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Background Mild Isolated Ventriculomegaly affects 0.15–0.7% of pregnancies.1 The developmental prognosis for children seems to be better than that described for ventriculomegaly associated with other anomalies.2 But the risk of developmental delay is still unclear and presents a challenge to physicians for managing and counselling prospective parents. Aim To evaluate the prenatal management and prognosis of isolated mild cerebral ventriculomegaly. This is the first study on ventriculomegaly in Wales. Methods 63 cases of ventriculomegaly were reported from the healthboard to CARIS database with Hydrocephalus during 2003–2012. 35 were identified as isolated mild ventriculomegaly. 30 case notes were reviewed as 5 case notes could not be traced. Of the 30, 3 were lost to follow-up as they moved out of the area. Results 28 cases were diagnosed at second trimester anomaly scan, while one patient booked late at 28 weeks and in another the scan was normal at anomaly but developed later. 100% of women were screened for TORCH infection, all were negative for current infections. All women were offered amniocentesis, 9(30%) of them accepted, all 9 (30%) were normal karyotype. All women had scans every 4 weeks. Two women underwent termination due to progression of ventriculomegaly. In 17 (63%) cases of ventriculomegaly resolved in third trimester, it is difficult to asses the prognosis of these babies as they did not have cranial ultrasound or neurodevelopmental assessment routinely. Conclusions In our study all routine investigations including TORCH and karyotype are normal. 63% of the cases of mild isolated ventriculomegaly resolved in utero. It has highlighted the lack of uniform policy in neonatal assessment. There are limitations including the retrospective model, small sample size and not having the neonatal follow up. References Wax JR, Bookman BS, Cartin A, Pinette MG, Blackstone DO. Mild fetal cerebral ventriculomegaly: diagnosis, clinical associations and outcomes. Obstet and Gynaecol survey. 2003; 58(6):407–414 Mercier A, Eurin D, Mercier PY, Verspyck E, Marpeau L, Marret S. Isolated mild fetal cerebral ventriculomegaly: a retrospective analysis of 26 cases. Prenat Diagnosis 2001;21:589–595 Pilu G, Falco P, Gabrielli S, Perolo A, Sandri F, Bovicelli L. The clinical significance of fetal isolated cerebral borderline ventriculomegaly: report of 31 cases and review of literature. Ultrasound Obstet Gynecol. 1999;14:320–6

Background Eudicots are the most diverse group of flowering plants that compromise five well-defined lineages: core eudicots, Ranunculales, Proteales, Trochodendrales, and Buxales. However, the phylogenetic relationships between these five lineages and their chromosomal evolutions remain unclear, and a lack of high-quality genome analyses for Buxales has hindered many efforts to address this knowledge gap. Results Here, we present a high-quality chromosome-level genome of Buxus austro-yunnanensis (Buxales). Our phylogenomic analyses revealed that Buxales and Trochodendrales are genetically similar and classified as sisters. Additionally, both are sisters to the core eudicots, while Ranunculales was found to be the first lineage to diverge from these groups. Incomplete lineage sorting and hybridization were identified as the main contributors to phylogenetic discordance (34.33%) between the lineages. In fact, B. austro-yunnanensis underwent only one whole-genome duplication event, and collinear gene phylogeny analyses suggested that separate independent polyploidizations occurred in the five eudicot lineages. Using representative genomes from these five lineages, we reconstructed the ancestral eudicot karyotype (AEK) and generated a nearly gapless karyotype projection for each eudicot species. Within core eudicots, we recovered one common chromosome fusion event in asterids and malvids, respectively. Further, we also found that the previously reported fused AEKs in Aquilegia (Ranunculales) and Vitis (core eudicots) have different fusion positions, which indicates that these two species have different karyotype evolution histories. Conclusions Based on our phylogenomic and karyotype evolution analyses, we revealed the likely relationships and evolutionary histories of early eudicots. Ultimately, our study expands genomic resources for early-diverging eudicots.

