Clinical Utility of the Prenatal BACs-on-Beads™ Assay in Invasive Prenatal Diagnosis

Background: The prenatal BACs-on-Beads™ (PNBoBs™) assay has been applied worldwide for prenatal diagnosis. However, there are neither guidelines nor consensus on choosing patients, sample types, or clinical pathways for using this technique. Moreover, different perspectives have emerged regarding its clinical value. This study aimed to evaluate its clinical utility in the context of clinical practice located in a prenatal diagnostic center in Xiamen, a city in southeast China.Methods: We tested 2,368 prenatal samples with multiple referral indications using both conventional karyotyping and PNBoBs™. Positive results from PNBoBs™ were verified using current gold-standard approaches.Results: The overall rates for the detection of pathogenic copy number variation (pCNV) by karyotyping and PNBoBs™ were 1.9% (46/2,368) and 2.0% (48/2,368), respectively. The overall detection rate of karyotyping combined with PNBoBs™ for pCNV was 2.3% (54/2,368). A total of 13 cases of copy number variation (CNV)with a normal karyotype were detected by PNBoBs™. Another case with a normal karyotype that was detected as a CNV of sex chromosomes by PNBoBs™ was validated to be maternal cell contamination by short tandem repeat analysis.Conclusion: Karyotyping combined with PNBoBs™ can improve both the yield and efficiency of prenatal diagnosis and is appropriate in the second trimester in all patients without fetal ultrasound anomalies who undergo invasive prenatal diagnosis.

A genomic autopsy identifies causes of perinatal death and provides options to prevent recurrence

Perinatal death, of a fetus or newborn, is a devastating event for families. Following nationwide multicentre recruitment, we assessed ‘genomic autopsy’ as an adjunct to standard autopsy for 200 families who experienced perinatal death, and provided a definite or candidate genetic diagnosis in 105 families. From this understudied cohort, half of the (candidate) diagnoses were phenotype expansions or novel disease genes, revealing previously unknown in-utero presentations of existing developmental disorders, and genomic disorders that are likely incompatible with life. Among the definite diagnoses, 43% were recessively or dominantly inherited, posing a 25% or 50% recurrence risk for future pregnancies. Ten families used their diagnosis for preimplantation or prenatal diagnosis of 12 pregnancies, facilitating the delivery of ten healthy newborns and management of two affected pregnancies. We emphasize the clinical importance of genomic investigations of perinatal death, with short turn-around times, enabling accurate counselling and options for families to prevent recurrence.

Prenatal diagnosis lowers neonatal cardiac care costs in resource-limited settings

Background: Prenatal diagnosis of critical CHDs and planned peripartum care is an emerging concept in resource-limited settings. Objective: To report the impact of prenatal diagnosis and planned peripartum care on costs of neonatal cardiac care in a resource-limited setting. Methods: Prospective study (October 2019 to October 2020). Consecutive neonates undergoing surgery or catheter-based interventions included. Patients were divided into prenatal (prenatal diagnosis) and post-natal (diagnosis after birth) groups. Costs of cardiac care (total, direct, and indirect) and health expenses to income ratio were compared between study groups; factors impacting costs were analysed. Results: A total of 105 neonates were included, including 33 in prenatal group. Seventy-seven neonates (73.3%) underwent surgical procedures while the rest needed catheter-based interventions. Total costs were 16.2% lower in the prenatal group (p = 0.008). Direct costs were significantly lower in the prenatal group (18%; p = 0.02), especially in neonates undergoing surgery (20.4% lower; p = 0.001). Health expenses to income ratio was also significantly lower in the prenatal group (2.04 (1.03–2.66) versus post-natal:2.58 (1.55–5.63), p = 0.01);, particularly in patients undergoing surgery (prenatal: 1.58 (1.03–2.66) vs. post-natal: 2.99 (1.91–6.02); p = 0.002). Prenatal diagnosis emerged as the only modifiable factor impacting costs on multivariate analysis. Conclusion: Prenatal diagnosis and planned peripartum care of critical CHD is feasible in resource-limited settings and is associated with significantly lower costs of neonatal cardiac care. The dual benefit of improved clinical outcomes and lower costs of cardiac care should encourage policymakers in resource-limited settings towards developing more prenatal cardiac services.

