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BACKGROUND:Prenatal screening has historically focused primarily on detection of fetal aneuploidies. Cell-free DNA (cfDNA) now enables noninvasive screening for subchromosomal copy number variants, including 22q11.2 deletion syndrome (22q11.2DS or DiGeorge syndrome), which is the most common microdeletion and a leading cause of congenital heart defects and neurodevelopmental delay. Although smaller studies have demonstrated the feasibility of screening for 22q11.2DS, large cohort studies with postnatal confirmatory testing to assess test performance have not been reported. OBJECTIVE:To assess the performance of SNP-based cfDNA prenatal screening for detection of 22q11.2DS. STUDY DESIGN/METHODS:Patients who had SNP-based cfDNA prenatal screening for 22q11.2DS were prospectively enrolled at 21 centers in 6 countries. Prenatal or newborn DNA samples were requested in all cases for genetic confirmation with chromosomal microarray. The primary outcome was sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of cfDNA for detection of all deletions, including the classical deletion and nested deletions that are ≥500kb, in the 22q11.2 low copy repeat A-D region. Secondary outcomes included the prevalence of 22q11.2DS and performance of an updated cfDNA algorithm that was evaluated blinded to pregnancy outcome. RESULTS:Of 20,887 women enrolled, genetic outcome was available in 18,289 (87.6%). Twelve 22q11.2DS cases were confirmed in the cohort, including five (41.7%) nested deletions, yielding a prevalence of 1:1524. In the total cohort, cfDNA reported 17,976 (98.3%) as low risk for 22q11.2DS and 38 (0.2%) as high-risk; 275 (1.5%) were non-reportable. Overall, 9 of 12 cases of 22q11.2 were detected, yielding a sensitivity of 75.0% (95% CI: 42.8, 94.5); specificity of 99.84% (95% CI: 99.77, 99.89); PPV of 23.7% (95% CI: 11.44, 40.24) and NPV of 99.98% (95% CI: 99.95, 100). None of the cases with a non-reportable result was diagnosed with 22q11.2DS. The updated algorithm detected 10/12 cases (83.3%; 95% CI: 51.6-97.9) with a lower false positive rate (0.05% vs. 0.16%, p<0.001) and a PPV of 52.6% (10/19; 95% CI 28.9-75.6). CONCLUSIONS:Noninvasive cfDNA prenatal screening for 22q11.2DS can detect most affected cases, including smaller nested deletions, with a low false positive rate.

Objective: Non-invasive prenatal screening with cell free DNA (cfDNA) includes the option to screen for microdeletion syndromes but data on test performance are limited. We report on performance of cfDNA for detection of 4 microdeletion syndromes: Cri-Du-Chat (5p-), Prader-Willi syndrome (PWS), Angelman syndrome (AS) and 1p36del syndrome.
Study Design: Secondary analysis of the SMART multicenter prospective study, which assessed cfDNA performance for 22q11.2 deletion. Newborn or fetal samples were requested in all cases for genetic confirmation with chromosomal microarray (CMA). SNP-based cfDNA screening for 4 microdeletion syndromes was performed using an investigational algorithm on patients who requested testing for these syndromes or who agreed to future research; results were compared to blinded CMA confirmation. Differentiation between PWS and AS, caused by a similar deletion/imprinting mechanism, was accomplished by comparing neonatal SNPs on CMA and maternal SNPs, if available from the cfDNA sample, in the affected region. Deletions >500kb in the syndrome critical region were considered positive. Deletions < 500kb or not including the disease-causing genes were classified as variants of uncertain significance (VUS).
Result(s): Overall, 10,971 had both cfDNA and DNA confirmation results. Median gestational age at enrollment was 13.3 weeks (8.9-36.1). CMA confirmed 5 PWS cases (1:2194), one case of PWS/AS and one 5p- (Table). Four 5p- deletions and one 1p36del were classified as VUS. Of the 7 confirmed microdeletion cases, 6 were detected by cfDNA (86.7%), including all PWS/AS cases; the 5p- case was not detected. cfDNA was reported as high-risk in 14 cases (0.12%), with FP=0.07%, a PPV of 62.5% (5/8) for PWS, and 0% (0/6) for the remaining 3 conditions. None of the confirmed cases had increased NT or structural anomalies at the time of the anatomic survey. One PWS case was diagnosed with fetal anomalies at 32wks and 2 PWS cases were diagnosed with abnormalities after birth.