Lancelets (‘amphioxus’) are the modern survivors of an ancient chordate lineage, with a fossil record dating back to the Cambrian period. Here we describe the structure and gene content of the highly polymorphic ∼520-megabase genome of the Florida lancelet Branchiostoma floridae , and analyse it in the context of chordate evolution. Whole-genome comparisons illuminate the murky relationships among the three chordate groups (tunicates, lancelets and vertebrates), and allow not only reconstruction of the gene complement of the last common chordate ancestor but also partial reconstruction of its genomic organization, as well as a description of two genome-wide duplications and subsequent reorganizations in the vertebrate lineage. These genome-scale events shaped the vertebrate genome and provided additional genetic variation for exploitation during vertebrate evolution. The amphioxus genome: The key to the genetics of the last common chordate ancestor This issue sees the publication of the draft genome sequence of an animal that has been studied by biologists for many years as a model for a primitive chordate. The amphioxus or lancelet is a small worm-like creature, usually to be found buried in sand on the sea floor. Comparative analysis of the genome of the Florida lancelet, Branchiostoma floridae , reveals 17 ancestral chordate linkage groups conserved in the modern amphioxus and vertebrate genomes despite more than half a billion years of independent evolution. From this it possible to make a virtual reconstruction of the 17 chromosomes of the last common chordate ancestor. This reconstruction conforms that two rounds of whole genome duplication have occurred during evolution of the jawed vertebrate lineage. And it illuminates the murky relationships between the three chordate groups, the tunicates, lancelets and vertebrates. The cover shows four adult amphioxus collected in Apalachee Bay, Florida, with anterior towards the top and dorsal to the right. Yellow ovals are gonads. (Photo by Nicholas Putnam, DOE Joint Genome Institute.

Aims and objectives We aim to investigate the antenatal course and subsequent neonatal outcome of isolated mild to moderate (10-15mm) ventriculomegaly (VM) at mid-trimester scan or subsequently in pregnancy. Material and methods We did a retrospective review of all cases of mild to moderate VM diagnosed at our hospital within the fetal medicine unit from 1 January 2006 to 31 May 2011. Data was collected from electronic databases from clinical notes. All mothers with initial diagnosis of isolated mild to moderate VM in the fetus had infection screen (toxoplasma, CMV and Parvo), invasive testing was offered based on serum screening results. MRI was offered if other CNS abnormalities were suspected or imaging was found to be inadequate. Observations Isolated mild to moderate VM was found in 33 (77%) fetuses at mid-trimester and in 10(23%) fetuses at subsequent scans. Two (4.5%) women had abnormal karyotype. None had abnormal infection screen. Isolated mild VM progressed to severe VM in 6 (14%) fetuses, was stable in 23 (53%) fetuses and resolved in 14 (33%) fetuses. There was one intrauterine fetal demise, 3 MTOP and 2NND. Three (8%) babies had other abnormalities. Two babies had global development delay. All other babies had normal neurological outcome. Conclusions In conclusion 2 (5%) of the livebirths had abnormal neurological outcome at 6 months- 5 year (Mean 20 months) follow up. Total perinatal loss including TOP was 7(18%). Thus truly normal outcome was seen in 29 (77%) fetuses with initial diagnosis of isolated mild to moderateVM.

Background Classically monozygotic (MZ) twins are considered identical. However, there are a number of cases of MZ twins concordant for genotype but not phenotype. A review of these cases was performed in our institution. Methods Patients who had monozygotic twin pregnancies with discordant anomalies but normal karyotype were identified from the Fetal Assessment Unit Database of the Rotunda Hospital between January 2006 and July 2011. A retrospective chart review was then performed. Results Fifteen pairs of monozygotic twins who were genotypically identical but phenotypically different were identified. Average maternal age was 28.6 years. 93% were spontaneously conceived and all had ultrasound assignment of chorionicity prior to 16 weeks gestation. Discordant anomalies detected by ultrasound included two cystic hygromas, one duodenal atresia, three spinal abnormalities, three cerebral abnormalities one Congenital Diaphragmatic Hernia, two Gastroschisis, one bilateral hydronephrosis, one single vessel cord and one twin with a two vessel cord. 73% confirmed normal karyotype with invasive testing. Two patients underwent laser ablation of connecting vessels and this was associated with intrauterine demise of the affected twin. Regarding outcomes of the other pregnancies, three had intrauterine death of both twins. The twin with CDH had an early neonatal death. Conclusion This is an interesting series which highlights the non-identical nature that can occur in monozygotic twin pregnancies. Emerging data shows that there are different types of genetic/epigenetic and prenatal post-zygotic mechanisms that can cause discordance within such twin pairs. This possibility should be included in counselling patients with monozygotic pregnancies.

