Successful antenatal treatment of MAGED2-related Bartter syndrome and review of treatment options and efficacy.

A new form of transient antenatal Bartter syndrome (aBS) was recently identified that is associated with the X-linked MAGED2 variant. Case reports demonstrate that this variant leads to severe polyhydramnios that may result in preterm birth or pregnancy loss. There is limited but promising evidence that amnioreductions may improve fetal outcomes in this rare condition. We report a woman with two affected pregnancies. In the first pregnancy, the patient was diagnosed with mild-to-moderate polyhydramnios in the second trimester that ultimately resulted in preterm labor and delivery at 25 weeks with fetal demise. Whole exome sequencing of the amniotic fluid sample resulted after the pregnancy loss and revealed a c.1337G>A MAGED2 variant that was considered diagnostically. The subsequent pregnancy was confirmed by chorionic villi sampling to also be affected by this variant. The pregnancy was managed with frequent ultrasounds and three amnioreductions that resulted in spontaneous vaginal delivery at 37 weeks and 6 days of a viable newborn with no evidence of overt electrolyte abnormalities suggesting complete resolution. A detailed review of the published cases of MAGED2-related transient aBS is provided. Our review focuses on individuals who received antenatal treatment. A total of 31 unique cases of MAGED2-related transient aBS were compiled. Amnioreduction was performed in 23 cases and in 18 cases no amnioreduction was performed. The average gestational age at delivery was significantly lower in cases without serial amnioreduction (28.7 vs. 30.71 weeks, p = 0.03). Neonatal mortality was seen in 5/18 cases without serial amnioreduction, and no mortality was observed in the cases with serial amnioreduction. In cases of second trimester severe polyhydramnios without identifiable cause, whole exome sequencing should be considered. Intensive ultrasound surveillance and serial amnioreduction is recommended for the management of MAGED2-related transient aBS.

Successful Management of Fetal Torsades de Pointes and Long QT Syndrome by a Cardio-Obstetrical Team.

A 32-week fetus with tachycardia and bradycardia, diagnosed with torsades de pointes, atrioventricular block, and sinus bradycardia due to a de novo KCNH2 mutation was successfully managed by a cardio-obstetrical team. Maternal/fetal pharmacogenomic testing resulted in appropriate drug dosing without toxicity and delivery of a term infant in sinus rhythm.

Congenital diaphragmatic hernia in siblings with PIGA-related congenital disorder of glycosylation.

There are over 150 proteins involved in glycosylphosphatidylinositol (GPI)-anchored protein biosynthesis, a class within the larger category of congenital disorders of glycosylation (CDG). Pathogenic variants identified in phosphatidylinositol glycan class A protein (PIGA) are associated with X-linked PIGA-CDG, a GPI-anchor defect. The disease has primarily been characterized by hypotonia, epilepsy, and global developmental delay; however, only 89 known cases are reported, so the phenotypic spectrum has likely not yet been fully delineated. Congenital diaphragmatic hernia (CDH) has been reported in patients with various GPI-anchor related defects but has only been described in one prior individual with PIGA-CDG. Here, we describe the second and third reported cases of CDH in two brothers with PIGA-CDG caused by a pathogenic missense variant in PIGA: c.355C > T, p.R119W. Chromosomal microarray and whole exome sequencing did not reveal another plausible explanation for the CDH. We relate our patients' clinical features to the single previously reported individual with CDH and PIGA-CDG. We then compare this case series with the subset of individuals with CDH and other GPI-anchor defects. These findings suggest that CDH should be considered in the phenotypic disease spectrum of PIGA-CDG.

Piloting a multidisciplinary approach to improve outcomes of fetal whole exome sequencing: An overview of workflow and case example.

INTRODUCTION: Whole exome sequencing (WES) has increasingly become integrated into prenatal care and genetic testing pathways. Current studies of prenatal WES have focused on diagnostic yield. The possibility of obtaining a variant of uncertain significance and lack of provider expertise are frequently described as common barriers to clinical integration of prenatal WES. We describe the implementation and workflow for a multidisciplinary approach to effectively integrate prenatal WES into maternal-fetal care to overcome these barriers. METHODS: A multidisciplinary team reviews and approves potential cases for WES. This team reviews WES results, reclassifying variants as appropriate and provides recommendations for postnatal care. A detailed description of this workflow is provided, and a case example is included to demonstrate effectiveness of this approach. Our team has approved 62 cases for WES with 45 patients ultimately pursuing WES. We have achieved a diagnostic yield of 40% and the multidisciplinary team has played a role in variant interpretation in 50% of the reported variants of uncertain significance. CONCLUSIONS: This approach facilitates communication between prenatal and postnatal care teams and provides accurate interpretation and recommendations for identified fetal variants. This model can be replicated to ensure appropriate patient care and effective integration of novel genomic technologies into prenatal settings.

