Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targeted-panel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.

First-trimester FGR and PAPP-A<5th percentile are associated with delivery of an SGA infant. Neither of these parameters or the combination of the two are sufficient powerful predictors of SGA to be clinically useful screening tools.

Obstetricians were more likely to think cardiac surgery was ethical if the prognosis or the outcome was good. Most respondents did not think that insurance companies should be required to subsidize the cost of cardiac surgeries for all babies with trisomy 18 or 13.

We evaluated the impact of assisted reproductive technology (ART) on the association between first-trimester pregnancy-associated plasma protein A (PAPP-A) and human chorionic gonadotropin (β-hCG) and adverse pregnancy outcomes. PAPP-A and β-hCG levels were obtained between 11 and 13 (6)/ (7) weeks' gestation and converted to multiples of the median (MoM). MoM < 5th percentile was defined as low PAPP-A or β-hCG and those > 90th percentile as high. Adverse outcomes included small-for-gestational-age (SGA) infants, preeclampsia, pregnancy loss, and preterm delivery (PTD). Univariate and multivariate analyses were used to estimate the association. Of 4000 women meeting the inclusion criteria, 265 (7.6%) pregnancies were conceived by ART. ART pregnancies with low PAPP-A had a higher risk of having an SGA infant (odds ratio [OR] = 4.1, 95% confidence interval [CI] 1.2, 14.0) or PTD < 32 weeks (OR = 5.3, 95% CI 1.5, 18.6) compared with non-ART pregnancies with low PAPP-A (OR = 2.8, 95% CI 1.7, 4.7; OR = 3.9, 95% CI 2.1, 7.0, respectively). High PAPP-A was associated with pregnancy loss (OR = 6.1, 95% CI 1.1, 33.7) in ART pregnancies. Low β-hCG was associated with increased risk for PTD only in ART pregnancies (OR = 8.3, 95% CI 1.9, 35.9) for PTD < 37 weeks (OR 6.1, 95% CI 1.6, 23.0) for PTD < 35 weeks and (OR = 10.8, 95% CI 2.7, 43.7) for PTD < 32 weeks. High β-hCG was associated with increased risk for SGA (OR = 1.6, 95% CI 1.0, 2.5) and PTD < 37 weeks (OR = 1.4, 95% CI 1.0, 1.9) in non-ART pregnancies. The association between PAPP-A and β-hCG with adverse pregnancy outcomes is influenced by the mode of conception.

The types, interpretation, and use of first- and second-trimester aneuploidy screening are often unclear for many women. This impairs appropriate decision making and understanding of the implications of prenatal genetic testing options. The purpose of this study was to examine the utilization of Stepwise Sequential screening in our Midwestern population, demographic factors associated with choice of screening and method of risk reporting and it’s potential impact on women’s choices. First trimester screening was performed for 2,634 women during the study period. Results were not reported or “framed” as “positive” or “negative”. Rather, the specific age-risk and screen-risk for T21 were relayed, along with options for follow-up Stepwise Sequential screening and invasive testing. Nearly 80 % of women declined Stepwise Sequential screening. Minorities and women of lower education were least likely to pursue further screening. Less than 4 % of the study population elected invasive testing. First trimester screening was associated with a 53 % reduction in amniocenteses and 20 % fewer CVS’s compared to pre-first trimester screening availability. Reporting age-and screen-risks for T21, rather than classifying results as “positive” or “negative” based on a pre-determined threshold, was associated with a low uptake of further testing.

With a slight reduction in the Down syndrome detection rate, the use of the likelihood ratio approach was associated with a significantly lower false-positive rate compared with the logistic regression approach.

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