Diagnostic conundrums in antenatal presentation of a skeletal dysplasia with description of a heterozygous C-propeptide mutation in COL1A1 associated with a severe presentation of osteogenesis imperfecta

Prompt and accurate diagnosis of skeletal dysplasias can play a crucial role in ensuring appropriate counseling and management (both antenatal and postnatal). When a skeletal dysplasia is detected during the antenatal period, especially early in the pregnancy, it can be associated with a poor prognosis. It is important to make a diagnosis in antenatal presentation of skeletal dysplasias to inform diagnosis, predict prognosis, provide accurate recurrence risks, and options for prenatal genetic testing in future pregnancies. Prenatal ultrasound scanning is a useful tool to detect several skeletal dysplasias and sonographic measurements serve as reliable indicators of lethality. The lethality depends on various factors including gestational age at which features are identified, size of the chest and progression of malformations. Although, it is important to type the skeletal presentation as accurately as possible, this is not always possible in an antenatal presentation and it is important to acknowledge this uncertainty. In the case of a live birth, it is always important to reassess the infant. Osteogenesis imperfecta (OI) is a heterogeneous group of disorders characterized by fragile bones. Here, we report an infant with severe OI born following a twin pregnancy in whom the bone disease is caused by a heterozygous pathogenic mutation, c.4160C >T, p.(Ala1387Val) located in the C-propeptide region of COL1A1. An assumption of lethality antenatally complicated his management in early life. We discuss this patient with particular emphasis on the neonatal presentation of a severe skeletal dysplasia and the lessons that may be learned in such situations. © 2016 Wiley Periodicals, Inc

Toward Open Science at the European Scale: Geospatial Semantic Array Programming for Integrated Environmental Modelling

[Excerpt] Interfacing science and policy raises challenging issues when large spatial-scale (regional, continental, global) environmental problems need transdisciplinary integration within a context of modelling complexity and multiple sources of uncertainty. This is characteristic of science-based support for environmental policy at European scale, and key aspects have also long been investigated by European Commission transnational research. Approaches (either of computational science or of policy-making) suitable at a given domain-specific scale may not be appropriate for wide-scale transdisciplinary modelling for environment (WSTMe) and corresponding policy-making. In WSTMe, the characteristic heterogeneity of available spatial information and complexity of the required data-transformation modelling (D-TM) appeal for a paradigm shift in how computational science supports such peculiarly extensive integration processes. In particular, emerging wide-scale integration requirements of typical currently available domain-specific modelling strategies may include increased robustness and scalability along with enhanced transparency and reproducibility. This challenging shift toward open data and reproducible research (open science) is also strongly suggested by the potential - sometimes neglected - huge impact of cascading effects of errors within the impressively growing interconnection among domain-specific computational models and frameworks. Concise array-based mathematical formulation and implementation (with array programming tools) have proved helpful in supporting and mitigating the complexity of WSTMe when complemented with generalized modularization and terse array-oriented semantic constraints. This defines the paradigm of Semantic Array Programming (SemAP) where semantic transparency also implies free software use (although black-boxes - e.g. legacy code - might easily be semantically interfaced). A new approach for WSTMe has emerged by formalizing unorganized best practices and experience-driven informal patterns. The approach introduces a lightweight (non-intrusive) integration of SemAP and geospatial tools - called Geospatial Semantic Array Programming (GeoSemAP). GeoSemAP exploits the joint semantics provided by SemAP and geospatial tools to split a complex D-TM into logical blocks which are easier to check by means of mathematical array-based and geospatial constraints. Those constraints take the form of precondition, invariant and postcondition semantic checks. This way, even complex WSTMe may be described as the composition of simpler GeoSemAP blocks. GeoSemAP allows intermediate data and information layers to be more easily and formally semantically described so as to increase fault-tolerance, transparency and reproducibility of WSTMe. This might also help to better communicate part of the policy-relevant knowledge, often diffcult to transfer from technical WSTMe to the science-policy interface. [...

