Fetal Nasal Bone Length in the East African Population.

OBJECTIVES: To establish normal ranges of fetal nasal bone length throughout gestation in the East African population and to subsequently compare these measurements with the standardized reference. METHODS: A retrospective cross-sectional study was performed at the University of Minnesota from January 2011 to December 2016. Fetal nasal bone length measurements were generated in a midsagittal plane at an angle of insonation of 45° from ultrasound images of 1407 nonanomalous fetuses of 1130 mothers of East African decent between 14 and 40 weeks' gestation. The proportion of fetal nasal bone lengths of less than 5.2 mm at week 20 of gestation in the East African population was then compared with the 5% noted by the standardized reference by a χ2 test. RESULTS: The fetal nasal bone length increased linearly with advancing gestational age in fetuses of East African mothers (R2 = 0.53; P < .0001). The fetal nasal bone lengths of the East African fetuses were found to be shorter at all ages of gestation compared with the standard reference. At 20 weeks' gestation 17% (95% confidence interval, 13%-22%) of the nasal bone lengths of the East African fetuses were less than 5.2 mm compared with 5% of white and African American fetuses. CONCLUSIONS: Using the standard reference may lead to a greater than 3.5-fold overdiagnosis of hypoplastic nasal bones in the East African population. To improve aneuploidy risk stratification and patient counseling in the East African population, the introduction of a standardized East African-based fetal nasal bone length reference seems warranted.

Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy.

Glutamatergic neurotransmission governs excitatory signaling in the mammalian brain, and abnormalities of glutamate signaling have been shown to contribute to both epilepsy and hyperkinetic movement disorders. The etiology of many severe childhood movement disorders and epilepsies remains uncharacterized. We describe a neurological disorder with epilepsy and prominent choreoathetosis caused by biallelic pathogenic variants in FRRS1L, which encodes an AMPA receptor outer-core protein. Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities of glutamatergic neurotransmission in this monogenic neurological disease of childhood.

Impact of labor induction at 39 weeks gestation compared with expectant management on maternal and perinatal morbidity among a cohort of low-risk women.

OBJECTIVE: To determine maternal and perinatal outcomes after induction of labor (IOL) at 39 weeks compared with expectant management. METHODS: This is a retrospective national cohort study from the National Center for Health Statistics birth database. The study included singleton, low-risk pregnancies with a non-anomalous fetus delivered at 39-42 weeks gestation between 2015 and 2018. Maternal outcomes available included chorioamnionitis (Triple I), blood transfusion, intensive care unit (ICU) admission, uterine rupture, cesarean delivery (CD), and cesarean hysterectomy. Fetal and infant outcomes included stillbirth, 5-min Apgar ≤3, prolonged ventilation, seizures, ICU admission, and death within 28 days. We compared women undergoing IOL at 39 weeks to those managed expectantly. Non-adjusted and adjusted relative risks (aRRs) were estimated using multivariate log-binomial regression analysis. RESULTS: There were 15,900,956 births available for review of which 5,017,524 met inclusion and exclusion criteria. For the maternal outcomes, the IOL group was less likely to require a CD (aRR 0.880; 95% CI [0.874-0.886]; p value < .01) or develop Triple I (aRR 0.714; 95% CI [0.698-0.730]; p value < .01) but demonstrated a small increase in the cesarean hysterectomy rate (aRR 1.231; 95% CI [1.029-1.472]; p value < .01). Among perinatal outcomes, the stillbirth rate (aRR 0.195; 95% CI [0.153-0.249]; p value < .01), 5-min Apgar ≤3 (aRR 0.684; 95% CI [0.647-0.723]; p value < .01), prolonged ventilation (aRR 0.840; 95% CI [0.800-0.883]; p value < .01), neonatal intensive care (NICU) admission (aRR 0.862; 95% CI [0.849-0.875]; p value < .01) were lower after 39 week IOL compared with expectant management. There were no differences in risk for neonatal seizures (aRR 0.848; 95% CI [0.718-1.003]; p value 0.011) or death (aRR 1.070; 95% CI [0.722-1.586]; p value 0.660). CONCLUSIONS: IOL at 39 weeks of gestation in a low-risk cohort is associated with a lower risk of CD and maternal infection, stillbirth, and lower neonatal morbidity. There was no effect on the risk for neonatal seizures or death.

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.

Prenatal Identification and Molecular Characterization of Two Simultaneous De Novo Interstitial Duplications of Chromosomal Regions 7p22.1p21.1 and 15q24.1.

