Consanguinity and pregnancy outcomes in a multi-ethnic, metropolitan European population

Objective: The aim of the present study was to assess the risk of major anomalies in the offspring of consanguineous couples, including data on the prenatal situation. Methods: Over 20years (1993-2012), 35391 fetuses were examined by prenatal sonography. In 675 cases (1.9%), parents were consanguineous, with 307 couples (45.5%) related as first cousins, 368 couples (54.5%) beyond first cousins. Detailed information was retrieved on 31710 (89.6%) fetuses, (consanguineous 568: 1.8%). Results: Overall prevalence of major anomalies among fetuses with non-consanguineous parents was 2.9% (consanguineous, 10.9%; first cousins, 12.4%; beyond first cousins, 6.5%). Adjusting the overall numbers for cases having been referred because of a previous index case, the prevalences were 2.8% (non-consanguineous) and 6.1% (consanguineous) (first cousin, 8.5%; beyond first cousin, 3.9%). Further adjustment for differential rates of trisomic pregnancies indicated 2.0%/5.9% congenital anomalies (non-consanguineous/consanguineous groups), that is, a consanguinity-associated excess of 3.9%, 6.1% in first cousin progeny and 1.9% beyond first cousin. Conclusions: The prevalence of major fetal anomalies associated with consanguinity is higher than in evaluations based only on postnatal life. It is important that this information is made available in genetic counselling programmes, especially in multi-ethnic and multi-religious communities, to enable couples to make informed decisions

