Discovery of pathogenic variants in EFEMP2 and RAG1 and undetectable fetal phenotype: A challenge of prenatal exome sequencing.

BACKGROUND: Exome sequencing in prenatal context confronts with pathogenic variants associated with phenotypes that are not detectable prenatally. MATERIALS AND METHODS: A consanguineous couple was referred at 24 weeks of gestation for prenatal genetic investigations after ultrasonography findings including decreased fetal movements, hypoplastic male external genitalia, retrognathia, prefrontal edema, anomalies of the great vessels with pulmonary atresia and dilated tortuous aorta. RESULT: Prenatal trio exome sequencing identified two homozygous likely pathogenic variants, i.e. a missense in EFEMP2 involved in cutis laxa and a nonsense in RAG1 involved in several types of severe combined immunodeficiency. DISCUSSION: The fetal ultrasonographic phenotype was partially compatible with previously reported prenatal presentations secondary to EFEMP2 biallelic variants, but prenatal presentations have never been reported for RAG1 related disorders because the RAG1 phenotype is undetectable during pregnancy. CONCLUSION: Both EFEMP2 and RAG1 variants were disclosed to the couple because the EFEMP2 variant was considered causative for the fetal ultrasonographic phenotype and the RAG1 variant was considered a finding of strong interest for genetic counselling and monitoring of future pregnancies following the American College of Medical Genetics and Genomics recommendations about the discovery of incidental findings in fetal exome sequencing in prenatal diagnosis.

The clinical value of optical genome mapping in the rapid characterization of RB1 duplication and 15q23q24.2 triplication, for more appropriate prenatal genetic counselling.

BACKGROUND: Despite recent advances in prenatal genetic diagnosis, medical geneticists still face considerable difficulty in interpreting the clinical outcome of copy-number-variant duplications and defining the mechanisms underlying the formation of certain chromosomal rearrangements. Optical genome mapping (OGM) is an emerging cytogenomic tool with proved ability to identify the full spectrum of cytogenetic aberrations. METHODS: Here, we report on the use of OGM in a prenatal diagnosis setting. Detailed breakpoint mapping was used to determine the relative orientations of triplicated and duplicated segments in two unrelated foetuses harbouring chromosomal aberrations: a de novo 15q23q24.2 triplication and a paternally inherited 13q14.2 duplication that overlapped partially with the RB1 gene. RESULTS: OGM enabled us to suggest a plausible mechanism for the triplication and confirmed that the RB1 duplication was direct oriented and in tandem. This enabled us to predict the pathogenic consequences, refine the prognosis and adapt the follow-up and familial screening appropriately. CONCLUSION: Along with an increase in diagnostic rates, OGM can rapidly highlight genotype-phenotype correlations, improve genetic counselling and significantly influence prenatal management.

Is gestational age at term a risk factor for ongoing pregnancies in nulliparous women: A prospective cohort study.

BACKGROUND: The results of American observational studies and 1 large, randomized trial show that elective induction of labor among nulliparous women can reduce cesarean delivery rates and suggest that gestational age at delivery may be a risk factor for cesarean delivery in pregnancies managed expectantly. However, data on the risk of cesarean delivery at term in ongoing pregnancies are sparse, especially in high-income countries, and further information is needed to explore the external validity of these previous studies. OBJECTIVE: This study aimed to evaluate the risk of cesarean delivery for each gestational week of ongoing pregnancy in nulliparous women with a singleton fetus in the cephalic presentation at term in a French population. STUDY DESIGN: This retrospective study was conducted in a perinatal network of 10 maternity units from January 1, 2016, to December 31, 2017, and included all nulliparous women with a singleton fetus in the cephalic presentation who gave birth at term (≥37 0/7 weeks of gestation). From the start of term (37 completed weeks) and at the start of each subsequent week of completed gestation (each week + 0 days), ongoing pregnancy was defined as that of a woman who was still pregnant and who gave birth at any time after that date. For each week of gestation for these ongoing pregnancies, the cesarean delivery rate was defined as the number of cesarean deliveries performed in each ongoing pregnancy group divided by the number of women in this group. Separate models for each week of gestation, adjusted by maternal characteristics and hospital status, were used to compare the cesarean delivery risk between ongoing pregnancies and those delivered the preceding week. The same methods were applied to subgroups defined according to the mode of labor onset. Odds ratios were calculated after adjusting for maternal age and educational level, presence of severe preeclampsia, and maternity unit status. RESULTS: The study included 11,308 nulliparous women, 2544 (22.5%) of whom had a cesarean delivery. These rates remained stable for ongoing pregnancies at 37 0/7, 38 0/7, and 39 0/7 weeks of gestation; the rates were 22.5% (95% confidence interval, 21.7-23.2), 22.6% (95% confidence interval, 21.8-23.3); and 22.7% (95% confidence interval, 21.9-23.6), respectively. The risk of cesarean delivery started to increase in ongoing pregnancies at 40 0/7 weeks of gestation (24.3%; 95% confidence interval, 23.1-25.4) and especially at 41 0/7 weeks of gestation (30.7%; 95% confidence interval, 28.9-32.5). Similar trends were also shown for all modes of labor onset and in every maternity unit. In univariate and multivariate analyses, ongoing pregnancy at or beyond 40 0/7 weeks of gestation was associated with a higher risk of cesarean delivery than pregnancy delivered the previous week: 24.3% of ongoing pregnancies at 40 0/7 weeks of gestation vs 19.9% of deliveries between 39 0/7 weeks of gestation and 39 6/7 weeks of gestation. The odds ratios were 1.28 (95% confidence interval, 1.15-1.44) or 30.4% of ongoing pregnancies at 41 0/7 weeks of gestation vs 1.73 (95% confidence interval, 1.51-1.96) or 19.6% of deliveries between 40 0/7 weeks of gestation and 40 6/7 weeks of gestation. CONCLUSION: Cesarean delivery rates increased starting at 40 0/7 weeks of gestation in ongoing pregnancies regardless of the mode of labor onset.

Effects of the implementation of second-line prenatal cell-free DNA testing on termination of pregnancy in a French perinatal network.

OBJECTIVE: To evaluate the impact of implementing cell-free DNA (cfDNA) testing on gestational age (GA) at termination of pregnancy in a French perinatal network. METHODS: We conducted a retrospective study. All women having undergone a termination of pregnancy between 1 January 2012 and 31 December 2017 were included. We compared the periods before and after the introduction of second-line cfDNA testing, which started on 1 January 2015. Throughout the study period, the invasive procedures were foetal karyotyping and chromosomal microarray analysis. The primary study outcome was GA at termination. The secondary outcomes were GA at termination for trisomy 21 and the frequency and GA at the time of invasive procedures. RESULTS: During the 6-year study period, 840 women underwent termination. The median GA at termination before and after the implementation of cfDNA testing was 19.4 and 19.0 weeks, respectively (p = 0.38). Although the frequency of termination for trisomy 21 increased significantly from 23% to 32% (p < 0.01), the median GA at termination did not change significantly (p = 0.80). The implementation of cfDNA testing was associated with a decrease in the frequency of invasive procedures in general and chorionic villus sampling in particular (p = 0.04). CONCLUSION: The introduction of cfDNA testing does not increase the GA at termination for trisomy21.