We present a rare case of fetal α thalassaemia with hydrops fetalis born to a Filipino couple. Maternal Hb suggested α-thalassaemia trait. Given the high risk ethnic background for α0-thalassaemia the couple were tested for α-globin gene cluster which showed highly unstable alpha-chain variant Hb Adana leading to an α+thalassaemia phenotype. The risk for hydrops fetalis was 1 in 4. Amniocentesis showed normal karyotype. DNA analysis from amniocytes showed the fetus to be compound heterozygous for the α0–thalassaemia deletion and the Hb Adana mutation (genotype --FIL/ααAdana). The partners declined any interventions. Hydrops fetalis developed and intrauterine fetal death was diagnosed 28 weeks of gestation. National screening algorithm aims to identify couples at risk of Hb Barts hydrops fetalis due to homozygous α0-thalassaemia. Couples at risk for non deletional Hb H disease in England may not be identified by routine screening.

Celery (Apium graveolens L. 2n = 2x = 22), a member of the Apiaceae family, is among the most important and globally grown vegetables. Here, we report a high-quality genome sequence assembly, anchored to 11 chromosomes, with total length of 3.33 Gb and N50 scaffold length of 289.78 Mb. Most (92.91%) of the genome is composed of repetitive sequences, with 62.12% of 31 326 annotated genes confined to the terminal 20% of chromosomes. Simultaneous bursts of shared long-terminal repeats (LTRs) in different Apiaceae plants suggest inter-specific exchanges. Two ancestral polyploidizations were inferred, one shared by Apiales taxa and the other confined to Apiaceae. We reconstructed 8 Apiales proto-chromosomes, inferring their evolutionary trajectories from the eudicot common ancestor to extant plants. Transcriptome sequencing in three tissues (roots, leaves and petioles), and varieties with different-coloured petioles, revealed 4 and 2 key genes in pathways regulating anthocyanin and coumarin biosynthesis, respectively. A remarkable paucity of NBS disease-resistant genes in celery (62) and other Apiales was explained by extensive loss and limited production of these genes during the last ~10 million years, raising questions about their biotic defence mechanisms and motivating research into effects of chemicals, for example coumarins, that give off distinctive odours. Celery genome sequencing and annotation facilitates further research into important gene functions and breeding, and comparative genomic analyses in Apiales.

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). 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. 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). 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. UK Department of Health and Social Care and The Wellcome Trust.

Background Knowledge on the prevalence of sex chromosome abnormalities (SCAs) is limited, and delayed diagnosis or non-diagnosis of SCAs are a continuous concern. We aimed to investigate change over time in incidence, prevalence and age at diagnosis among Turner syndrome (TS), Klinefelter syndrome (KS), Triple X syndrome (Triple X) and Double Y syndrome (Double Y). Methods This study is a nationwide cohort study in a public health care system. The Danish Cytogenetic Central Registry (DCCR) holds information on all karyotypes performed in Denmark since 1961. We identified all individuals in the DCCR with a relevant SCA during 1961–2014; TS: n  = 1156; KS: n  = 1235; Triple X: n  = 197; and Double Y: n  = 287. From Statistics Denmark, which holds an extensive collection of data on the Danish population, complete data concerning dates of death and migrations in and out of Denmark were retrieved for all individuals. Results The prevalence among newborns was as follows: TS: 59 per 100,000 females; KS: 57 per 100,000 males; Triple X: 11 per 100,000 females; and Double Y: 18 per 100,000 males. Compared with the expected number among newborns, all TS, 38% of KS, 13% of Triple X, and 18% of Double Y did eventually receive a diagnosis. The incidence of TS with other karyotypes than 45,X ( P  < 0.0001), KS ( P  = 0.02), and Double Y ( P  = 0.03) increased during the study period whereas the incidence of 45,X TS decreased ( P  = 0.0006). The incidence of Triple X was stable ( P  = 0.22). Conclusions The prevalence of TS is higher than previously identified, and the karyotypic composition of the TS population is changing. Non-diagnosis is extensive among KS, Triple X and Double Y, whereas all TS seem to become diagnosed. The diagnostic activity has increased among TS with other karyotypes than 45,X as well as among KS and Double Y.