Christian M. Parobek

Objective: Mirror syndrome is a rare, life‐threatening condition in which maternal fluid overload mirrors fetal hydrops. Data on genetic findings in affected pregnancies are limited. We compared genetic diagnoses in hydrops cases with and without mirror syndrome. Methods: We conducted a retrospective cohort study (2012–2023) of pregnancies with non‐immune hydrops at a single fetal center. Clinical data along with prenatal and postnatal genetic testing results were analyzed. Mirror syndrome was defined as fetal hydrops with new or worsening hypertension and significant maternal edema. Genetic testing rates and diagnostic yields were compared between the groups. Results: Of the 192 cases, 140 (73%) underwent genetic testing. Testing rates were similar between mirror (24/31, 77%) and non‐mirror cases (116/161, 72%; p = 0.54). Abnormal findings explaining the phenotype were identified in 29% of mirror and 32% of non‐mirror cases ( p = 0.79). Rates of single‐gene disorders, aneuploidy, and copy‐number variants did not differ ( p > 0.05). Most single‐gene diagnoses involve cardiovascular or lymphatic pathways. Conclusion: The rates and types of genetic diagnoses were similar in hydrops cases with and without mirror syndrome. Despite limited power to detect subtle differences, these findings support a similar approach to genetic counseling and evaluation for hydrops cases with and without mirror syndrome.

Objective: While RNAseq has enhanced variant interpretation in postnatal cases, its potential in the prenatal setting remains underexplored. This study investigates the utility of RNAseq in prenatal diagnostics by analyzing the expression profiles of cultured chorionic villus samples (cCVS) and amniotic fluid (cAF) samples. Methods: We performed RNAseq on 25 prenatal samples (10 cCVS and 15 cAF) and compared their expression profiles with those of postnatal tissues—blood and skin fibroblasts. Results: To evaluate the clinical relevance of gene expression in these samples, we curated a list of genes associated with fetal‐onset genetic disorders ( n = 375). Using this curated list as a reference, our analysis revealed that cAF samples have the highest proportion of highly expressed genes (60%), surpassing cCVS (54%), fibroblasts (54%), and blood (34%). Differential expression analysis identified unique gene expression patterns in cCVS and cAF samples, reflecting their distinct tissue origins. Specifically, cAF samples showed elevated expression of genes involved in fetal kidney development, whereas cCVS samples were enriched for genes related to trophoblast function. Conclusions: These findings demonstrate that prenatal RNAseq reliably detects clinically relevant gene expressions, offering insights into prenatal conditions and fetal organ development. This underscores the potential of prenatal RNAseq as a valuable tool for supporting genetic variant interpretation.

Objective: Chronic kidney disease (CKD) can significantly affect pregnancy management and outcomes. Although up to 40% of adults with renal disease have an identifiable genetic cause, most pregnant patients with CKD do not undergo genetic testing, hindering tailored management during and after pregnancy. We assessed which pregnant patients with CKD were more likely to be referred for and undergo genetic counseling and testing. Study design: This was an Institutional Review Board–approved retrospective cohort study of all patients who received prenatal care at Texas Children's Hospital between 2011 and 2024 and had a diagnosis of CKD or end‐stage renal disease (ESRD). Patients were identified using International Classification of Diseases, 10th Revision (ICD‐10) codes in the electronic medical record. Demographic, clinical, and genetic data were abstracted and overlaid with social vulnerability index data (2022 release). Bivariate analyses were used to assess associations between demographic and clinical factors and genetic evaluation. Results: A total of 103 pregnant patients had a diagnosis of CKD or ESRD. The median gestational age at entry to prenatal care was 8.6 weeks. While a majority of patients (64%) were referred to genetic counseling for any reason, only one in four (27%) referrals mentioned a renal indication. Even fewer patients (8%) underwent genetic testing before, during, or after pregnancy to determine the etiology of their chronic renal disease. Among demographic, socioeconomic, and clinical variables, only renal transplant and a family history of renal disease were associated with a recommendation for a renal genetic workup. Commercial insurance coverage was associated with completion of a renal genetic workup. Conclusions: The majority of pregnant patients with renal disease did not undergo renal genetic testing before, during, or after pregnancy. Commercial insurance coverage was the only demographic, socioeconomic, or clinical factor significantly associated with completion of a genetic workup. While genetic evaluation for renal disease among pregnant patients is associated with insurance status, it is underutilized across demographic and socioeconomic sectors and should be considered for pregnant patients with renal disease.