Free and Open Source Software underpinning the European Forest Data Centre

Worldwide, governments are growingly focusing on free and open source software (FOSS) as a move toward transparency and the freedom to run, copy, study, change and improve the software. The European Commission (EC) is also supporting the development of FOSS [...]. In addition to the financial savings, FOSS contributes to scientific knowledge freedom in computational science (CS) and is increasingly rewarded in the science-policy interface within the emerging paradigm of open science. Since complex computational science applications may be affected by software uncertainty, FOSS may help to mitigate part of the impact of software errors by CS community- driven open review, correction and evolution of scientific code. The continental scale of EC science-based policy support implies wide networks of scientific collaboration. Thematic information systems also may benefit from this approach within reproducible integrated modelling. This is supported by the EC strategy on FOSS: "for the development of new information systems, where deployment is foreseen by parties outside of the EC infrastructure, [F]OSS will be the preferred choice and in any case used whenever possible". The aim of this contribution is to highlight how a continental scale information system may exploit and integrate FOSS technologies within the transdisciplinary research underpinning such a complex system. A European example is discussed where FOSS innervates both the structure of the information system itself and the inherent transdisciplinary research for modelling the data and information which constitute the system content. [...

A family with partially penetrant multicentric carpotarsal osteolysis due to gonadal mosaicism: First reported case

Multicentric carpotarsal osteolysis (MCTO) is an autosomal dominant condition characterized by carpal-tarsal abnormalities; over half of affected individuals also develop renal disease. MCTO is caused by mutations of MAFB; however, there is no clear phenotype-genotype correlation. We describe the first reported family of variable MCTO phenotype due to mosaicism: the proband had classical skeletal features and renal involvement due to focal segmental glomerulosclerosis (FSGS), and the father had profound renal impairment due to FSGS, necessitating kidney transplantation. Mosaicism was first suspected in this family due to unequal allele ratios in the sequencing chromatograph of the initial blood sample of proband's father and confirmed by sequencing DNA extracted from the father's hair, collected from different bodily parts. This case highlights the need for a high index of clinical suspicion to detect low-level parental mosaicism, as well as a potential role for MAFB mutation screening in individuals with isolated FSGS.Peer reviewe

Australian human research ethics committee members' confidence in reviewing genomic research applications.

Human research ethics committees (HRECs) are evaluating increasing quantities of genomic research applications with complex ethical considerations. Genomic confidence is reportedly low amongst many non-genetics-experts; however, no studies have evaluated genomic confidence levels in HREC members specifically. This study used online surveys to explore genomic confidence levels, predictors of confidence, and genomics resource needs of members from 185 HRECs across Australia. Surveys were fully or partially completed by 145 members. All reported having postgraduate 94 (86%) and/or bachelor 15 (14%) degrees. Participants consisted mainly of researchers (n = 45, 33%) and lay members (n = 41, 30%), affiliated with either public health services (n = 73, 51%) or public universities (n = 31, 22%). Over half had served their HREC [Formula: see text]3 years. Fifty (44%) reviewed genomic studies [Formula: see text]3 times annually. Seventy (60%) had undertaken some form of genomic education. While most (94/103, 91%) had high genomic literacy based on familiarity with genomic terms, average genomic confidence scores (GCS) were moderate (5.7/10, n = 119). Simple linear regression showed that GCS was positively associated with years of HREC service, frequency of reviewing genomic applications, undertaking self-reported genomic education, and familiarity with genomic terms (p < 0.05 for all). Conversely, lay members and/or those relying on others when reviewing genomic studies had lower GCSs (p < 0.05 for both). Most members (n = 83, 76%) agreed further resources would be valuable when reviewing genomic research applications, and online courses and printed materials were preferred. In conclusion, even well-educated HREC members familiar with genomic terms lack genomic confidence, which could be enhanced with additional genomic education and/or resources

Free and open source software underpinning the european forest data centre

Excerpt: Worldwide, governments are growingly focusing on free and open source software (FOSS) as a move toward transparency and the freedom to run, copy, study, change and improve the software. The European Commission (EC) is also supporting the development of FOSS [...]. In addition to the financial savings, FOSS contributes to scientific knowledge freedom in computational science (CS) and is increasingly rewarded in the science-policy interface within the emerging paradigm of open science. Since complex computational science applications may be affected by software uncertainty, FOSS may help to mitigate part of the impact of software errors by CS community- driven open review, correction and evolution of scientific code. The continental scale of EC science-based policy support implies wide networks of scientific collaboration. Thematic information systems also may benefit from this approach within reproducible integrated modelling. This is supported by the EC strategy on FOSS: "for the development of new information systems, where deployment is foreseen by parties outside of the EC infrastructure, [F]OSS will be the preferred choice and in any case used whenever possible". The aim of this contribution is to highlight how a continental scale information system may exploit and integrate FOSS technologies within the transdisciplinary research underpinning such a complex system. A European example is discussed where FOSS innervates both the structure of the information system itself and the inherent transdisciplinary research for modelling the data and information which constitute the system content. [...

