Termination of pregnancy for fetal anomaly after 23 weeks of gestation: a European register-based study.

Objective To determine the prevalence of termination of pregnancy for fetal anomaly (TOPFA) after 23 weeks of gestation in European countries, and describe the spectrum of anomalies for which late TOPFA is recorded. Design Population-based study. Setting Twelve European countries. Population Nineteen registries of congenital anomaly in 12 European countries between 2000 and 2005. The number of total births covered was 2 695 832. Methods TOPFAs in singleton pregnancies from the European Surveillance of Congenital Anomalies and Twins (EUROCAT)database. Main outcome measures The prevalence of TOPFA and type of anomaly. Results There were 10 233 TOPFAs, 678 (6.6%) of which were performed at 24 weeks or more. The rate of TOPFA before 24 weeks was 3.4 per 1000 births, at 24-25 weeks 0.14 per 1000 births and at 26 weeks or more 0.11 per 1000 births. There was significant variation in the prevalence of TOPFA at ?24 weeks between countries (P < 0.001), with all countries in the range 0-0.55 per 1000 births, except France (Paris) at 2.65 per 1000 births. The large majority of late TOPFAs had a gestational age of 24-27 weeks (516/678, 76%). The proportion of TOPFAs from 24 weeks or more varied by type of anomaly, with 4% of all TOPFAs for chromosomal anomalies and 9% of all TOPFAs for nonchromosomal anomalies resulting in late TOPFA (P < 0.001). For transposition of the great arteries, single ventricle, hypoplastic left heart and hydrocephaly, the percentage of late TOPFA was 12-23%. The median time interval between diagnosis and late TOPFA was 2 weeks for most anomalies, but longer (?5 weeks) for diaphragmatic hernia, omphalocoele, arthrogryposis multiplex and Turner\u27s syndrome. Conclusion Late TOPFA is rare in Europe, and varies in prevalence between countries. Compared with earlier TOPFA, late TOPFA is more often performed for a nonchromosomal isolated major structural anomaly and less often for a fetus with a chromosomal syndrome or multiple anomalies

