Diagnostic exome sequencing in 266 Dutch patients with visual impairment

Inherited eye disorders have a large clinical and genetic heterogeneity, which makes genetic diagnosis cumbersome. An exome-sequencing approach was developed in which data analysis was divided into two steps: the vision gene panel and exome analysis. In the vision gene panel analysis, variants in genes known to cause inherited eye disorders were assessed for pathogenicity. If no causative variants were detected and when the patient consented, the entire exome data was analyzed. A total of 266 Dutch patients with different types of inherited eye disorders, including inherited retinal dystrophies, cataract, developmental eye disorders and optic atrophy, were investigated. In the vision gene panel analysis (likely), causative variants were detected in 49% and in the exome analysis in an additional 2% of the patients. The highest detection rate of (likely) causative variants was in patients with inherited retinal dystrophies, for instance a yield of 63% in patients with retinitis pigmentosa. In patients with developmental eye defects, cataract and optic atrophy, the detection rate was 50, 33 and 17%, respectively. An exome-sequencing approach enables a genetic diagnosis in patients with different types of inherited eye disorders using one test. The exome approach has the same detection rate as targeted panel sequencing tests, but offers a number of advantages. For instance, the vision gene panel can be frequently and easily updated with additional (novel) eye disorder genes. Determination of the genetic diagnosis improved the clinical diagnosis, regarding the assessment of the inheritance pattern as well as future disease perspective

The attenuated end of the phenotypic spectrum in MPS III: from late-onset stable cognitive impairment to a non-neuronopathic phenotype

BACKGROUND: The phenotypic spectrum of many rare disorders is much wider than previously considered. Mucopolysaccharidosis type III (Sanfilippo syndrome, MPS III), is a lysosomal storage disorder traditionally considered to be characterized by childhood onset, progressive neurocognitive deterioration with a rapidly or slowly progressing phenotype. The presented MPS III case series demonstrates adult onset phenotypes with mild cognitive impairment or non-neuronopathic phenotypes. METHODS: In this case series all adult MPS III patients with a mild- or non-neuronopathic phenotype, who attend the outpatient clinic of 3 expert centers for lysosomal storage disorders were included. A mild- or non-neuronopathic phenotype was defined as having completed regular secondary education and attaining a level of independency during adulthood, involving either independent living or a paid job. RESULTS: Twelve patients from six families, with a median age at diagnosis of 43 years (range 3-68) were included (11 MPS IIIA, 1 MPS IIIB). In the four index patients symptoms which led to diagnostic studies (whole exome sequencing and metabolomics) resulting in the diagnosis of MPS III; two patients presented with retinal dystrophy, one with hypertrophic cardiomyopathy and one with neurocognitive decline. The other eight patients were diagnosed by family screening. At a median age of 47 years (range 19-74) 9 out of the 12 patients had normal cognitive functions. Nine patients had retinal dystrophy and 8 patients hypertrophic cardiomyopathy. CONCLUSION: We show the very mild end of the phenotypic spectrum of MPS III, ranging from late-onset stable neurocognitive impairment to a fully non-neuronopathic phenotype. Awareness of this phenotype could lead to timely diagnosis and genetic counseling

A First Search for coincident Gravitational Waves and High Energy Neutrinos using LIGO, Virgo and ANTARES data from 2007

We present the results of the first search for gravitational wave bursts associated with high energy neutrinos. Together, these messengers could reveal new, hidden sources that are not observed by conventional photon astronomy, particularly at high energy. Our search uses neutrinos detected by the underwater neutrino telescope ANTARES in its 5 line configuration during the period January - September 2007, which coincided with the fifth and first science runs of LIGO and Virgo, respectively. The LIGO-Virgo data were analysed for candidate gravitational-wave signals coincident in time and direction with the neutrino events. No significant coincident events were observed. We place limits on the density of joint high energy neutrino - gravitational wave emission events in the local universe, and compare them with densities of merger and core-collapse events.Comment: 19 pages, 8 figures, science summary page at http://www.ligo.org/science/Publication-S5LV_ANTARES/index.php. Public access area to figures, tables at https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=p120000

