Exploring the diagnostic utility of genome sequencing for fetal congenital heart defects.

OBJECTIVE: The diagnostic yield for congenital heart defects (CHD) with routine genetic testing is around 10%-20% when considering pathogenic CNVs or aneuploidies as positive findings. This is a pilot study to investigate the utility of genome sequencing (GS) for prenatal diagnosis of CHD. METHODS: Genome sequencing (GS, 30X) was performed on 13 trios with CHD for which karyotyping and/or chromosomal microarray results were non-diagnostic. RESULTS: Trio GS provided a diagnosis for 4/13 (30.8%) fetuses with complex CHDs and other structural anomalies. Findings included pathogenic or likely pathogenic variants in DNAH5, COL4A1, PTPN11, and KRAS. Of the nine cases without a genetic etiology by GS, we had outcome follow-up data on eight. For five of them (60%), the parents chose to keep the pregnancy. A balanced translocation [46,XX,t(14; 22)(q32.33; q13.31)mat] was detected in a trio with biallelic DNAH5 mutations, which together explained the recurrent fetal situs inversus and dextrocardia that was presumably due to de novo Phelan-McDermid syndrome. A secondary finding of a BRCA2 variant and carrier status of HBB, USH2A, HBA1/HBA2 were detected in the cohort. CONCLUSIONS: GS expands the diagnostic scope of mutation types over conventional testing, revealing the genetic etiology for fetal heart anomalies. Patients without a known genetic abnormality indicated by GS likely opted to keep pregnancy especially if the heart defect could be surgically repaired. We provide evidence to support the application of GS for fetuses with CHD.

Clinical utility of expanded non-invasive prenatal screening and chromosomal microarray analysis in high-risk pregnancy.

OBJECTIVE: To evaluate the utility of expanded non-invasive prenatal screening (NIPS), compared with chromosomal microarray analysis (CMA), for the detection of chromosomal abnormalities in high-risk pregnancies. METHODS: This was a multicenter retrospective study of singleton pregnancies at high risk for chromosomal abnormality. Patients who underwent expanded NIPS and CMA sequentially during pregnancy from 2015 to 2019 were included in the analysis. Pregnancies with a positive result for sex chromosome aneuploidy were excluded as the full details could not be retrieved. The utility of expanded NIPS and CMA for detection of chromosomal abnormalities in this cohort was compared by assessing the concordance between the results. RESULTS: Of the 774 included high-risk pregnancies, 550 (71.1%) had a positive NIPS result, while a positive CMA result was detected in 308 (39.8%) cases. The rate of full or partial concordance between NIPS and CMA was 82.2%, 59.6% and 25.0% for trisomies 21, 18 and 13, respectively. For rare aneuploidies and segmental imbalances, NIPS and CMA results were fully or partially concordant in 7.5% and 33.3% of cases, respectively. Copy-number variants < 5 Mb were detected more often by CMA, with an incidence of 7.9% (61/774) compared with 3.1% (24/774) by NIPS. A genetic aberration was detected by CMA in 1 in 17 (5.8%) high-risk pregnancies that had a negative or non-reportable NIPS result. CONCLUSION: CMA allows for comprehensive detection of genome-wide chromosomal abnormalities in high-risk pregnancies. CMA should be offered instead of expanded NIPS for high-risk pregnancies. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.