Objective: The purpose of this study was to investigate the relationship between fetal fraction (FF) and placenta accreta spectrum (PAS) pathology in patients with prenatally suspected PAS.Methods: This was a case‐control study utilizing a database of pregnancies with suspected or proven PAS delivered between 6/2012 and 7/2024 at a single institution. Pregnancies were excluded if FF was not reported. The primary outcome was mean FF in pregnancies with a final clinical diagnosis of low FIGO grade (no PAS or FIGO1‐2) versus high FIGO grade (FIGO3) placenta accreta. Results were reported as mean FF ± standard error of the mean. Adjusted means were also reported after assessing confounders.Results: Of the 468 pregnancies assessed, 128 met the full inclusion criteria. While the unadjusted mean FF in the low‐grade group did not differ from the high‐grade group (9.6% ± 0.49, n = 81 vs. 10.7% ± 0.64, n = 47; p = 0.22), the adjusted mean FF in the low‐grade group was significantly lower than that in the high‐grade group (9.3% ± 0.48 vs. 11.1% ± 0.64; p = 0.03).Conclusions: While FF alone is unlikely to be clinically useful in predicting PAS pathology, NIPT results have the potential to improve the diagnostic precision of other clinical tools for PAS prediction.

Objective: Exome sequencing (ES) benefits the genetic work‐up for fetuses with structural anomalies, but data on its utility for fetuses without anomalies and stillbirths is more limited. We report our experience with prenatal ES for all three indications.Method: We retrospectively reviewed results from 344 trio‐ES performed for fetuses with structural anomalies (N = 262), stillbirths (N = 39), and fetuses without anomalies (N = 43), many of which had a relevant family history. We classified pathogenic variants (P), likely pathogenic variants (LP), or variants of uncertain significance (VUS) favoring pathogenicity in a gene consistent with the fetal phenotype as diagnostic results. We used Fisher's exact test for statistical analysis.Results: Trio‐ES provided a diagnosis for 93/262 (35.5%) fetuses with structural anomalies, with comparable yields for multiple and single anomalies (p = 0.81). A molecular diagnosis was made for 10/39 stillbirths (25.6%), of which all but one had structural anomalies, and 66.6% had multiple anomalies. In the absence of structural anomalies, one of 43 fetuses (2.3%) was found to have compound heterozygous pathogenic variants in ORC6 associated with Meier‐Gorlin syndrome.Conclusion: Prenatal trio‐ES yields molecular diagnoses across a spectrum of indications. Larger studies are needed to further define the added benefits and challenges of diagnostic ES for fetuses without anomalies.

Objective: To receive feedback on the design and content of a prenatal genetics video tool and explore pregnant patients' views on genetic information privacy.Methods: Video education covered prenatal aneuploidy screening and diagnosis and genetic privacy of cell‐free DNA (cfDNA). English or Spanish‐speaking adult patients, presenting for pregnancy dating ultrasound at a health center or clinic were eligible to answer a demographic questionnaire and view video education. Virtual, in‐depth semi‐structured interviews were then performed. Thematic analysis of transcripts was performed; all were double coded.Results: Twenty participants completed interviews, achieving data saturation. Demographics: median age 30.5 years, 50% Spanish‐speaking, 55% White, 60% Hispanic, 65% had a high‐school degree or less, 60% parous. Themes: The intervention was acceptable, accessible, and aided in decision‐making. Tangible adjunctive resources were desired. Content misunderstandings included absolute risk of diagnostic testing and perception of aneuploidy as hereditary. Genetic privacy played a minor role in decision‐making. Participants were amenable to data‐sharing with third parties, but wanted to be informed. They misunderstood that genetic data could never truly be de‐identified. No differences were found in opinions on sharing fetal versus maternal data or with academic versus private institutions.Conclusion: Video education was acceptable and comprehensible, yet participants showed limited awareness of cfDNA privacy implications.

