Investigating the molecular basis of Jeune and Cenani-Lenz syndromes.

This thesis describes an investigation into the molecular basis of two rare autosomal recessive conditions: Jeune asphyxiating thoracic dystrophy (JATD) and Cenani-Lenz syndrome (CLS). JATD is a skeletal dysplasia sometimes complicated by chronic nephritis, hepatic and pancreatic fibrosis, and retinal degeneration. Although it is a serious condition with a high mortality and morbidity, predominantly from respiratory insufficiency in infancy and chronic renal failure in childhood, its molecular basis is currently unknown. This project focused on twelve consanguineous and nineteen non-consanguineous affected families. Haplotype analysis was undertaken in the consanguineous families to exclude linkage to several previously proposed candidate genes and loci. A homozygosity mapping approach was then adopted, and a genome-wide linkage scan was carried out in the three most statistically powerful consanguineous families. Each family was consistent with linkage to a different locus, on chromosomes 3q24-q26, 8q24 and 14q24-q32. The remaining families were genotyped across each locus to define minimal critical intervals. A number of candidate genes were then selected and screened for mutations in families which were consistent with linkage, but no mutations were identified. CLS is a distal limb malformation characterised by total digit syndactyly and radio ulnar synostosis. Limb deformity (Id) mice have a very similar phenotype. The Id phenotype is caused by mutations in the Formin-1 gene, leading to loss of Gremlin expression in the limb bud mesenchyme. In this project, haplotype analysis in one consanguineous CLS family excluded linkage both to FORMIN-1 (FMN-1) and to GREMLIN, which are immediately adjacent to each other on chromosome 15ql3. Haplotype analysis in another consanguineous CLS family was consistent with linkage to this region, but no mutations were identified in either FMN-1 or GREMLIN. The coding sequence of GREMLIN was analysed in two further consanguineous and three non-consanguineous CLS families, but no mutations were identified

Opportunities and technical challenges in next-generation sequencing for diagnosis of rare pediatric diseases

INTRODUCTION: Rare pediatric diseases are clinically severe with high rates of mortality and morbidity. This paper outlines how next-generation sequencing (NGS) can be used to greatly advance identification of the underlying genetic causes. AREAS COVERED: This manuscript is a blend of evidence obtained from literature searches from PubMed and rare disease related websites, laboratory experience and the author’s opinions. The paper covers the current state of the field and identifies where the challenges lie and how they are being overcome, using up-to-date references. EXPERT COMMENTARY: The field of NGS is still relatively new but it has already transformed the field of rare disease research. Technological advances in instrumentation, computational hardware and software have resulted in the identification of many causative genes, but as sequencing moves into population-scale initiatives standardisation and data sharing is going to be of paramount importance to ensure we derive the maximum benefit for patients

A large-scale empirical exploration on refactoring activities in open source software projects

Refactoring is a well-established practice that aims at improving the internal structure of a software system without changing its external behavior. Existing literature provides evidence of how and why developers perform refactoring in practice. In this paper, we continue on this line of research by performing a large-scale empirical analysis of refactoring practices in 200 open source systems. Specifically, we analyze the change history of these systems at commit level to investigate: (i) whether developers perform refactoring operations and, if so, which are more diffused and (ii) when refactoring operations are applied, and (iii) which are the main developer-oriented factors leading to refactoring. Based on our results, future research can focus on enabling automatic support for less frequent refactorings and on recommending refactorings based on the developer's workload, project's maturity and developer's commitment to the project

Preassociative aggregation functions

The classical property of associativity is very often considered in aggregation function theory and fuzzy logic. In this paper we provide axiomatizations of various classes of preassociative functions, where preassociativity is a generalization of associativity recently introduced by the authors. These axiomatizations are based on existing characterizations of some noteworthy classes of associative operations, such as the class of Acz\'elian semigroups and the class of t-norms.Comment: arXiv admin note: text overlap with arXiv:1309.730

