ovotesticular DSD (OTDSD), testicular tissue is present in the gonad. Although the testis-determining geneSRYis present in many cases, the etiology is unknown in mostSRY-negative patients. We performed exome sequencing on 78 individuals with 46,XX TDSD/OTDSD of unknown genetic etiology and identified seven (8.97%) with heterozygous variants affecting the fourth zinc finger (ZF4) of Wilms’ tumor 1 (WT1) (p.Ser478Thrfs*17, p.Pro481Leufs*15, p.Lys491Glu, p.Arg495Gln [x3], p.Arg495Gly). The variants were de novo in six families (P= 4.4 × 10−6), and the incidence of WT1 variants in 46,XX DSD is enriched compared to control populations (P< 1.8 × 10−4). The introduction of ZF4 mutants into a human granulosa cell line resulted in up-regulation of endogenous Sertoli cell transcripts andWt1Arg495Gly/Arg495GlyXX mice display masculinization of the fetal gonads. The phenotype could be explained by the ability of the mutated proteins to physically interact with and sequester a key pro-ovary factor β-CATENIN, which may lead to up-regulation of testis-specific pathway. Our data show that unlike previous association of WT1 and 46,XY DSD, ZF4 variants of WT1 are a relatively common cause of 46,XX TDSD/OTDSD. This expands the spectrum of phenotypes associated with WT1 variants and shows that the WT1 protein affecting ZF4 can function as a protestis factor in an XX chromosomal context.

Background Female sex is an independent predictor of stroke in patients with atrial fibrillation (AF). Older data suggest undertreatment with anticoagulation among women compared with men. However, it is unknown if novel therapies and updated guidelines have impacted sex differences in AF treatment and outcomes. Methods and Results We performed a retrospective cohort study of 2.3 million women and men with a new diagnosis of AF and CHA 2 DS 2 ‐VASc ≥2 from Marketscan US commercial claims data from 2008 to 2015 to determine whether women with AF remain undertreated and whether this difference mediates observed differences in outcomes. There were 358 649 patients with newly diagnosed AF (43% women). Compared with men, women were older, with higher CHA 2 DS 2 ‐VASc scores, and higher comorbidity burden ( P <0.0001 for all). Oral anticoagulation‐eligible women with CHA 2 DS 2 ‐VASc scores ≥2 were more likely to not receive anticoagulation (50.0% women versus 43.9% men). Women, compared with men, had a higher risk of ischemic stroke (adjusted hazard ratio [aHR], 1.27; 95% CI, 1.21–1.32; P <0.0001) and hospitalization (aHR, 1.06; 95% CI, 1.05–1.07, P <0.0001) but had a lower risk of intracranial bleeding (aHR, 0.91; 95% CI, 0.83–0.99, P =0.03). In mediation analysis, nonreceipt of oral anticoagulation partially mediated the observed increased risk of stroke and decreased risk of intracranial bleeding in women. Conclusions In the care of newly diagnosed AF in the United States, women, compared with men, are less likely to receive oral anticoagulation. This appears to mediate the increased risk of both stroke and hospitalization but also appears to mediate lower observed intracranial bleeding risk.

Missense variants in the RNA-helicase DHX37 are associated with either 46,XY gonadal dysgenesis or 46,XY testicular regression syndrome (TRS). DHX37 is required for ribosome biogenesis, and this subgroup of XY DSD is a new human ribosomopathy. In a cohort of 140 individuals with 46,XY DSD, we identified 7 children with either 46,XY complete gonadal dysgenesis or 46,XY TRS carrying rare or novel DHX37 variants. A novel p.R390H variant within the RecA1 domain was identified in a girl with complete gonadal dysgenesis. A paternally inherited p.R487H variant, previously associated with a recessive congenital developmental syndrome, was carried by a boy with a syndromic form of 46,XY DSD. His phenotype may be explained in part by a novel homozygous loss-of-function variant in the <i>NGLY1</i> gene, which causes a congenital disorder of deglycosylation. Remarkably, a homozygous p.T477H variant was identified in a boy with TRS. His fertile father had unilateral testicular regression with typical male genital development. This expands the DSD phenotypes associated with DHX37. Structural analysis of all variants predicted deleterious effects on helicase function. Similar to all other known ribosomopathies, the mechanism of pathogenesis is unknown.