Objective: Fetal pleural effusions are often associated with underlying genetic etiologies; however, data describing the incidence of genetic abnormalities are limited. We evaluated the rate of genetic abnormalities in pregnancies affected by primary unilateral and bilateral fetal pleural effusion.Methods: This study is a retrospective cohort study of all patients evaluated at our center with a prenatal diagnosis of primary fetal pleural effusion from 2010 to 2022. All patients with a singleton pregnancy and diagnostic genetic testing were included. Patients were separated into two groups: those with unilateral or bilateral effusions at initial diagnosis. Genetic diagnoses, fetal interventions, and pregnancy outcomes were evaluated.Results: Among 229 cases of fetal pleural effusion, 30 met the inclusion criteria. Unilateral effusion was seen in 14/30 cases (47%) and bilateral effusion in 16/30 cases (53%). Genetic abnormalities were present in 7/14 (50%) unilateral and 2/14 (14%) bilateral effusions (p = 0.046). Cases of bilateral effusion had higher rates of fetal intervention with thoracoamniotic shunt (69% vs. 14%; p = 0.004) and earlier delivery (33 vs. 36 weeks, p = 0.002). Bilateral effusions were found to have higher rates of respiratory distress syndrome and neonatal death (p = 0.03 and 0.04), respectively.Conclusion: Pregnancies affected by primary fetal pleural effusion have a high rate of genetic abnormalities. Although bilateral fetal pleural effusions have worse perinatal outcomes, unilateral fetal pleural effusions have a high rate of genetic diagnosis and both unilateral and bilateral fetal pleural effusions warrant comprehensive prenatal genetic testing.

Objectives: Although serum screening for aneuploidies has become less prevalent, maternal‐serum alpha‐fetoprotein (MSAFP) screening for body‐wall defects remains widespread. We explored whether MSAFP screening is associated with earlier omphalocele detection than ultrasound alone.Methods: This is a retrospective cohort study of prenatally detected omphalocele cases at our center from 2007 to 2023. We explored the association between MSAFP screening, gestational age at omphalocele detection, and clinical outcomes.Results: Among 101 pregnancies with prenatally diagnosed omphalocele, 27 (26.7%) had MSAFP screening. The median gestational age at MSAFP screening was 17 weeks 4 days. Of those who received MSAFP screening, 11 (41%) had values ≥2.5 multiples of the median (MoM) and 16 (59%) were not elevated. MSAFP results did not correlate with omphalocele size and were not associated with prenatal or postnatal outcomes. MSAFP screening did not result in earlier suspicion for or confirmation of omphalocele (P = .97 and P = .87, respectively). In contrast, first‐trimester ultrasound screening was associated with earlier suspicion for and confirmation of omphalocele (P < .01 and P = .01, respectively). There were no clinical or demographic differences between those who received MSAFP screening and those who did not (including body mass index or commute distance to an urban center).Conclusion: MSAFP screening is not associated with earlier omphalocele detection. Furthermore, in pregnancies with prenatally diagnosed omphalocele, the results of MSAFP screening are not predictive of clinical outcomes.

Hypoxic–ischemic encephalopathy (HIE) occurs in up to 7 out of 1000 births and accounts for almost a quarter of neonatal deaths worldwide. Despite the name, many newborns with HIE have little evidence of perinatal hypoxia. We hypothesized that some infants with HIE have genetic disorders that resemble encephalopathy. We reviewed genetic results for newborns with HIE undergoing exome or genome sequencing at a clinical laboratory (2014–2022). Neonates were included if they had a diagnosis of HIE and were delivered ≥35 weeks. Neonates were excluded for cardiopulmonary pathology resulting in hypoxemia or if neuroimaging suggested postnatal hypoxic–ischemic injury. Of 24 patients meeting inclusion criteria, six (25%) were diagnosed with a genetic condition. Four neonates had variants at loci linked to conditions with phenotypic features resembling HIE, including KIF1A, GBE1, ACTA1, and a 15q13.3 deletion. Two additional neonates had variants in genes not previously associated with encephalopathy, including DUOX2 and PTPN11. Of the six neonates with a molecular diagnosis, two had isolated HIE without apparent comorbidities to suggest a genetic disorder. Genetic diagnoses were identified among neonates with and without sentinel labor events, abnormal umbilical cord gasses, and low Apgar scores. These results suggest that genetic evaluation is clinically relevant for patients with perinatal HIE.