Identification of novel candidate genes and variants for hearing loss and temporal bone anomalies

Background: Hearing loss remains an important global health problem that is potentially addressed through early identification of a genetic etiology, which helps to predict outcomes of hearing rehabilitation such as cochlear implantation and also to mitigate the long-term effects of comorbidities. The identification of variants for hearing loss and detailed descriptions of clinical phenotypes in patients from various populations are needed to improve the utility of clinical genetic screening for hearing loss. Methods: Clinical and exome data from 15 children with hearing loss were reviewed. Standard tools for annotating variants were used and rare, putatively deleterious variants were selected from the exome data. Results: In 15 children, 21 rare damaging variants in 17 genes were identified, including: 14 known hearing loss or neurodevelopmental genes, 11 of which had novel variants; and three candidate genes IST1, CBLN3 and GDPD5, two of which were identified in children with both hearing loss and enlarged vestibular aqueducts. Patients with variants within IST1 and MYO18B had poorer outcomes after cochlear implantation. Conclusion: Our findings highlight the importance of identifying novel variants and genes in ethnic groups that are understudied for hearing loss

Exome sequencing reveals novel variants and unique allelic spectrum for hearing impairment in Filipino cochlear implantees

Genetic hearing impairment is mostly nonsyndromic (80%), and >6,000 causal variants in >100 genes have been identified. Generally in hearing-impaired patients of Asian descent, GJB2 variants are most common (36%), followed by variants in SLC26A4 (MIM 605646), MYO15A (MIM 602666) and CDH23 (MIM 605516). Here we report seven novel variants in Filipino cochlear implantees, suggesting that the allelic spectrum for non-/syndromic hearing impairment in Filipinos is unique

A2ML1 and otitis media: novel variants, differential expression, and relevant pathways

A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media

FUT2 Variants Confer Susceptibility to Familial Otitis Media

Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154∗) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p.Arg202∗) variant co-segregates with otitis media in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European-American children (p = 1.2 × 10−5) and US trios (TDT p = 0.01). The c.461G>A (p.Trp154∗) variant was also over-transmitted in US trios (TDT p = 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p 20 were combined, FUT2 variants were over-transmitted in trios (TDT p = 0.001). Fut2 is transiently upregulated in mouse middle ear after inoculation with non-typeable Haemophilus influenzae. Four FUT2 variants—namely p.Ala104Val, p.Arg138Cys, p.Trp154∗, and p.Arg202∗—reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our families demonstrate marked intra-familial genetic heterogeneity, suggesting that multiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait

Early detection and screening for childhood deafness in the Philippines

Contains fulltext : 115715.pdf (publisher's version ) (Open Access)Radboud Universiteit Nijmegen, 21 mei 2013Promotores : Cremers, C.W.R.J., Snik, A.F.M

Understanding socio-technical change: A system-network-agent approach

Transitions are processes of change that have always occurred in society: for example, the production of goods changed from handcraft to machine-made. In recent years, these transitions attract more and more attention, mainly because societies now wish to actively bring about certain changes, such as the reduction of the use of fossil fuels – the so-called energy transition. This raises several questions, such as: how do ‘transitions’ evolve and to what extent can the course of such a process be influenced? This PhD thesis tries to improve the understanding of those transitions that have both a social and a technological aspect. This thesis presents a method of analysis with which these processes of socio-technical change can be captured in their full breadth and be modelled, which can serve as a basis for the simulation of a transition. Central to this approach is that we analyse the dynamics of the entire system, of the individual actors and of the actor networks at the same time as well as the interactions between these levels. This is the ‘System-Network-Agent approach’ that is proposed in this thesis. This method of analysis was applied in two in-depth case studies: about the transition in Brazil towards the use of bio-ethanol as car fuel, and the transition in the Netherlands towards a supply-chain approach for the treatment of household waste. Several lessons can be learned from these case studies. First, government can affect a transition, but not effect it. Government can try to start a transition process, but it depends on many other circumstances and actors – which cannot be controlled by government – whether the desired change is actually achieved. Moreover, both case studies show that a hierarchical government with a clear policy focus is more effective in bringing about changes than a government that keeps all options open and seeks to reach social consensus first. For example, the most significant change concerning the treatment of household waste in the last century in the Netherlands occurred during the German occupation in World War II. Drastic events, such as a crisis or very high oil prices, play an important role in transitions. They can be an incentive for the development of alternatives to the current practice or help to align the preferences of different actors. As such, drastic events can provide a window of opportunity in a transition, but they could also hinder such a process. From the case studies we conclude that the system, network and agent levels are all needed in a transition. A ‘top-down transition’ needs bottom-up acceptance, whereas a ‘bottom-up transition’ will not succeed if it is blocked from the top. The proposed ‘System-Network-Agent approach’ has proven to be a powerful tool to capture exactly those interdependencies, as this thesis shows.Infrastructure Systems & ServicesTechnology, Policy and Managemen

Studying transition dynamics via focusing on underlying feedback interactions: Modelling the Dutch waste management transition

The emerging need for societal transitions raises the need for a better understanding of the dynamic nature of large scale societal systems, and therefore the development of an analytical approach for drawing dynamic conclusions based on system’s dynamic mechanisms, feedback relationships and interacting components. The objective of this study is to explore the degree to which System Dynamics as an approach enhances the process of understanding transition dynamics in socio-technical systems. In other words, it is aimed to reveal the type of insights that can be developed about such systems and their dynamic behaviour using the approach, as well as the shortcomings of the approach in this challenging task. In order to do so, a modeling study aiming to understand the underlying mechanisms of the waste management transition in the Netherlands is conducted. The quantitative model developed is based on the historical case of the waste management transition of the Netherlands, and it portrays issues as the dynamics of actors’ preferences, development of infrastructure and environmental consequences of dominant mode of functioning and provides an instance for demonstrating and evaluating the feedback-focused perspective discussed in this paper. Finally, the paper discusses a set of points regarding the utilized approach, System Dynamics, observed during this study both in general and in the specific context of transitions. In short, System Dynamics stands as a promising approach mainly due to its strength in explaining the source of complex dynamics based on interacting feedback loops, but it also has certain drawbacks in the context of transitions.Technology, Policy and Managemen

Review of clinical manifestations of biochemically-advanced prostate cancer cases

Asian Journal of Surgery283202-206AJSU