Megacystis Associated With an Underlying ACTA2 Variant and Diagnosis of Multisystemic Smooth Muscle Dysfunction Syndrome: A Case Report.

Fetal megacystis, or an enlarged fetal bladder, is most often attributed to embryological defects, occurring early in gestation. Recent investigations have demonstrated that the underlying etiology of megacystis may be more myriad than originally thought. We present the third reported patient with megacystis due to an ACTA2 Arg179 substitution variant causing Multisystemic Smooth Muscle Dysfunction Syndrome. We also provide a description of pediatric evaluation and follow up. The growing number of cases in which this ACTA2 variant has been identified in fetal megacystis suggests that molecular sequencing is an appropriate consideration, particularly prenatally, when other features of Multisystemic Smooth Muscle Dysfunction Syndrome cannot be detected.

Evaluating for disparities in prenatal genetic counseling.

BACKGROUND: Guidelines recommend that all pregnant women should be offered prenatal genetic counseling, which includes discussions of aneuploidy and carrier screening. Previous studies have demonstrated racial and ethnic disparities in the completion of prenatal genetic testing, but few studies have evaluated for disparities in the offering of these tests. Prenatal genetic screening is a covered provision of Colorado Medicaid. We hypothesized that in the absence of a financial barrier, disparities in prenatal genetic counseling would be eliminated. OBJECTIVE: To evaluate disparities in prenatal genetic counseling by directly assessing if patients received counseling at the time of their first prenatal visit. STUDY DESIGN: This retrospective cross-sectional study included patients presenting for their first prenatal visit at <20 weeks' gestation. Patients who completed prenatal genetic testing were classified as counseled, and the remaining patients' medical records were reviewed. Moreover, patients were divided into 2 groups based on their counseling status (yes or no), separately for aneuploidy and carrier screening. RESULTS: Of 1103 patients who met the inclusion criteria, 97.2% were counseled for aneuploidy screening, whereas 73.3% were counseled on carrier screening. For aneuploidy, younger age, Black race, a relationship status of single, and presentation at a later gestational age were associated with lack of aneuploidy counseling on univariate analysis. After multivariable analysis, only maternal age (odds ratio, 1.09; 95% confidence interval, 1.01-1.19) and gestational age (odds ratio, 0.84; 95% confidence interval, 0.76-0.93) were statistically significantly associated with aneuploidy counseling. Treatment by a physician care team, having a comorbidity score of ≥1, and presenting at a later gestational age were associated with not receiving carrier screening counseling (univariate analysis). Multivariable analysis indicated significant associations with gestational age (odds ratio, 0.90; 95% confidence interval, 0.86-0.94) and having a comorbidity (odds ratio, 0.72; 95% confidence interval, 0.55-0.94). CONCLUSION: Prenatal genetic counseling was less likely to be provided to women who present for prenatal care at a later gestational age. This finding was of concern because women who are less privileged were more likely to present to prenatal care at a later gestational age. Providing access to early prenatal care and developing specialized care pathways for women entering prenatal care in the second trimester of pregnancy could address disparities in prenatal genetic counseling.

Small increase in dolutegravir trough, but equivalent total dolutegravir exposure with simeprevir in HIV/HCV seronegative volunteers.

BACKGROUND: Dolutegravir, an HIV integrase strand-transfer inhibitor, and simeprevir, an HCV NS3/4A PI, have the potential to interact as dolutegravir is a P-glycoprotein, uridine glucuronosyl transferase 1A1 and cytochrome P4503A substrate and simeprevir has been shown to mildly inhibit these. OBJECTIVES: To compare dolutegravir and simeprevir pharmacokinetics (PK) when given separately versus in combination. METHODS: Healthy volunteers received: (i) 150 mg of simeprevir once daily for 7 days; (ii) 50 mg of dolutegravir once daily for 7 days; and (iii) 150 mg of simeprevir once daily plus 50 mg of dolutegravir once daily for 7 days, with randomization to treatment sequence. Twenty-four hour intensive PK sampling was performed on day 7 of each sequence following observed dosing and a standardized meal. PK parameters were determined using non-compartmental methods and compared using paired t-tests. Bioequivalence for area under the curve (AUCtau) and maximum concentration (Cmax) were also assessed. NCT02404805. RESULTS: Twenty-four subjects completed all three sequences. Dolutegravir trough was increased 24% (P = 0.0003) with simeprevir. Dolutegravir AUCtau was increased 15% (P = 0.002), but was deemed bioequivalent as the 90% CI for the geometric mean ratio was 107%-123%. Dolutegravir Cmax was bioequivalent. Simeprevir PK was unaffected by dolutegravir. There were no discontinuations due to adverse events and all adverse events were mild to moderate in severity. CONCLUSIONS: Dolutegravir trough was increased slightly with simeprevir, but AUCtau was bioequivalent. Despite the increase in trough, dolutegravir concentrations were well within the range with established safety data. Suggesting that simeprevir and dolutegravir can be safely co-administered.