Prenatal diagnosis by trio exome sequencing in fetuses with ultrasound anomalies: A powerful diagnostic tool.

Introduction: Prenatal ultrasound (US) anomalies are detected in around 5%-10% of pregnancies. In prenatal diagnosis, exome sequencing (ES) diagnostic yield ranges from 6% to 80% depending on the inclusion criteria. We describe the first French national multicenter pilot study aiming to implement ES in prenatal diagnosis following the detection of anomalies on US. Patients and methods: We prospectively performed prenatal trio-ES in 150 fetuses with at least two US anomalies or one US anomaly known to be frequently linked to a genetic disorder. Trio-ES was only performed if the results could influence pregnancy management. Chromosomal microarray (CMA) was performed before or in parallel. Results: A causal diagnosis was identified in 52/150 fetuses (34%) with a median time to diagnosis of 28 days, which rose to 56/150 fetuses (37%) after additional investigation. Sporadic occurrences were identified in 34/56 (60%) fetuses and unfavorable vital and/or neurodevelopmental prognosis was made in 13/56 (24%) fetuses. The overall diagnostic yield was 41% (37/89) with first-line trio-ES versus 31% (19/61) after normal CMA. Trio-ES and CMA were systematically concordant for identification of pathogenic CNV. Conclusion: Trio-ES provided a substantial prenatal diagnostic yield, similar to postnatal diagnosis with a median turnaround of approximately 1 month, supporting its routine implementation during the detection of prenatal US anomalies.

Predicting Outcome of Congenital Cytomegalovirus Infection by Differentiating and Revisiting Severe versus Mild Prenatal Imaging Features.

INTRODUCTION: Our objective was to evaluate the outcome of fetuses with first- and second-trimester fetal cytomegalovirus infection (CMVi) according to prenatal imaging patterns, especially fetuses presenting with mild imaging features (MF), being currently of uncertain prognosis. MATERIAL AND METHODS: In a retrospective study of 415 suspected CMVi cases, 59 cases were confirmed. Among prenatal imaging features, microcephaly, cortical disorder, and cerebellar hypoplasia as well as severe IUGR and fetal hydrops were considered as severe imaging features (SF). Other imaging features were considered as MF. Postnatal outcome was classified as "normal outcome," "mild sequelae" characterized mainly by sensorineural disorder (SND) and "severe sequelae" characterized by cognitive impairment. RESULTS: Only first-trimester (T1) and second-trimester (T2) CMVi cases were included in our study (n = 49) since all third-trimester cases (n = 10) had normal imaging and outcome. Sixteen fetuses had normal prenatal imaging and normal outcome, except one showing SND. Abnormal ultrasound findings were present in 33 fetuses, including SF noted in 16 fetuses, related exclusively to first-trimester CMVi. Termination of pregnancy was performed in 18 cases. Twelve first-trimester infected fetuses presented SF, whereas 6 fetuses (T1: n = 5, T2: n = 1) presented isolated MF. Four fetal deaths were encountered. Live-born babies with abnormal imaging included 10 fetuses with MF and one with SF. Among the 10 live babies with isolated MF, SND was encountered in 5 cases, whereas 5 children demonstrated normal outcome. Overall, 50% of our babies showing MF suffered from SND. No case of cognitive disorders was reported in babies showing only MF. CONCLUSION: SF were encountered only in first-trimester CMVi and should be distinguished from MF. Among our 10 live babies with prenatal MF following first- or second-trimester infection, 50% showed SND, whereas none presented severe sequelae. In 16 fetuses displaying normal fetal imaging, SND was encountered in one first-trimester case (6%).

GGCX-related congenital combined vitamin K-dependent clotting factors deficiency-1: Description of a fetus with chondrodysplasia punctata.

Congenital combined vitamin K-dependent clotting factors deficiency (VKCFD) is a rare autosomal recessive disease resulting in hemorrhagic symptoms usually associated with developmental disorders and bone abnormalities. Pathogenic variants in two genes encoding enzymes of the vitamin K cycle, GGCX and VKORC1, can lead to this disorder. We present the case of a male fetus with a brachytelephalangic chondrodysplasia punctata (CDP), absence of nasal bone, growth restriction, and bilateral ventriculomegaly at 18 weeks of gestation. Pathological examination showed a Binder phenotype, hypoplastic distal phalanges, stippled epiphyses, and brain abnormalities suggestive of a brain hemorrhage. Two GGCX pathogenic variants inherited respectively from the mother and the father were identified. To our knowledge, this is the first prenatal description of VKCFD. Even if it remains a rare etiology, which is mostly described in children or adult patients, VKCFD should be considered in fetuses with CDP.

