Identification of a novel splice-site mutation in the Lebercilin (LCA5) gene causing Leber congenital amaurosis

Purpose: Leber congenital amaurosis (LCA) is one of the most common causes of hereditary blindness in infants. To date, mutations in 13 known genes and at two other loci have been implicated in LCA causation. An examination of the known genes highlights several processes which, when defective, cause LCA, including photoreceptor development and maintenance, phototransduction, vitamin A metabolism, and protein trafficking. In addition, it has been known for some time that defects in sensory cilia can cause syndromes involving hereditary blindness. More recently evidence has come to light that non-syndromic LCA can also be a “ciliopathy.” Methods: Here we present a homozygosity mapping analysis in a consanguineous sibship that led to the identification of a mutation in the recently discovered LCA5 gene. Homozygosity mapping was done using Affymetrix 10K Xba I Gene Chip and a 24.5cM region on chromosome 6 (6q12- q16.3) was identified to be significantly homozygous. The LCA5 gene on this region was sequenced and cDNA sequencing also done to characterize the mutation. Results: A c.955G>A missense mutation in the last base of exon 6 causing disruption of the splice donor site was identified in both the affected sibs. Since there is a second consensus splice donor sequence 5 bp into the adjacent intron, this mutation results in a transcript with a 5 bp insertion of intronic sequence, leading to a frameshift and premature truncation. Conclusions: We report a missense mutation functionally altering the splice donor site and leading to a truncated protein. This is the second report of LCA5 mutations causing LCA. It may also be significant that one affected child died at eleven months of age due to asphyxia during sleep. To date the only phenotype unambiguously associated with mutations in this gene is LCA. However the LCA5 gene is known to be expressed in nasopharynx, trachea and lungs and was originally identified in the proteome of bronchial epithelium ciliary axonemes. The cause of death in this child may therefore imply that LCA5 mutations can in fact cause a wider spectrum of phenotypes including respiratory disease

Knowledge priorities on climate change and water in the Upper Indus Basin : a horizon scanning exercise to identify the top 100 research questions in social and natural sciences

This study was partially supported by core funds of ICIMOD contributed by the governments of Afghanistan, Australia, Austria, Bangladesh, Bhutan, China, India, Myanmar, Nepal, Norway, Pakistan, Sweden, and Switzerland. AO was supported by funding from the National Environmental Research Council (NERC) National Capability Overseas Development Assistance under the grant ‘Polar expertise –Supporting development’ (NE/R000107/1).River systems originating from the Upper Indus Basin (UIB) are dominated by runoff from snow and glacier melt and summer monsoonal rainfall. These water resources are highly stressed as huge populations of people living in this region depend on them, including for agriculture, domestic use, and energy production. Projections suggest that the UIB region will be affected by considerable (yet poorly quantified) changes to the seasonality and composition of runoff in the future, which are likely to have considerable impacts on these supplies. Given how directly and indirectly communities and ecosystems are dependent on these resources and the growing pressure on them due to ever-increasing demands, the impacts of climate change pose considerable adaptation challenges. The strong linkages between hydroclimate, cryosphere, water resources, and human activities within the UIB suggest that a multi- and inter-disciplinary research approach integrating the social and natural/environmental sciences is critical for successful adaptation to ongoing and future hydrological and climate change. Here we use a horizon scanning technique to identify the Top 100 questions related to the most pressing knowledge gaps and research priorities in social and natural sciences on climate change and water in the UIB. These questions are on the margins of current thinking and investigation and are clustered into 14 themes, covering three overarching topics of 'governance, policy, and sustainable solutions', 'socioeconomic processes and livelihoods', and 'integrated Earth System processes'. Raising awareness of these cutting-edge knowledge gaps and opportunities will hopefully encourage researchers, funding bodies, practitioners, and policy makers to address them.Peer reviewe

Characterising the refractive error in paediatric patients with congenital stationary night blindness: a multicentre study

