Novel early first trimester ultrasound measures in the prediction of miscarriage, small-for-gestational age neonates and maternal hypertensive disorders

One of the primary roles of obstetric care is the prediction of adverse fetal and maternal outcomes. Ultrasound is commonly used prior to 11 weeks gestation however there is a paucity of published research investigating the value of ultrasound features at this early stage in the prediction of adverse fetal and maternal outcomes later in pregnancy. Adverse pregnancy outcomes of small-for-gestational age/intrauterine growth restriction and maternal hypertensive disorders (gestational hypertension and pre-eclampsia) are significant pregnancy complications that often result in poor short- and long-term outcomes for both child and mother. Early prediction coupled with prophylactic intervention has been demonstrated to reduce the prevalence of these outcomes. First trimester miscarriage is common, and while its prediction may not influence the outcome, ultrasound is uniquely situated to significantly impact the clinical management of these women. The research presented in this thesis investigates the potential for a combination of conventional and novel ultrasound measures prior to 11 weeks gestation to predict adverse pregnancy outcomes including miscarriage prior to 12 weeks gestation and the development of small-for-gestational age and maternal hypertensive disorders later in pregnancy. We found that when measured prior to 11 weeks gestation, less than expected trophoblast volume for gestational age is significantly associated with all three adverse outcomes of interest. In addition, together with maternal characteristics and biochemistry, trophoblast volume measurements may add to the value of current prediction methods for small-for-gestational age and maternal hypertensive disorders and may enable prediction at an earlier gestational age

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling

The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative. We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology. Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory. Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function