The drivers of career success of the job-hopping professional in the new networked economy : The challenges of being an entrepreneur and an employee

In Western economies the number of independent professionals (a.k.a. freelancers) is on the rise. The independent professional is a relatively new phenomenon that does not fit the traditional industrial era distinction between entrepreneurs and employees. In some aspects these independent professionals resemble entrepreneurs as they constantly look for new clients and new products to bring to the market. In other aspects they are similar to employees. The thesis looks into the three main questions: 1) why the number of freelancers is growing, 2) what the drivers are of freelance career success, and 3) how the growth of freelancing impacts traditional organizations. The thesis argues that the growth of freelancing is irreversible attached to the growth in the knowledge sector and is caused by technology developments that have given more power to the individual and decreased transaction costs. The study defines freelance career success both in monetary terms as well as in satisfaction terms. It shows that monetary success is largely determined by market factors (e.g. supply and demand, monopoly power, et cetera), human capital, and social capital. Personality, business strategy and motivation are less important for monetary success. For career satisfaction, it is almost the other way round; personality, business strategy and social capital are at the heart of freelance career satisfaction. Human capital, market factors and motivation are not so important for freelance career satisfaction. Finally the thesis shows that freelance growth can be an asset for existing organizations when these organizations are actively using the extra creativity and flexibility that freelancers bring. But the growth in freelance markets also poses a threat to knowledge organizations. Knowledge organizations have to adapt their strategy to make sure that they bring something to their clients that freelance markets have difficulty to offer (e.g. quality guarantees)

The drivers of freelance success

Recent evidence shows that the frequently proclaimed collapse of the traditional career model is actually not supported by job tenure data. This paper argues that the observed stability of job tenure might be explained by an increasing number of shamrock organizations. This organizational form has three types of workers: core employees, professional freelancers, and routine workers. In such an organization, two very different career models coexist. The organization largely determines the career of the core employee, whereas the individual essentially shapes that of the professional freelancer. This paper studies extensively the career of this second group: the professional freelancer, a growing phenomenon in many developed countries but not yet the focus of many career studies. We develop a freelance career success model on basis of the intelligent career framework augmented by insights from literature on entrepreneurship. Data are from a web survey with responses from about 1600 independent professionals in the Netherlands, in combination with 51 in-depth interviews. We provide two main contributions. First, we report findings from the first large-scale quantitative study into freelance career success. Second, this study enhances our understanding of the success of the modern career by building bridges between career and entrepreneurship literatures. We conclude that the external environment in which an individual freelancer operates is the most important factor determining career success. The study therefore suggests that more work needs to be performed on the relationship between the environment and individual career success

The drivers of freelance success

Recent evidence shows that the frequently proclaimed collapse of the traditional career model is actually not supported by job tenure data. This paper argues that the observed stability of job tenure might be explained by an increasing number of shamrock organizations. This organizational form has three types of workers: core employees, professional freelancers, and routine workers. In such an organization, two very different career models coexist. The organization largely determines the career of the core employee, whereas the individual essentially shapes that of the professional freelancer. This paper studies extensively the career of this second group: the professional freelancer, a growing phenomenon in many developed countries but not yet the focus of many career studies. We develop a freelance career success model on basis of the intelligent career framework augmented by insights from literature on entrepreneurship. Data are from a web survey with responses from about 1600 independent professionals in the Netherlands, in combination with 51 in-depth interviews. We provide two main contributions. First, we report findings from the first large-scale quantitative study into freelance career success. Second, this study enhances our understanding of the success of the modern career by building bridges between career and entrepreneurship literatures. We conclude that the external environment in which an individual freelancer operates is the most important factor determining career success. The study therefore suggests that more work needs to be performed on the relationship between the environment and individual career success