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Purpose: MYRF‐related cardiac‐urogenital syndrome (MYRF‐CUGS) is a rare condition associated with heterozygous MYRF variants. The description of MYRF‐CUGS phenotype is mostly based on postnatal cases and 36 affected individuals have been published so far. We aim now to delineate the prenatal phenotype of MYRF‐CUGS by reporting clinical data from fetuses and neonates with a pathogenic MYRF variant. Methods: Detailed radiographic, pathological, clinical, and molecular data from 12 prenatal cases were collected through an international collaborative study. Adding the five fetuses previously published, we were able to study a cohort of 17 cases. Results: Main ultrasound‐accessible manifestations of MYRF‐CUGS include congenital heart defects (13/17, 76%), congenital diaphragmatic hernia (10/17, 59%) and disorders of sexual differentiation in 46, XY fetuses (7/14; 50%). Postnatal examination and/or autopsy data highlighted additional birth defects and neurological findings with a large spectrum of severity. Molecular results revealed ten previously unpublished variants, one missense and nine predicted truncating variants (three frameshift, three nonsense and three splice site variants). Conclusion: We report the first prenatal cohort of MYRF‐CUGS, allowing us to further characterize the variable expressivity of this rare disorder in fetuses. Severe congenital anomalies with a poor prognosis are more frequent than previously described in postnatal cases. Our data suggest that MYRF‐CUGS is characterized by a recurrent recognizable malformative association, accessible to prenatal diagnosis, with a significant intrafamilial phenotypic variability making genetic counseling challenging. [ABSTRACT FROM AUTHOR]

A vanishing twin (VT) occurs in up to 30% of early diagnosed twin pregnancies and is associated with an increased risk of fetal aneuploidy. Here, we describe our experience in a large VT population of 847 patients that underwent noninvasive prenatal testing (NIPT) for common fetal trisomies over a three-year period. All patients underwent an ultrasound examination prior to NIPT. Two comparison populations were included, namely, the singleton (n = 105,560) and the viable multiple gestation pregnancy samples (n = 9691) collected over the same period. All NIPT samples in the VT population received a result, of which 14 were high-risk for trisomy 21 (1.6%), nine for trisomy 18 (1.1%), and six for trisomy 13 (0.7%). Diagnostic testing confirmed the presence of trisomy 21 in 6/12 samples, giving a positive predictive value of 50%. One trisomy 18 case and no trisomy 13 cases were confirmed. The time between fetal demise and NIPT sampling did not appear to affect the number of true- or false-positive cases. In conclusion, NIPT is an effective screening method for trisomy 21 in the surviving fetus(es) in VT pregnancies. For trisomies 18 and 13, a positive NIPT should be interpreted carefully and ultrasound monitoring is preferrable over invasive diagnostic testing. [ABSTRACT FROM AUTHOR]

A supernumerary marker chromosome (SMC) is a structurally abnormal chromosome that cannot be characterized by conventional banding cytogenetics. Marker chromosomes are present in 0.075% of prenatal cases. They are associated with variable phenotypes, ranging from normal to severely abnormal, and the prognosis is largely dependent on the results of further cytogenomic analysis. Here, we report the identification and characterization of a marker chromosome following prenatal screening in a 39-year-old pregnant patient. The patient had a normal first trimester ultrasound but was high-risk for fetal chromosome anomalies based on the results of maternal serum parameters. Chorionic villus sampling was performed, and analysis of chorionic villi revealed the presence of two identical marker chromosomes. In the interest of a rapid identification of the markers, we performed noninvasive prenatal testing (NIPT) together with chorionic villus sampling. A pericentromeric 29 Mb duplication of chromosome 20: dup (20) (p13q11.21) was identified and thereafter confirmed by targeted metaphasic FISH. Wholegenome sequencing-based NIPT was instrumental in rapid characterization of the SMCs and allowed us to obviate the need for multiple expensive and timeconsuming FISH analyses. [ABSTRACT FROM AUTHOR]

Atypical fetal chromosomal anomalies are more frequent than previously recognized and can affect fetal development. We propose a screening strategy for a genome-wide non-invasive prenatal test (NIPT) to detect these atypical chromosomal anomalies (ACAs). Two sample cohorts were tested. Assay performances were determined using Cohort A, which consisted of 192 biobanked plasma samples—42 with ACAs, and 150 without. The rate of additional invasive diagnostic procedures was determined using Cohort B, which consisted of 3097 pregnant women referred for routine NIPT. Of the 192 samples in Cohort A, there were four initial test failures and six discordant calls; overall sensitivity was 88.1% (37/42; CI 75.00–94.81) and specificity was 99.3% (145/146; CI 96.22–99.88). In Cohort B, there were 90 first-pass failures (2.9%). The rate of positive results indicating an anomaly was 1.2% (36/3007) and 0.57% (17/3007) when limited to significant unbalanced chromosomal anomalies and trisomies 8, 9, 12, 14, 15, 16, and 22. These results show that genome-wide NIPT can screen for ACAs with an acceptable sensitivity and a small increase in invasive testing, particularly for women with increased risk following maternal serum screening and by limiting screening to structural anomalies and the most clinically meaningful trisomies. [ABSTRACT FROM AUTHOR]