Outcome of publicly funded nationwide first-tier noninvasive prenatal screening.

PURPOSE: Noninvasive prenatal screening (NIPS) using cell-free DNA has transformed prenatal care. Belgium was the first country to implement and fully reimburse NIPS as a first-tier screening test offered to all pregnant women. A consortium consisting of all Belgian genetic centers report the outcome of two years genome-wide NIPS implementation. METHODS: The performance for the common trisomies and for secondary findings was evaluated based on 153,575 genome-wide NIP tests. Furthermore, the evolution of the number of invasive tests and the incidence of Down syndrome live births was registered. RESULTS: Trisomies 21, 18, and 13 were detected in respectively 0.32%, 0.07%, and 0.06% of cases, with overall positive predictive values (PPVs) of 92.4%, 84.6%, and 43.9%. Rare autosomal trisomies and fetal segmental imbalances were detected in respectively 0.23% and 0.07% of cases with PPVs of 4.1% and 47%. The number of invasive obstetric procedures decreased by 52%. The number of trisomy 21 live births dropped to 0.04%. CONCLUSION: Expanding the scope of NIPS beyond trisomy 21 fetal screening allows the implementation of personalized genomic medicine for the obstetric population. This genome-wide NIPS approach has been embedded successfully in prenatal genetic care in Belgium and might serve as a framework for other countries offering NIPS.

Population screening for 15q11-q13 duplications: corroboration of the difference in impact between maternally and paternally inherited alleles.

Maternally inherited 15q11-q13 duplications are generally found to cause more severe neurodevelopmental anomalies compared to paternally inherited duplications. However, this assessment is mainly inferred from the study of patient populations, causing an ascertainment bias towards patients at the more severe end of the phenotypic spectrum. Here, we analyze the low coverage genome-wide cell-free DNA sequencing data obtained from pregnant women during non-invasive prenatal screening (NIPS). We detect 23 15q11-q13 duplications in 333,187 pregnant women (0.0069%), with an approximately equal distribution between maternal and paternal duplications. Maternally inherited duplications are always associated with a clinical phenotype (ranging from learning difficulties to intellectual impairment, epilepsy and psychiatric disorders), while paternal duplications are normal or associated with milder phenotypes (mild learning difficulties and dyslexia). This data corroborates the difference in impact between paternally and maternally inherited 15q11-q13 duplications, contributing to the improvement of genetic counselling. We recommend reporting 15q11-q13 duplications identified during genome-wide NIPS with appropriate genetic counselling for these pregnant women in the interest of both mothers and future children.

Performance and Diagnostic Value of Genome-Wide Noninvasive Prenatal Testing in Multiple Gestations.

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.

Host-dependence of in vitro reassortment dynamics among the Sathuperi and Shamonda Simbuviruses.

Orthobunyaviruses are arboviruses (Arthropod Borne Virus) and possess multipartite genomes made up of three negative RNAs corresponding to the small (S), medium (M) and large (L) segments. Reassortment and recombination are evolutionary driving forces of such segmented viruses and lead to the emergence of new strains and species. Retrospective studies based on phylogenetical analysis are able to evaluate these mechanisms at the end of the selection process but fail to address the dynamics of emergence. This issue was addressed using two Orthobunyaviruses infecting ruminants and belonging to the Simbu serogroup: the Sathuperi virus (SATV) and the Shamonda virus (SHAV). Both viruses were associated with abortion, stillbirth and congenital malformations occurring after transplacental transmission and were suspected to spread together in different ruminant and insect populations. This study showed that different viruses related to SHAV and SATV are spreading simultaneously in ruminants and equids of the Sub-Saharan region. Their reassortment and recombination potential was evaluated in mammalian and in insect contexts. A method was set up to determine the genomic background of any clonal progeny viruses isolated after in vitro coinfections assays. All the reassortment combinations were generated in both contexts while no recombinant virus was isolated. Progeny virus populations revealed a high level of reassortment in mammalian cells and a much lower level in insect cells. In vitro selection pressure that mimicked the host switching (insect-mammal) revealed that the best adapted reassortant virus was connected with an advantageous replicative fitness and with the presence of a specific segment.