Mutations in the Human UBR1 Gene and the Associated Phenotypic Spectrum

Johanson-Blizzard syndrome (JBS) is a rare, autosomal recessive disorder characterized by exocrine pancreatic insufficiency, typical facial features, dental anomalies, hypothyroidism, sensorineural hearing loss, scalp defects, urogenital and anorectal anomalies, short stature, and cognitive impairment of variable degree. This syndrome is caused by a defect of the E3 ubiquitin ligase UBR1, which is part of the proteolytic N-end rule pathway. Herein, we review previously reported (n=29) and a total of 31 novel UBR1 mutations in relation to the associated phenotype in patients from 50 unrelated families. Mutation types include nonsense, frameshift, splice site, missense, and small in-frame deletions consistent with the hypothesis that loss of UBR1 protein function is the molecular basis of JBS. There is an association of missense mutations and small in-frame deletions with milder physical abnormalities and a normal intellectual capacity, thus suggesting that at least some of these may represent hypomorphic UBR1 alleles. the review of clinical data of a large number of molecularly confirmed JBS cases allows us to define minimal clinical criteria for the diagnosis of JBS. for all previously reported and novel UBR1 mutations together with their clinical data, a mutation database has been established at LOVD.German Research FoundationUniv Hosp Magdeburg, Inst Human Genet, D-39120 Magdeburg, GermanyUniv Hosp Erlangen, Inst Human Genet, Erlangen, GermanyHosp Nacl Ninos Dr Carlos Saenz Herrera, Dept Med, San Jose, Costa RicaKlinikum Bremen Mitte, Bremen, GermanyCHU Vaudois, Dept Med Genet, CH-1011 Lausanne, SwitzerlandUniv Hosp, Dept Pediat Surg, Poitiers, FranceHosp La Fe, Dept Pediat, E-46009 Valencia, SpainAMC Univ Hosp, Dept Pediat Genet, Amsterdam, NetherlandsVanderbilt Univ, Monroe Carell Jr Childrens Hosp, Div Pediat Gastroenterol Hepatol & Nutr, Nashville, TN 37235 USACleveland Clin, Genom Med Inst, Cleveland, OH 44106 USAGuys Hosp, London SE1 9RT, EnglandKariminejad Najmabadi Pathol & Genet Ctr, Tehran, IranGreenwood Genet Ctr, Greenwood, SC 29646 USAUmea Univ, Dept Med Biosci Med & Clin Genet, Umea, SwedenWomens & Childrens Hosp, SA Clin Genet Serv, Adelaide, SA, AustraliaStiftung Deutsch Klin Diagnost GmbH, Fachbereich Kinder & Jugendmed, Wiesbaden, GermanyUniv São Paulo, Dept Pediat, São Paulo, BrazilUniv British Columbia, Dept Pediat, Div Biochem Dis, BC Childrens Hosp, Vancouver, BC V6T 1W5, CanadaCtr Human Genet, Ingelheim, GermanyNanjing Med Univ, Nanjing Childrens Hosp, Dept Digest Dis, Nanjing, Jiangsu, Peoples R ChinaUniv Klinikum Bonn, Zentrum Kinderheilkunde, Bonn, GermanyUniv Tehran Med Sci, Childrens Med Ctr, Res Ctr Immunodeficiencies, Tehran, IranUniv Tehran Med Sci, Dept Immunol, Tehran, IranKing Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi ArabiaOndokuz Mayis Univ, Dept Med, Samsun, TurkeyOndokuz Mayis Univ, Dept Pediat Genet, Samsun, TurkeyAl Thawra Teaching Hosp, Dept Pediat, Sanaa, YemenHosp Gen Mexico City, Fac Med, Dept Human Genet, Mexico City, DF, MexicoUniv Med Ctr Utrecht, Dept Med Genet, Utrecht, NetherlandsNatl Childrens Hosp, San Jose, Costa RicaSisli Etfal Res Hosp, Dept Med Genet, Istanbul, TurkeyNizams Inst Med Sci, Dept Med Genet, Hyderabad, Andhra Pradesh, IndiaMaulana Azad Med Coll, Dept Pediat, New Delhi, IndiaDeenanath Mangeshkar Hosp & Res Ctr, Dept Genet, Erandawane, IndiaMinist Hlth, Dept Pediat, Manama, BahrainUniv Fed Bahia, Fac Med, Hosp Univ Prof Edgar Santos, Pediat Endocrinol Unit, Salvador, BA, BrazilErnst Moritz Arndt Univ Greifswald, Univ Med, Dept Med A, Greifswald, GermanyTech Univ Munich, Else Kroner Fresenius Zentrum Ernahrungsmed, Freising Weihenstephan, GermanyTech Univ Munich, Zent Inst Ernahrungs & Lebensmittelforsch, Freising Weihenstephan, GermanyTech Univ Munich, Klinikum Rechts Isar, Dept Pediat, D-80290 Munich, GermanyGerman Research Foundation: DFG ZE 524/2-3Web of Scienc

Paper 6: EUROCAT member registries: Organization and activities

Background: EUROCAT is a network of population-based congenital anomaly registries providing standardized epidemiologic information on congenital anomalies in Europe. There are three types of EUROCAT membership: full, associate, or affiliate. Full member registries send individual records of all congenital anomalies covered by their region. Associate members transmit aggregate case counts for each EUROCAT anomaly subgroup by year and by type of birth. This article describes the organization and activities of each of the current 29 full member and 6 associate member registries of EUROCAT.Methods: Each registry description provides information on the history and funding of the registry, population coverage including any changes in coverage over time, sources for ascertaining cases of congenital anomalies, and upper age limit for registering cases of congenital anomalies. It also details the legal requirements relating to termination of pregnancy for fetal anomalies, the definition of stillbirths and fetal deaths, and the prenatal screening policy within the registry. Information on availability of exposure information and denominators is provided. The registry description describes how each registry conforms to the laws and guidelines regarding ethics, consent, and confidentiality issues within their own jurisdiction. Finally, information on electronic and web-based data capture, recent registry activities, and publications relating to congenital anomalies, along with the contact details of the registry leader, are provided.Conclusions: The registry description gives a detailed account of the organizational and operational aspects of each registry and is an invaluable resource that aids interpretation and evaluation of registry prevalence data. <br/

Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes

Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts’ maps could uncover functionally and clinically related genes