The impact of prenatal screening tests on prenatal diagnosis in Taiwan from 2006 to 2019: a regional cohort study

Background The purpose of this study is to evaluate the impact of prenatal screening tests on prenatal diagnosis in Taiwan’s 14 years from 2006 to 2019. Methods The prenatal screening methods evolved from the second-trimester serum screening to combined first-trimester screening (cFTS) and then followed by the non-invasive cell-free DNA prenatal test (NIPT). The data used by the Department of Statistics, the Ministry of Health and Welfare and Department of Household Registration, Ministry of the Interior public website. Results This regional registry-based cohort retrospective study examined a total of 2,775,792 births from January 2006 to December 2019. The proportion of advanced maternal age (AMA) pregnancies increased from 11.63% in 2006 to 30.94% in 2019. Overall, invasive diagnostic testing was used in 87.22% of AMA pregnancies. The prenatal detection rate of trisomy 21 and 18 increased from 74.1% and 83.3% in 2006 to 96.9% and 98.8% in 2019, respectively. Conclusion During the second-trimester and cFTS periods, the percentage of AMA pregnancies increased every year and the number of invasive procedures also accompany with increased percentage of AMA. However, during the period that NIPT were implemented, the percentage of invasive procedures decreased.

Pregnancy Outcomes of Non-Visualization of The Foetal Gallbladder From A Chinese Tertiary Single Centre And Literature Review

Objection To explore the clinical features and prognosis of non-visualization of fetal gallbladder (NVFGB). Methods 65 cases diagnosed of NVFGB in the Peking University First Hospital was collected retrospectively from January, 2019 to December, 2020. Results 49 cases were successfully followed up. Among them, the gallbladder of 21 fetuses (42.9%) was visible later, either in the later pregnancy or after birth. In the rest 28 cases (57.1%), the gallbladders were not seen during the whole pregnancy. 11 of 28 fetuses (39.3%) with NVFGB were complicated with other structure anomaly. In the remaining 17 cases of isolated NVFGB (60.7%), one case was diagnosed of congenital biliary atresia, 3 cases of small gallbladder, 1 case of gallstone and one case of irregular size of gallbladder. There are 9 cases who underwent prenatal diagnosis, with 4 cases of abnormal result. Conclusion Prenatal ultrasound plays a role in the early recognize of abnormal gallbladder, which will improve the postnatal prognosis.

Noninvasive Prenatal Testing of Methylmalonic Acidemia cblC Type Using the cSMART Assay for MMACHC Gene Mutations

Noninvasive prenatal testing (NIPT) for monogenic disorders has been developed in recent years; however, there are still significant technical and analytical challenges for clinical use. The clinical feasibility of NIPT for methylmalonic acidemia cblC type (cblC type MMA) was investigated using our circulating single-molecule amplification and re-sequencing technology (cSMART). Trios molecular diagnosis was performed in 29 cblC type MMA-affected children and their parents by traditional Sanger sequencing. In the second pregnancy, invasive prenatal diagnosis (IPD) of the pathogenic MMACHC gene was used to determine fetal genotypes, and NIPT was performed using a novel MMACHC gene–specific cSMART assay. Maternal–fetal genotypes were deduced based on the mutation ratio in maternal plasma DNA. Concordance of fetal genotypes between IPD and NIPT, and the sensitivity and specificity of NIPT were determined. After removing two cases with a low P value or reads, the concordance ratio for NIPT and IPD was 100.00% (27/27), and the sensitivity and specificity were 100.00% (54.07–100.00%) and 100.00% (83.89–100.00%), respectively. This study demonstrates that NIPT using the cSMART assay for cblC type MMA was accurate in detecting fetal genotypes. cSMART has a potential clinical application as a prenatal diagnosis and screening tool for carrier and low-risk genotypes of cblC type MMA and other monogenic diseases.