Background Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES). Methods In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly. Findings The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8.5%; 95% CI 6.4-11.0) of 610 fetuses assessed and an additional 24 (3.9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15.4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11.1%) of 81 fetuses with cardiac anomalies, and ten (15.4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (>= 4.0 mm) in the first trimester (in three [3.2%] of 93 fetuses). Interpretation WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness. Funding UK Department of Health and Social Care and The Wellcome Trust. Copyright (c) 2019 The Author(s). Published by Elsevier Ltd.

(Abstracted from Lancet 2019;393:747–757) Fetal structural anomalies, detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs), and pathogenic sequence variants in developmental genes. Conventional prenatal cytogenetic analysis was historically the first-line method to investigate these anomalies, but chromosomal microarray analysis has been adopted more recently, as this test is able to detect smaller, but significant, CNVs.

Individuals with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,293 families with individuals with DDs, and meta-analysed these data with published data on 3,287 individuals with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the affected individual, the relatedness of their parents and the age of both father and mother. We identified 94 genes enriched for damaging de novo mutation at genome-wide significance (P < 7 × 10 −7 ), including 14 genes for which compelling data for causation was previously lacking. We have characterised the phenotypic diversity among these genetic disorders. We demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42% of our cohort carry pathogenic DNMs (single nucleotide variants and indels) in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder resulting in altered-function (e.g. activating, dominant negative). We established that most haplo insufficient developmental disorders have already been identified, but that many altered-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that developmental disorders caused by DNMs have an average birth prevalence of 1 in 213 to 1 in 448 (0.22-0.47% of live births), depending on parental age. Abbreviations PTV Protein-Truncating Variant DNM De Novo Mutation DD Developmental Disorder DDD Deciphering Developmental Disorders study

Prenatal DiagnosisVolume 21, Issue 6 p. 513-513 Letter to the Editor Prenatal testing for uniparental disomy (UPD) Anne M. Jay, Anne M. Jay West Midlands Regional Genetics Laboratories, Birmingham Women's Hospital NHS Trust, Edgbaston, Birmingham B15 2TG, UKSearch for more papers by this authorE. Roberts, Corresponding Author E. Roberts West Midlands Regional Genetics Laboratories, Birmingham Women's Hospital NHS Trust, Edgbaston, Birmingham B15 2TG, UKRegional Genetics Laboratories, Birmingham Women's Hospital NHS Trust, Edgbaston, Birmingham B15 2TG, UK.Search for more papers by this authorT. Davies, T. Davies South West Regional Cytogenetics Centre, Southmead Hospital, Bristol, UKSearch for more papers by this authorI. Barnes, I. Barnes North Trent Cytogenetics Service, Sheffield Children's Hospital NHS Trust, Western Bank, Sheffield, UKSearch for more papers by this authorM. Curtis, M. Curtis Genetic Diagnostic Laboratory, Medical Genetics Service for Wales, University Hospital of Wales, Heath Park, Cardiff, UKSearch for more papers by this authorK. Healey, K. Healey Leicestershire Cytogenetics Department, Leicester Royal Infirmary, Leicester, UKSearch for more papers by this authorE. V. Davison, E. V. Davison West Midlands Regional Genetics Laboratories, Birmingham Women's Hospital NHS Trust, Edgbaston, Birmingham B15 2TG, UKSearch for more papers by this author Anne M. Jay, Anne M. Jay West Midlands Regional Genetics Laboratories, Birmingham Women's Hospital NHS Trust, Edgbaston, Birmingham B15 2TG, UKSearch for more papers by this authorE. Roberts, Corresponding Author E. Roberts West Midlands Regional Genetics Laboratories, Birmingham Women's Hospital NHS Trust, Edgbaston, Birmingham B15 2TG, UKRegional Genetics Laboratories, Birmingham Women's Hospital NHS Trust, Edgbaston, Birmingham B15 2TG, UK.Search for more papers by this authorT. Davies, T. Davies South West Regional Cytogenetics Centre, Southmead Hospital, Bristol, UKSearch for more papers by this authorI. Barnes, I. Barnes North Trent Cytogenetics Service, Sheffield Children's Hospital NHS Trust, Western Bank, Sheffield, UKSearch for more papers by this authorM. Curtis, M. Curtis Genetic Diagnostic Laboratory, Medical Genetics Service for Wales, University Hospital of Wales, Heath Park, Cardiff, UKSearch for more papers by this authorK. Healey, K. Healey Leicestershire Cytogenetics Department, Leicester Royal Infirmary, Leicester, UKSearch for more papers by this authorE. V. Davison, E. V. Davison West Midlands Regional Genetics Laboratories, Birmingham Women's Hospital NHS Trust, Edgbaston, Birmingham B15 2TG, UKSearch for more papers by this author First published: 20 June 2001 https://doi.org/10.1002/pd.25Citations: 8AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume21, Issue6June 2001Pages 513-513 RelatedInformation

In order to determine the outcome and associated chromosomal and structural anomalies in fetuses diagnosed in utero as having a congenital diaphragmatic hernia, we reviewed 48 consecutive cases referred to our regional Fetal Diagnostic Unit between 1988 and 1995. All babies were delivered in units with appropriate neonatal resuscitation facilities. Thirteen babies [34 per cent of those tested, confidence interval (CI) 19-49 per cent] had karyotypic abnormalities. Three had trisomies but the other nine had more complex karyotypic abnormalities including translocations, deletions, and marker chromosomes. Twenty-one fetuses (44 per cent, CI 30-58 per cent) had additional ultrasound abnormalities which affected the heart in ten cases (21 per cent). Overall, 13 babies survived (27 per cent, CI 14-40 per cent). In babies with normal chromosomes and no additional structural abnormalities the survival rate was 50 per cent (CI 25-75 per cent). Poor outcome was not predicted by early gestation at diagnosis, the hernial contents, or the presence of polyhydramnios. We conclude that parents should be counselled about prognosis with information derived from series of prenatally diagnosed diaphragmatic hernias. The investigations offered should include a detailed ultrasound examination, particularly of the heart, and karyotyping by fetal blood sampling.