The clinical utility of microarray technologies applied to prenatal cytogenetics in the presence of a normal conventional karyotype: a review of the literature.

The clinical utility of microarray technologies when used in the context of prenatal diagnosis lies in the technology's ability to detect sub-microscopic copy number changes that are associated with clinically significant outcomes. We have carried out a systematic review of the literature to calculate the utility of prenatal microarrays in the presence of a normal conventional karyotype. Amongst 12362 cases in studies that recruited cases from all prenatal ascertainment groups, 295/12362 (2.4%) overall were reported to have copy number changes with associated clinical significance (pCNC), 201/3090 (6.5%) when ascertained with an abnormal ultrasound, 50/5108 (1.0%) when ascertained because of increased maternal age and 44/4164 (1.1%) for all other ascertainment groups (e.g. parental anxiety, abnormal serum screening result etc). When additional prenatal microarray studies are included in which ascertainment was restricted to fetuses with abnormal ultrasound scans, 262/3730 (7.0%) were reported to have pCNCs. This article is protected by copyright. All rights reserved

Multiplex ligation-dependent probe amplification versus karyotyping in prenatal diagnosis: the M.A.K.E. study

Abstract BACKGROUND: In the past 30 years karyotyping was the gold standard for prenatal diagnosis of chromosomal aberrations in the fetus. Traditional karyotyping (TKT) has a high accuracy and reliability. However, it is labor intensive, the results take 14-21 days, the costs are high and unwanted findings such as abnormalities with unknown clinical relevance are not uncommon. These disadvantages challenged the practice of karyotyping. Multiplex ligation-dependent probe amplification (MLPA) is a new molecular genetic technique in prenatal diagnosis. Previous preclinical evidence suggests equivalence of MLPA and traditional karyotyping (TKT) regarding test performance. METHODS/DESIGN: The proposed study is a multicentre diagnostic substitute study among pregnant women, who choose to have amniocentesis for the indication advanced maternal age and/or increased risk following prenatal screening test. In all subjects, both MLPA and karyotyping will be performed on the amniotic fluid sample. The primary outcome is diagnostic accuracy. Secondary outcomes will be maternal quality of life, women's preferences and costs. Analysis will be intention to treat and per protocol analysis. Quality of life analysis will be carried out within the study population. The study aims to include 4500 women. DISCUSSION: The study results are expected to help decide whether MLPA can replace traditional karyotyping for 'low-risk' pregnancies in terms of diagnostic accuracy, quality of life and women's preferences. This will be the first clinical study to report on all relevant aspects of the potential replacement

The APPLe Study: A Randomized, Community-Based, Placebo-Controlled Trial of Azithromycin for the Prevention of Preterm Birth, with Meta-Analysis

In a randomized trial in Malawi of azithromycin versus placebo in over 2,000 pregnant women, Jim Neilson and colleagues show no benefit of azithromycin for a number of outcomes including preterm birth and prenatal death

The role of routine post-natal abdominal ultrasound for newborns in a resource-poor setting: a longitudinal study

<p>Abstract</p> <p>Background-</p> <p>Neonatal abdominal ultrasound is usually performed in Nigeria to investigate neonatal symptoms rather than as a follow up to evaluate fetal abnormalities which were detected on prenatal ultrasound. The role of routine obstetric ultrasonography in the monitoring of pregnancy and identification of fetal malformations has partly contributed to lowering of fetal mortality rates. In Nigeria which has a high maternal and fetal mortality rate, many pregnant women do not have ante-natal care and not infrequently, women also deliver their babies at home and only bring the newborns to the clinics for immunization. Even when performed, most routine obstetric scans are not targeted towards the detection of fetal abnormalities.</p> <p>The aim of the present study is to evaluate the benefit of routinely performing abdominal scans on newborns with a view to detecting possible abnormalities which may have been missed ante-natally.</p> <p>Methods-</p> <p>This was a longitudinal study of 202 consecutive, apparently normal newborns. Routine clinical examination and abdominal ultrasound scans were performed on the babies by their mother's bedside, before discharge. Neonates with abnormal initial scans had follow-up scans.</p> <p>Results-</p> <p>There were 108 males and 94 females. There were 12 (5.9%) abnormal scans seen in five male and seven female neonates. Eleven of the twelve abnormalities were in the kidneys, six on the left and five on the right. Three of the four major renal anomalies- absent kidney, ectopic/pelvic kidney and two cases of severe hydronephrosis were however on the left side. There was one suprarenal abnormality on the right suspected to be a possible infected adrenal haemorrage. Nine of the abnormal cases reported for follow- up and of these, two cases had persistent severe abnormalities.</p> <p>Conclusions-</p> <p>This study demonstrated a 5.9% incidence of genito urinary anomalies on routine neonatal abdominal ultrasound in this small population. Routine obstetric USS is very useful but inadequate availability of skilled personnel and cost implications create great challenges in poor resource settings like Nigeria. However, awareness should be created so that parents who can afford such investigations can make informed decisions.</p

100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report

BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection. METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis. RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives. CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.)

Recent developments in genetics and medically assisted reproduction : from research to clinical applications

Two leading European professional societies, the European Society of Human Genetics and the European Society for Human Reproduction and Embryology, have worked together since 2004 to evaluate the impact of fast research advances at the interface of assisted reproduction and genetics, including their application into clinical practice. In September 2016, the expert panel met for the third time. The topics discussed highlighted important issues covering the impacts of expanded carrier screening, direct-to-consumer genetic testing, voiding of the presumed anonymity of gamete donors by advanced genetic testing, advances in the research of genetic causes underlying male and female infertility, utilisation of massively parallel sequencing in preimplantation genetic testing and non-invasive prenatal screening, mitochondrial replacement in human oocytes, and additionally, issues related to cross-generational epigenetic inheritance following IVF and germline genome editing. The resulting paper represents a consensus of both professional societies involved.Peer reviewe