Free and open source software underpinning the european forest data centre

Excerpt: Worldwide, governments are growingly focusing on free and open source software (FOSS) as a move toward transparency and the freedom to run, copy, study, change and improve the software. The European Commission (EC) is also supporting the development of FOSS [...]. In addition to the financial savings, FOSS contributes to scientific knowledge freedom in computational science (CS) and is increasingly rewarded in the science-policy interface within the emerging paradigm of open science. Since complex computational science applications may be affected by software uncertainty, FOSS may help to mitigate part of the impact of software errors by CS community- driven open review, correction and evolution of scientific code. The continental scale of EC science-based policy support implies wide networks of scientific collaboration. Thematic information systems also may benefit from this approach within reproducible integrated modelling. This is supported by the EC strategy on FOSS: "for the development of new information systems, where deployment is foreseen by parties outside of the EC infrastructure, [F]OSS will be the preferred choice and in any case used whenever possible". The aim of this contribution is to highlight how a continental scale information system may exploit and integrate FOSS technologies within the transdisciplinary research underpinning such a complex system. A European example is discussed where FOSS innervates both the structure of the information system itself and the inherent transdisciplinary research for modelling the data and information which constitute the system content. [...

Free and open source software underpinning the european forest data centre

Excerpt: Worldwide, governments are growingly focusing on free and open source software (FOSS) as a move toward transparency and the freedom to run, copy, study, change and improve the software. The European Commission (EC) is also supporting the development of FOSS [...]. In addition to the financial savings, FOSS contributes to scientific knowledge freedom in computational science (CS) and is increasingly rewarded in the science-policy interface within the emerging paradigm of open science. Since complex computational science applications may be affected by software uncertainty, FOSS may help to mitigate part of the impact of software errors by CS community- driven open review, correction and evolution of scientific code. The continental scale of EC science-based policy support implies wide networks of scientific collaboration. Thematic information systems also may benefit from this approach within reproducible integrated modelling. This is supported by the EC strategy on FOSS: "for the development of new information systems, where deployment is foreseen by parties outside of the EC infrastructure, [F]OSS will be the preferred choice and in any case used whenever possible". The aim of this contribution is to highlight how a continental scale information system may exploit and integrate FOSS technologies within the transdisciplinary research underpinning such a complex system. A European example is discussed where FOSS innervates both the structure of the information system itself and the inherent transdisciplinary research for modelling the data and information which constitute the system content. [...

Mutations in MAP3K7 that Alter the Activity of the TAK1 Signaling Complex Cause Frontometaphyseal Dysplasia.

Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia affecting the long bones and skull. The cause of FMD in some individuals is gain-of-function mutations in FLNA, although how these mutations result in a hyperostotic phenotype remains unknown. Approximately one half of individuals with FMD have no identified mutation in FLNA and are phenotypically very similar to individuals with FLNA mutations, except for an increased tendency to form keloid scars. Using whole-exome sequencing and targeted Sanger sequencing in 19 FMD-affected individuals with no identifiable FLNA mutation, we identified mutations in two genes-MAP3K7, encoding transforming growth factor β (TGF-β)-activated kinase (TAK1), and TAB2, encoding TAK1-associated binding protein 2 (TAB2). Four mutations were found in MAP3K7, including one highly recurrent (n = 15) de novo mutation (c.1454C&gt;T [ p.Pro485Leu]) proximal to the coiled-coil domain of TAK1 and three missense mutations affecting the kinase domain (c.208G&gt;C [p.Glu70Gln], c.299T&gt;A [p.Val100Glu], and c.502G&gt;C [p.Gly168Arg]). Notably, the subjects with the latter three mutations had a milder FMD phenotype. An additional de novo mutation was found in TAB2 (c.1705G&gt;A, p.Glu569Lys). The recurrent mutation does not destabilize TAK1, or impair its ability to homodimerize or bind TAB2, but it does increase TAK1 autophosphorylation and alter the activity of more than one signaling pathway regulated by the TAK1 kinase complex. These findings show that dysregulation of the TAK1 complex produces a close phenocopy of FMD caused by FLNA mutations. Furthermore, they suggest that the pathogenesis of some of the filaminopathies caused by FLNA mutations might be mediated by misregulation of signaling coordinated through the TAK1 signaling complex