Conclusion(s): cfDNA prenatal screening detected 6/7 microdeletions, including all cases of PWS/AS, with a low false positive rate. [Formula presented]
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Introduction Fetal cardiac disease is strongly associated with maternal anti-SSA/Ro antibodies, but gaps in our knowledge include the influence of antibody specificity and titer, maternal diagnosis, overall non-cardiac adverse pregnancy outcomes (APOs), optimal surveillance protocols, and efficacy of rapid treatment. Methods The multi-center Surveillance and Treatment To Prevent Fetal AV Block Likely to Occur Quickly (STOP BLOQ) study recruited pregnant women with commercially positive anti-Ro antibodies and stratified them into high and low titers of anti-Ro60 and Ro52 based on a research ELISA, using a cutoff defined by that obtained for 50 mothers with previous AVB offspring. Mothers with anti-Ro60 and/or 52 antibodies at or above 1,000 I.U. were trained to perform FHRM. From 17-25 weeks of gestation, FHRM was completed 3x/day in addition to weekly or biweekly fetal echocardiograms (echo). Mothers texted all audio sounds to the coordinating center. Texts deemed abnormal by mothers were immediately sent to an on call pediatric cardiologist who either reassured if FHRM was normal or referred for emergency fetal echo in < 6 hours if abnormal. Results 250 anti-Ro pregnant women (22% Hispanic, 50% white, 12% Black, 12% Asian, 4% other) have been consented, including 28 whose previous child had AVB. Of mothers tested to date, 153 were provided home monitors given high titer anti-Ro60 and/or 52 antibodies (26 high titer anti-Ro60 alone, 21 high titer anti-Ro52 alone,105 high titer antibodies to both antigens). The 83 patients with low titers were surveilled with echos per local standard of care. Regarding maternal diagnosis, of 161 assessed to date, 39% were asym/UAS, 11% RA, 31% SS, 19% SLE. Antibody titers did not significantly differ by ethnicity, race or diagnosis (table 1). Non-AVB APOs occurred in 18% and were not predicted by Ro60 or 52 titers but rather SLE diagnosis (table 2). In total, 24,759 FHRM audiotexts were received from 131 patients (90 of whom have delivered) during the monitoring period. Of these, 22 were evaluated by the on-call pediatric cardiologist, who prompted an emergency echo (all completed in < 6 hrs). In 11 cases, the emergency echo was normal. In 9, there were premature atrial contractions, confirming the mother's perception. In 2 with 2degree block on urgent echo (both treated per protocol with IVIG and dexamethasone), 1 reverted to normal sinus rhythm and the other progressed to 3degree block. In 2 others, the mother did not perceive abnormal FHRM for > 24 hrs, echo identified 3degree block, and retrospective cardiology review of FHRM audio captures identified an abnormality prior to obtaining the echo. All 4 AVB developed in fetuses of mothers with high titer antibodies to both Ro60 and 52 (mean 32,451 and 34,991 respectively). Of the 18 mothers with a previous AVB child who followed the 400mg hydroxychloroquine PATCH protocol, 1 developed AVB in accord with the results of Step 1 in that study. Conclusion These data support that APOs in this clinically diverse group of mothers are not influenced by anti-Ro titer or specificity, but rather SLE diagnosis. All conduction defects were initially identified by FHRM and in mothers with high titer anti-Ro60 and 52. Hydroxychloroquine continues to show efficacy in reducing the AVB recurrence rate with rapid intervention of emergent block being promising

To better understand the impact of prenatal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on infants, this study sought to compare the risk of hospital visits and of postnatal SARS-CoV-2 infection between infants born to mothers with and without prenatal SARS-CoV-2 infection. In this retrospective observational cohort study of 6871 mothers and their infants, overall rates of emergency department (ED) visits and hospital admissions in the first 90 days of life were similar for infants born to mothers with and without prenatal SARS-CoV-2 infection. Infants born to negative mothers were more likely than infants of positive mothers to be hospitalized after ED visit (relative risk: 3.76; 95% confidence interval: 1.27-11.13, P = .003). Five infants tested positive; all were born to negative mothers, suggesting that maternal prenatal SARS-CoV-2 infection may protect infants from postnatal infection. The lower acuity ED visits for infants born to mothers with prenatal SARS-CoV-2 infection may reflect a heightened level of concern among these mothers.