Toward personalized medicine in Bardet-Biedl syndrome

Personalized medicine is becoming routine in the treatment of common diseases such as cancer, but has lagged behind in the field of rare diseases. It is currently in the early stages for the treatment of Bardet–Biedl syndrome. Advances in the understanding of ciliary biology and diagnostic techniques have opened up the prospect of treating BBS in a patient-specific manner. Owing to their structure and function, cilia provide an attractive therapeutic target and genetic therapies are being explored in ciliopathy treatment. Promising avenues include gene therapy, gene editing techniques and splice-correcting and read-through therapies. Targeted drug design has been successful in the treatment of genetic disease and research is underway in the discovery of known and novel drugs to treat Bardet–Biedl syndrome

Cost effectiveness of zofenopril in patients with left ventricular systolic dysfunction after acute myocardial infarction: a post- hoc analysis of the smile-4 study.

BACKGROUND: In SMILE-4 (the Survival of Myocardial Infarction Long-term Evaluation 4 study), zofenopril + acetylsalicylic acid (ASA) was superior to ramipril + ASA in reducing the occurrence of major cardiovascular events in patients with left ventricular dysfunction following acute myocardial infarction. The present post hoc analysis was performed to compare the cost-effectiveness of zofenopril and ramipril. METHODS: In total, 771 patients with left ventricular dysfunction and acute myocardial infarction were randomized in a double-blind manner to receive zofenopril 60 mg/day (n = 389) or ramipril 10 mg/day (n = 382) + ASA 100 mg/day and were followed up for one year. The primary study endpoint was the one-year combined occurrence of death or hospitalization for cardiovascular causes. The economic analysis was based on evaluation of cost of medications and hospitalizations and was applied to the intention-to-treat population (n = 716). Cost data were drawn from the National Health Service databases of the European countries participating in the study. The incremental cost-effectiveness ratio was used to quantify the cost per event prevented with zofenopril versus ramipril. RESULTS: Zofenopril significantly (P = 0.028) reduced the risk of the primary study endpoint by 30% as compared with ramipril (95% confidence interval, 4%-49%). The number needed to treat to prevent a major cardiovascular event with zofenopril was 13 less than with ramipril. The cost of drug therapies was higher with zofenopril (328.78 Euros per patient per year, n = 365) than with ramipril (165.12 Euros per patient per year, n = 351). The cost related to the occurrence of major cardiovascular events requiring hospitalization averaged 4983.64 Euros for zofenopril and 4850.01 Euros for ramipril. The incremental cost-effectiveness ratio for zofenopril versus ramipril was 2125.45 Euros per event prevented (worst and best case scenario in the sensitivity analysis was 3590.09 and 3243.96 Euros, respectively). CONCLUSION: Zofenopril is a viable and cost-effective treatment for managing patients with left ventricular dysfunction after acute myocardial infarction

ELMOD3-SH2D6 gene fusion as a possible co-star actor in autism spectrum disorder scenario

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by high heritability. It is known that genetic factors contribute to ASD pathogenesis. In particular, copy number variants (CNVs) are involved in ASD susceptibility and can affect gene expression regulation. 2p11.2 microdeletions encompassing ELMOD3, CAPG and SH2D6 genes have been described in four unrelated ASD families. The present study revealed that this microdeletion is responsible for the production of a chimeric transcript generated from the fusion between ELMOD3 and SH2D6. The identified transcript showed significantly higher expression levels in subjects carrying the deletion compared to control subjects, suggesting that it is not subjected to nonsense-mediated decay and might encode for a chimeric protein. In conclusion, this study suggests the possible involvement of this gene fusion, together with the other previously identified variants, in ASD

5.26 Left Ventricular Hypertrophy Prevalence by Different Left Ventricular Mass Indexes

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Novel missense variants in the RNF213 gene from a European family with Moyamoya disease

In this report, we present a European family with six individuals affected with Moyamoya disease (MMD). We detected two novel missense variants in the Moyamoya susceptibility gene RNF213, c.12553A>G (p.(Lys4185Glu)) and c.12562G>A (p.(Ala4188Thr)). Cosegregation of the variants with MMD, as well as a previous report of a variant affecting the same amino acid residue in unrelated MMD patients, supports the role of RNF213 in the pathogenesis of MM