The occurrence of simultaneous de novo chromosomal aberrations is extremely rare. Here, we describe two, previously unreported, simultaneous de novo interstitial duplications of chromosomes 7p and 15q. Amniocentesis was completed for a healthy gravida 4 para 3 woman due to her advanced maternal age and concurrent ultrasound findings of partial vermian agenesis, choroid-plexus cysts, and hypoplastic nasal bone. Cytogenetic analysis of cultured amniocytes by conventional chromosome analysis, comparative genomic hybridization, and fluorescence in situ hybridization revealed two interstitial duplications of the chromosomal regions 7p22.1p21.1 and 15q24.1, leading to partial trisomy of 7p and 15q and karyotype 46,XY,dup(7)(p22.1-p21.1),dup (15)(q24.1). Parental chromosomal analysis did not identify any heritable changes, suggesting both mutations were de novo in nature. Postnatal examination of the neonate was significant for low set ears, thick helices, flat nasal bridge, ankyloglossia, and aberrant head shape and size concerning for craniosynostosis. Postnatal MRI was consistent with Dandy-Walker variant showing hypogenesis of the inferior cerebellar vermis. To our knowledge, there are no prenatal or postnatal reports of comparable duplications involving these two regions simultaneously. Continued observation of the neonate may reveal further phenotypic consequences of these two simultaneous de novo interstitial duplications.

Neonatal Morbidity and Maternal Complication Rates in Women With a Delivery Body Mass Index of 60 or Higher.

OBJECTIVE: To investigate neonatal morbidity and maternal complication rates with delivery body mass index (BMI) 60 or greater. METHODS: This retrospective, multicenter cohort study included singleton pregnancies between 23 and 42 weeks of gestation from January 2005 to April 2016. Women with BMI 60 or greater were compared with a random sample of women with BMI 30-59. The primary outcome, composite neonatal morbidity, was defined as 5-minute Apgar score less than 7, hypoglycemia, respiratory distress syndrome, sepsis, hospital stay greater than 5 days, neonatal intensive care unit admission, or neonatal death. Secondary outcomes included maternal labor and delivery characteristics and complication rates. Kruskal-Wallis tests and χ or Fisher exact tests were used to compare BMI categories. Multivariable logistic regression was used for adjusted analysis. RESULTS: The study included 338 women, with 39 in the BMI 60 or greater group. An association between obesity and neonatal morbidity was found. Increasing BMI correlated with increasing neonatal morbidity, with the highest rates among those with BMI 60 or greater (BMI 30-39 [17%], 40-49 [19%], 50-59 [22%], 60 or greater [56%]; P<.001). After adjustment for confounders, obese women with BMI less than 60 had at least a 75% reduction in odds of neonatal morbidity compared with women with BMI 60 or greater (BMI 30-39 adjusted odds ratio [OR] 0.22 [0.1-0.5], 40-49 adjusted OR 0.23 [0.1-0.6], 50-59 adjusted OR 0.25 [0.1-0.6]). Maternal complication rates including labor induction, cesarean delivery, wound complication, postpartum hemorrhage, and hospital stay greater than 5 days were also significantly increased with BMI 60 or greater. CONCLUSION: A BMI 60 or greater at the time of delivery is significantly associated with increased neonatal morbidity and increased maternal complication rates. In addition, neonatal morbidity and maternal complication rates with BMI 60 or greater were significantly higher when compared with women in any lesser obese BMI cohort between 30 and 59.

Mutation in GM2A Leads to a Progressive Chorea-dementia Syndrome.

BACKGROUND: The etiology of many cases of childhood-onset chorea remains undetermined, although advances in genomics are revealing both new disease-associated genes and variant phenotypes associated with known genes. METHODS: We report a Saudi family with a neurodegenerative course dominated by progressive chorea and dementia in whom we performed homozygosity mapping and whole exome sequencing. RESULTS: We identified a homozygous missense mutation in GM2A within a prominent block of homozygosity. This mutation is predicted to impair protein function. DISCUSSION: Although discovered more than two decades ago, to date, only five patients with this rare form of GM2 gangliosidosis have been reported. The phenotype of previously described GM2A patients has been typified by onset in infancy, profound hypotonia and impaired volitional movement, intractable seizures, hyperacusis, and a macular cherry red spot. Our findings expand the phenotypic spectrum of GM2A mutation-positive gangliosidosis to include generalized chorea without macular findings or hyperacusis and highlight how mutations in neurodegenerative disease genes may present in unexpected ways.