Next-generation sequencing in a series of 80 fetuses with complex cardiac malformations and/or heterotaxy.

Herein, we report the screening of a large panel of genes in a series of 80 fetuses with congenital heart defects (CHDs) and/or heterotaxy and no cytogenetic anomalies. There were 49 males (61%/39%), with a family history in 28 cases (35%) and no parental consanguinity in 77 cases (96%). All fetuses had complex CHD except one who had heterotaxy and midline anomalies while 52 cases (65%) had heterotaxy in addition to CHD. Altogether, 29 cases (36%) had extracardiac and extra-heterotaxy anomalies. A pathogenic variant was found in 10/80 (12.5%) cases with a higher percentage in the heterotaxy group (8/52 cases, 15%) compared with the non-heterotaxy group (2/28 cases, 7%), and in 3 cases with extracardiac and extra-heterotaxy anomalies (3/29, 10%). The inheritance was recessive in six genes (DNAI1, GDF1, MMP21, MYH6, NEK8, and ZIC3) and dominant in two genes (SHH and TAB2). A homozygous pathogenic variant was found in three cases including only one case with known consanguinity. In conclusion, after removing fetuses with cytogenetic anomalies, next-generation sequencing discovered a causal variant in 12.5% of fetal cases with CHD and/or heterotaxy. Genetic counseling for future pregnancies was greatly improved. Surprisingly, unexpected consanguinity accounts for 20% of cases with identified pathogenic variants.

Prenatal Diagnosis of Trisomy 2p due to Terminal 2p Duplication including Interstitial Telomeric Sequences.

We report on a prenatally diagnosed unusual case of inverted terminal duplication of the short arm of chromosome 2, leading to interstitial telomeric sequences (ITSs) and partial trisomy 2p. To our knowledge, there are only 4 further cases of pure partial trisomy 2p reported prenatally. Here, the mother was referred at 22 weeks of gestation for isolated fetal congenital heart malformation at ultrasound. The karyotype of amniotic fluid cells displayed a large duplication of the short arm of chromosome 2 that was further investigated by array-CGH, which detected a 1-copy gain of 43.75 Mb in chromosome 2 at 2p21p25.3. FISH confirmed the presence of an inverted duplication in the short arm of chromosome 2 involving the region 2p21pter and revealed the presence of ITSs at the breakpoint in chromosome 2p21. This report contributes to the prenatal description of the syndrome. We also discuss the possible mechanisms leading to this duplication and the formation of ITSs which are rarely described in constitutional rearrangements.

Formalised consensus of the European Organisation for Treatment of Trophoblastic Diseases on management of gestational trophoblastic diseases.

Gestational trophoblastic disease (GTD) is a spectrum of cellular proliferations arising from trophoblast. Their invasive and metastatic potential sometimes requires chemotherapy and/or surgery. Current management is generally associated with favourable prognosis. Therefore, treatments must be chosen according to the desire for further childbearing of each patient. The European Organisation for Treatment of Trophoblastic Diseases (EOTTD) is dedicated to optimise diagnosis, treatment, follow-up and research in GTD by bringing together knowledge of clinicians and researchers from 29 countries working in the field of GTD in Europe. This study assessed the level of agreement among an expert panel of the EOTTD in order to rationalise the management of patients in Europe. The RAND/UCLA Appropriateness Method was used to combine the best available scientific evidence with the collective judgment of experts to yield a statement regarding the appropriateness of performing a procedure at the level of patient-specific symptoms, medical history and test results. There was an agreement for 54 statements while the experts showed a disagreement for two statements. As there is little evidence from randomised trials on which to base recommendations about management of GTD, many of these recommendations are based on expert opinion derived from changes in management fact that have improved outcomes from nearly 100% fatality to nearly 100% cure rates. However, a large agreement among experts is invaluable to the individual clinician who is struggling to decide whether a fertility-sparing treatment of hydatidiform mole or a low-risk GTN can be chosen and how it must be conducted.