OBJECTIVE: To evaluate the accuracy and diagnostic value of genome-wide noninvasive prenatal testing (NIPT) for the detection of fetal aneuploidies in multiple gestations, with a focus on dichorionic–diamniotic twin pregnancies. METHODS: We performed a retrospective cohort study including data from pregnant women with a twin or higher-order gestation who underwent genome-wide NIPT at one of the eight Belgian genetic centers between November 1, 2013, and March 1, 2020. Chorionicity and amnionicity were determined by ultrasonography. Follow-up invasive testing was carried out in the event of positive NIPT results. Sensitivity and specificity were calculated for the detection of trisomy 21, 18, and 13 in the dichorionic–diamniotic twin cohort. RESULTS: Unique NIPT analyses were performed for 4,150 pregnant women with a multiple gestation and an additional 767 with vanishing gestations. The failure rate in multiple gestations excluding vanishing gestations ranged from 0% to 11.7% among the different genetic centers. Overall, the failure rate was 4.8%, which could be reduced to 1.2% after single resampling. There were no common fetal trisomies detected among the 86 monochorionic–monoamniotic and 25 triplet cases. Two monochorionic–diamniotic twins had an NIPT result indicative of a trisomy 21, which was confirmed in both fetuses. Among 2,716 dichorionic–diamniotic twin gestations, a sensitivity of 100% (95% CI 74.12–100%) and a specificity of 100% (95% CI 99.86–100%) was reached for trisomy 21 (n=12). For trisomy 18 (n=3), the respective values were 75% (95% CI 30.06–95.44%) sensitivity and 100% (95% CI 99.86–100%) specificity, and for trisomy 13 (n=2), 100% (95% CI 20.65–100%) sensitivity and 99.96% (95% CI 99.79–99.99%) specificity. In the vanishing gestation group, 28 NIPT results were positive for trisomy 21, 18, or 13, with only five confirmed trisomies. CONCLUSION: Genome-wide NIPT performed accurately for detection of aneuploidy in dichorionic–diamniotic twin gestations.

Whole exome sequencing (WES) has become part of the postnatal diagnostic work-up of both pediatric and adult patients with a range of disorders. In the last years, WES is slowly being implemented in the prenatal setting as well, although some hurdles remain, such as quantity and quality of input material, minimizing turn-around times, and ensuring consistent interpretation and reporting of variants. We present the results of 1 year of prenatal WES in a single genetic center. Twenty-eight fetus-parent trios were analyzed, of which seven (25%) showed a pathogenic or likely pathogenic variant that explained the fetal phenotype. Autosomal recessive (4), de novo (2) and dominantly inherited (1) mutations were detected. Prenatal rapid WES allows for a timely decision-making in the current pregnancy, adequate counseling with the possibility of preimplantation or prenatal genetic testing in future pregnancies and screening of the extended family. With a diagnostic yield in selected cases of 25% and a turn-around time under 4 weeks, rapid WES shows promise for becoming part of pregnancy care in fetuses with ultrasound anomalies in whom chromosomal microarray did not uncover the cause.

Tetrasomy 9p is a chromosomal disorder characterized by the presence of a supernumerary chromosome. This rare abnormality exhibits a broad phenotypic variability and is not clearly distinguishable from other more frequent aneuploidies in the prenatal setting. We present two prenatal cases with dissimilar phenotypes, one with solely increased fetal nuchal translucency and one with multiple congenital anomalies, and discuss prior studies. These cases illustrate the difficulty of prenatally diagnosing this condition based on phenotypic information alone. We conclude that invasive prenatal diagnosis with (molecular) karyotyping is the best choice for the prenatal detection of tetrasomy 9p.

Objectives: This study evaluates the diagnostic yield of prenatal whole exome sequencing (WES) and its impact on outcome, such as termination of pregnancy (TOP) or neonatal management. Methods: A retrospective analysis of more than 4 years of prenatal WES at a single genetic center was performed. Inclusion criteria included normal genome-wide deletion/duplication analysis and ≥1 ultrasound anomaly. Trio analysis was performed, filtering for de novo , compound heterozygous, homozygous, and hemizygous variants, complemented by a genome-wide phenotype-driven analysis. Results: (Likely) pathogenic variants fitting the phenotype were identified in 36 of 171 cases (21.1 %), of which 19 were de novo , 14 autosomal recessive, one autosomal dominant, and 2 X-linked dominant. Median turnaround time was 16 days. Parents opted for TOP in 21 cases, three resulted in intrauterine death, 11 were carried to term and one was lost to follow-up. Among the neonates, the diagnosis led to optimized postnatal management in 8/11 (72.7 %), abstinence of care in two (18.2 %) and exclusion of syndromic disorders in one (9.1 %). Conclusions: Our findings indicate that in 1/5 pregnancies with ultrasound anomalies and normal deletion/duplication analysis, a (likely) pathogenic variant explaining the phenotype can be identified. The high proportion (17/36 or 47.2 %) of inherited variants highlights the importance of WES for recurrence risk assessment.