evaluation of 35.391 cases from the prenatal medical view

Derzeit leben ca. 10,4% der Weltbevölkerung in konsanguinen Partnerschaften und auch in Europa leben im Zuge der Globalisierung immer mehr Menschen aus Regionen, in denen konsanguine Ehen gehäuft vorkommen. Der Zusammenhang zwischen Konsanguinität und einer erhöhten Rate sog. Major Anomalies - definiert als Fehlbildungen, die intrauterin und/oder postpartal ohne therapeutisches Eingreifen zum Tod oder zu einer schweren Behinderung des Kindes führen - ist mehrfach durch Studien nachgewiesen worden, die jedoch lediglich kasuistischen Charakter hatten oder Kollektive beschrieben, die die Situation von Kindern postnatal aufarbeiteten. Dies ist jedoch von Bedeutung, da ein Teil der im Zusammenhang mit Konsanguinität auftretenden Anomalien zu intrauterinem Fruchttod oder neonatalem Tod führen und somit in der Betrachtung bisheriger Studien nicht auftauchen. Die vorliegende Studie diente daher der Erfassung des Risikos von Major Anomalies von Feten aus konsanguinen Partnerschaften unter Einbezug prä-, peri- und unmittelbar postnataler Daten. Über einen Zeitraum von 20 Jahren (1993-2012) wurden 35.391 Feten durch einen Arzt mittels pränatalen Ultraschalls untersucht. In 675 Fällen (1,9%) waren die Nachkommen von Eltern aus konsanguinen Partnerschaften, davon waren 307 Feten (45,5%) aus Partnerschaften von Cousin und Cousine 1. Grades (F=0,0625) und 368 (55,5%) aus Partnerschaften mit einem geringerem Verwandtschaftsgrad (F<0,0625). Rückmeldungen über den Verlauf erhielten wir in 31.709 der 35.391 Fälle (89,6%), davon 31.141 von 34.716 Feten (89,7%) nicht-konsanguiner Eltern und von 568 von 675 Feten (84,1%) konsanguiner Eltern (Cousin 1. Grades 275/307; Cousin <1\. Grades 293/368). Die Gesamtprävalenz für eine Major Anomaly lag in der Gruppe der Nicht-Konsanguinen bei 2,9% (893/31.141), in der Gruppe der Konsanguinen bei 10,9% (62/568; Cousin 1. Grades 13,8% (38/275); Cousin <1\. Grades 8,2% (24/293)). Die angepasste Prävalenz durch Ausschluss von Fällen mit einer Major Anomaly in vorhergegangenen Schwangerschaften und von Fällen mit möglichen beeinflussenden Variablen wie z.B. altersabhängigen Trisomien betrug in der Gruppe der Nicht-Konsanguinen 2,0% (621/30.869), in der Gruppe der Konsanguinen 5,9% (32/538; Cousin 1. Grades 8,1% (21/258); Cousin <1\. Grades 3,9% (11/280)). Dies bedeutet unter allen Konsanguinen eine mindeste Prävalenzsteigerung gegenüber Nicht-Konsanguinen von 3,9% (Cousin 1. Grades 6,1%; Cousin <1\. Grades 1,9%). Die Rate von Major Anomalies von Nachkommen aus konsanguinen Partnerschaften ist im Vergleich zu allen bisherigen Studien, die sich nur auf postnatale Daten bezogen, höher. Für eine bessere genetische Beratung ist diese Information für alle die Schwangerschaft betreffenden medizinischen Einrichtungen wichtig, vor allen in Gebieten mit einem hohen Anteil multi-ethnischer Zusammensetzung sowie mit einem hohen Anteil konsanguiner Beziehungen.Approximately 10.4% of the current world population is consanguineous. Due to the process of globalization an increasing number of people from regions where consanguineous marriage is widespread are now living in Europe. So far the connection of consanguineous marriage and an elevated risk for major anomalies - defined as malformations that lead to death or severe handicap without therapy - has been described by multiple studies either casuistic or focusing on the postnatal situation. But several of the anomalies related to consanguinity lead to intrauterine or early neonatal death and are not recorded in such studies. Therefore the aim of the study at hand is to assess the risk for major anomalies of the offspring from consanguineous parents including the data of the prenatal, perinatal and direct postnatal situation. During a time interval of 20 years (1993-2012) a total of 35.391 fetuses were examined by a single physician using prenatal sonography. In 675 cases of these examinations (1.9%) the parents were consanguineous, in 307 of these cases (45.5%) the couples were related by means of first cousins (F=0.0625), in 368 cases (55.5%) the couples were related beyond the degree of first cousin (F<0.0625). Information on the course of pregnancy was obtained in 31.709 of all 35.391 cases (89.6%), 31.141/34.716 (89.7%) from non- consanguineous couples and 568/675 (84.1%) from consanguineous couples (first cousin 275/307; beyond first cousin 293/368). The overall prevalence of major anomalies among fetuses with non-consanguineous parents was 2.9% (893/31.141), the overall prevalence among fetuses with consanguineous parents was 10.9% (62/568; first cousin 13.8% (38/275); beyond first cousin 8.2% (24/293)). Excluding fetuses with a major anomaly because of an index case in a mothers’ earlier pregnancy and extracting other cases probably influencing the statistics (e.g. age-dependent trisomies) the prevalence of major anomalies for non-consanguineous is 2.0% (621/30.869) and for consanguineous 5.9% (32/538; first cousin 8.1% (21/258); beyond first cousin 3.9% (11/280)). This results in a consanguinity-associated excess of at least 3.9% in comparison to a non-consanguineous population (first cousin 6.1%; beyond first cousin 1.9%). Our data shows that the frequency of fetal major anomalies in the offspring of consanguineous couples is higher than suggested by studies that are solely based on postnatal data. For a better genetic counseling it is essential to share this information with all pregnancies related medical institutions especially in regions with multi-ethnic population or with a high frequency of consanguinity

Correlation between spin structure oscillations and domain wall velocities

Magnetic sensing and logic devices based on the motion of magnetic domain walls rely on the precise and deterministic control of the position and the velocity of individual magnetic domain walls in curved nanowires. Varying domain wall velocities have been predicted to result from intrinsic effects such as oscillating domain wall spin structure transformations and extrinsic pinning due to imperfections. Here we use direct dynamic imaging of the nanoscale spin structure that allows us for the first time to directly check these predictions. We find a new regime of oscillating domain wall motion even below the Walker breakdown correlated with periodic spin structure changes. We show that the extrinsic pinning from imperfections in the nanowire only affects slow domain walls and we identify the magnetostatic energy, which scales with the domain wall velocity, as the energy reservoir for the domain wall to overcome the local pinning potential landscape.publishe

Four molybdenum-dependent steroid C-25 hydroxylases: heterologous overproduction, role in steroid degradation, and application for 25-hydroxyvitamin D3 synthesis.

