Key points: What is already known about this topic? In 2015, the International Society for Prenatal Diagnosis (ISPD) published its first position statement on the use of non‐invasive prenatal testing (NIPT) to screen for aneuploidy. Widespread uptake across the globe and subsequent published research has shed new light on test performance and implementation issues. What does this study add? This new position statement replaces the 2015 statement with updated information on the current technologies, clinical experience, and implementation practices. As an international organization, ISPD recognizes that there are important population‐specific considerations in the organization of prenatal screening and diagnosis. These opinions are designed to apply to high income settings where prenatal screening for aneuploidy is an established part of antenatal care. This position statement is not a clinical practice guideline but represents the consensus opinion of the current ISPD Board based on the current state of knowledge and clinical practice.

Whole genome sequencing (WGS) is a powerful tool for postnatal genetic diagnosis, but relevant clinical studies in the field of prenatal diagnosis are limited. The present study aimed to prospectively evaluate the utility of WGS compared with chromosomal microarray (CMA) and whole exome sequencing (WES) in the prenatal diagnosis of fetal structural anomalies. We performed trio WGS (≈40-fold) in parallel with CMA in 111 fetuses with structural or growth anomalies, and sequentially performed WES when CMA was negative (CMA plus WES). In comparison, WGS not only detected all pathogenic genetic variants in 22 diagnosed cases identified by CMA plus WES, yielding a diagnostic rate of 19.8% (22/110), but also provided additional and clinically significant information, including a case of balanced translocations and a case of intrauterine infection, which might not be detectable by CMA or WES. WGS also required less DNA (100 ng) as input and could provide a rapid turnaround time (TAT, 18 ± 6 days) compared with that (31 ± 8 days) of the CMA plus WES. Our results showed that WGS provided more comprehensive and precise genetic information with a rapid TAT and less DNA required than CMA plus WES, which enables it as an alternative prenatal diagnosis test for fetal structural anomalies.

Objective: To determine the incremental yield of exome sequencing (ES) over chromosomal microarray analysis (CMA) or karyotyping in prenatally diagnosed non‐immune hydrops fetalis (NIHF).Methods: A prospective cohort study (comprising an extended group of the Prenatal Assessment of Genomes and Exomes (PAGE) study) was performed which included 28 cases of prenatally diagnosed NIHF undergoing trio ES following negative CMA or karyotyping. These cases were combined with data from a systematic review of the literature. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov databases were searched electronically (January 2000 to October 2020) for studies reporting on the incremental yield of ES over CMA or karyotyping in fetuses with prenatally detected NIHF. Inclusion criteria for the systematic review were: (i) at least two cases of NIHF undergoing sequencing; (ii) testing initiated based on prenatal ultrasound‐based phenotype; and (iii) negative CMA or karyotyping result. The incremental diagnostic yield of ES was assessed in: (i) all cases of NIHF; (ii) isolated NIHF; (iii) NIHF associated with an additional fetal structural anomaly; and (iv) NIHF according to severity (i.e. two vs three or more cavities affected).Results: In the extended PAGE study cohort, the additional diagnostic yield of ES over CMA or karyotyping was 25.0% (7/28) in all NIHF cases, 21.4% (3/14) in those with isolated NIHF and 28.6% (4/14) in those with non‐isolated NIHF. In the meta‐analysis, the pooled incremental yield based on 21 studies (306 cases) was 29% (95% CI, 24–34%; P < 0.00001; I² = 0%) in all NIHF, 21% (95% CI, 13–30%; P < 0.00001; I² = 0%) in isolated NIHF and 39% (95% CI, 30–49%; P < 0.00001; I² = 1%) in NIHF associated with an additional fetal structural anomaly. In the latter group, congenital limb contractures were the most prevalent additional structural anomaly associated with a causative pathogenic variant, occurring in 17.3% (19/110) of cases. The incremental yield did not differ significantly according to hydrops severity. The most common genetic disorders identified were RASopathies, occurring in 30.3% (27/89) of cases with a causative pathogenic variant, most frequently due to a PTPN11 variant (44.4%; 12/27). The predominant inheritance pattern in causative pathogenic variants was autosomal dominant in monoallelic disease genes (57.3%; 51/89), with most being de novo (86.3%; 44/51).Conclusions: Use of prenatal next‐generation sequencing in both isolated and non‐isolated NIHF should be considered in the development of clinical pathways. Given the wide range of potential syndromic diagnoses and heterogeneity in the prenatal phenotype of NIHF, exome or whole‐genome sequencing may prove to be a more appropriate testing approach than a targeted gene panel testing strategy. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Wiedemann–Steiner syndrome (WDSTS) is a rare genetic disorder characterized by facial gestalt, neurodevelopmental delay, skeletal anomalies and growth retardation, which is caused by variation of KMT2A gene. To date, only 2 Chinese WDSTS patients have been reported. Here, we report the phenotypes and KMT2A gene variations in 14 unrelated Chinese WDSTS patients and investigate the phenotypic differences between the Chinese and French cohorts. Next generation sequencing was performed for each patient, and the variants in the KMT2A gene were validated by Sanger sequencing. The phenotypes of 16 Chinese WDSTS patients were summarized and compared to 33 French patients. Genetic sequencing identified 13 deleterious de novo KMT2A variants in 14 patients, including 10 truncating, 2 missenses and 1 splicing variants. Of the 13 variants, 11 are novel and two have been reported previously. One of the patients is mosaic in the KMT2A gene. The variation spectra and phenotypic profiles of the Chinese WDSTS patients showed no difference with patients of other ethnicities; however, differ in the frequencies of several clinical features. We demonstrated that variations in the KMT2A gene can lead to both advanced and delayed bone age. We identified 6 novel phenotypes, which include microcephaly, deep palmar crease, external ear deformity, carpal epiphyseal growth retardation, dyslipidemia, and glossoptosis. In addition, patients harbored missense variants in the CXXC zinc finger domain of KMT2A showed more severe neurophenotypes. Our study consists of the largest cohort of Chinese WDSTS patients that continues to expand the WDSTS phenotypic and variation spectrum. Our results support the notion that the CXXC zinc finger domain of KMT2A gene is a hotspot for missense variants associated with more severe neurophenotypes.