14 p.-5 fig.-3 tab.Side chain-containing steroids are ubiquitous constituents of biological membranes that are persistent to biodegradation. Aerobic, steroid-degrading bacteria employ oxygenases for isoprenoid side chain and tetracyclic steran ring cleavage. In contrast, a Mo-containing steroid C-25 dehydrogenase (S25DH) of the dimethyl sulfoxide (DMSO) reductase family catalyzes the oxygen-independent hydroxylation of tertiary C-25 in the anaerobic, cholesterol-degrading bacterium Sterolibacterium denitrificans. Its genome contains eight paralogous genes encoding active site α-subunits of putative S25DH-like proteins. The difficult enrichment of labile, oxygen-sensitive S25DH from the wild-type bacteria and the inability of its active heterologous production have largely hampered the study of S25DH-like gene products. Here we established a heterologous expression platform for the three structural genes of S25DH subunits together with an essential chaperone in the denitrifying betaproteobacterium Thauera aromatica K172. Using this system, S25DH1 and three isoenzymes (S25DH2, S25DH3, and S25DH4) were overproduced in a soluble, active form allowing a straightforward purification of nontagged αβγ complexes. All S25DHs contained molybdenum, four [4Fe-4S] clusters, one [3Fe-4S] cluster, and heme B and catalyzed the specific, water-dependent C-25 hydroxylations of various 4-en-3-one forms of phytosterols and zoosterols. Crude extracts from T. aromatica expressing genes encoding S25DH1 catalyzed the hydroxylation of vitamin D3 (VD3) to the clinically relevant 25-OH-VD3 with >95% yield at a rate 6.5-fold higher than that of wild-type bacterial extracts; the specific activity of recombinant S25DH1 was twofold higher than that of wild-type enzyme. These results demonstrate the potential application of the established expression platform for 25-OH-VD3 synthesis and pave the way for the characterization of previously genetically inaccessible S25DH-like Mo enzymes of the DMSO reductase family. IMPORTANCE Steroids are ubiquitous bioactive compounds, some of which are considered an emerging class of micropollutants. Their degradation by microorganisms is the major process of steroid elimination from the environment. While oxygenase-dependent steroid degradation in aerobes has been studied for more than 40 years, initial insights into the anoxic steroid degradation have only recently been obtained. Molybdenum-dependent steroid C-25 dehydrogenases (S25DHs) have been proposed to catalyze oxygen-independent side chain hydroxylations of globally abundant zoo-, phyto-, and mycosterols; however, so far, their lability has allowed only the initial characterization of a single S25DH. Here we report on a heterologous gene expression platform that allowed for easy isolation and characterization of four highly active S25DH isoenzymes. The results obtained demonstrate the key role of S25DHs during anoxic degradation of various steroids. Moreover, the platform is valuable for the efficient enzymatic hydroxylation of vitamin D3 to its clinically relevant C-25-OH form. © 2018 Jacoby et al.This work was funded by the Germany Research Foundation DFG (BO 1565, 15-1) and by the Ministry of Economy and Competitiveness of Spain (BIO2016-79736-R).Peer reviewe

Genomic evolution of antimicrobial resistance in <i>Escherichia coli</i>

The emergence of antimicrobial resistance (AMR) is one of the biggest health threats globally. In addition, the use of antimicrobial drugs in humans and livestock is considered an important driver of antimicrobial resistance. The commensal microbiota, and especially the intestinal microbiota, has been shown to have an important role in the emergence of AMR. Mobile genetic elements (MGEs) also play a central role in facilitating the acquisition and spread of AMR genes. We isolated Escherichia coli (n=627) from fecal samples in respectively 25 poultry, 28 swine, and 15 veal calf herds from 6 European countries to investigate the phylogeny of E. coli at country, animal host and farm levels. Furthermore, we examine the evolution of AMR in E. coli genomes including an association with virulence genes, plasmids and MGEs. We compared the abundance metrics retrieved from metagenomic sequencing and whole genome sequenced of E. coli isolates from the same fecal samples and farms. The E. coli isolates in this study indicated no clonality or clustering based on country of origin and genetic markers; AMR, and MGEs. Nonetheless, mobile genetic elements play a role in the acquisition of AMR and virulence genes. Additionally, an abundance of AMR was agreeable between metagenomic and whole genome sequencing analysis for several AMR classes in poultry fecal samples suggesting that metagenomics could be used as an indicator for surveillance of AMR in E. coli isolates and vice versa