BACKGROUND/AAIMS: Congenital stationary night blindness (CSNB) is an inherited retinal disease that is often associated with high myopia and can be caused by pathological variants in multiple genes, most commonly CACNA1F, NYX and TRPM1. High myopia is associated with retinal degeneration and increased risk for retinal detachment. Slowing the progression of myopia in patients with CSNB would likely be beneficial in reducing risk, but before interventions can be considered, it is important to understand the natural history of myopic progression. METHODS: This multicentre, retrospective study explored CSNB caused by variants in CACNA1F, NYX or TRPM1 in patients who had at least 6 measurements of their spherical equivalent of refraction (SER) before the age of 18. A mixed-effect model was used to predict progression of SER overtime and differences between genotypes were evaluated. RESULTS: 78 individuals were included in this study. All genotypes showed a significant myopic predicted SER at birth (-3.076D, -5.511D and -5.386D) for CACNA1F, NYX and TRPM1 respectively. Additionally, significant progression of myopia per year (-0.254D, -0.257D and -0.326D) was observed for all three genotypes CACNA1F, NYX and TRPM1, respectively. CONCLUSIONS: Patients with CSNB tend to be myopic from an early age and progress to become more myopic with age. Patients may benefit from long-term myopia slowing treatment in the future and further studies are indicated. Additionally, CSNB should be considered in the differential diagnosis for early-onset myopia

Rationale and protocol paper for the Asia Pacific Network for inherited eye diseases

PURPOSE: There are major gaps in our knowledge of hereditary ocular conditions in the Asia-Pacific population, which comprises approximately 60% of the world's population. Therefore, a concerted regional effort is urgently needed to close this critical knowledge gap and apply precision medicine technology to improve the quality of lives of these patients in the Asia-Pacific region. DESIGN: Multi-national, multi-center collaborative network. METHODS: The Research Standing Committee of the Asia-Pacific Academy of Ophthalmology and the Asia-Pacific Society of Eye Genetics fostered this research collaboration, which brings together renowned institutions and experts for inherited eye diseases in the Asia-Pacific region. The immediate priority of the network will be inherited retinal diseases (IRDs), where there is a lack of detailed characterization of these conditions and in the number of established registries. RESULTS: The network comprises 55 members from 35 centers, spanning 12 countries and regions, including Australia, China, India, Indonesia, Japan, South Korea, Malaysia, Nepal, Philippines, Singapore, Taiwan, and Thailand. The steering committee comprises ophthalmologists with experience in consortia for eye diseases in the Asia-Pacific region, leading ophthalmologists and vision scientists in the field of IRDs internationally, and ophthalmic geneticists. CONCLUSIONS: The Asia Pacific Inherited Eye Disease (APIED) network aims to (1) improve genotyping capabilities and expertise to increase early and accurate genetic diagnosis of IRDs, (2) harmonise deep phenotyping practices and utilization of ontological terms, and (3) establish high-quality, multi-user, federated disease registries that will facilitate patient care, genetic counseling, and research of IRDs regionally and internationally

Age and frailty are independently associated with increased COVID-19 mortality and increased care needs in survivors: results of an international multi-centre study

INTRODUCTION: Increased mortality has been demonstrated in older adults with COVID-19, but the effect of frailty has been unclear.METHODS: This multi-centre cohort study involved patients aged 18years and older hospitalised with COVID-19, using routinely collected data. We used Cox regression analysis to assess the impact of age, frailty, and delirium on the risk of inpatient mortality, adjusting for sex, illness severity, inflammation, and co-morbidities. We used ordinal logistic regression analysis to assess the impact of age, Clinical Frailty Scale (CFS), and delirium on risk of increased care requirements on discharge, adjusting for the same variables.RESULTS: Data from 5,711 patients from 55 hospitals in 12 countries were included (median age 74, IQR 54-83; 55.2% male). The risk of death increased independently with increasing age (>80 vs 18-49: HR 3.57, CI 2.54-5.02), frailty (CFS 8 vs 1-3: HR 3.03, CI 2.29-4.00) inflammation, renal disease, cardiovascular disease, and cancer, but not delirium. Age, frailty (CFS 7 vs 1-3: OR 7.00, CI 5.27-9.32), delirium, dementia, and mental health diagnoses were all associated with increased risk of higher care needs on discharge. The likelihood of adverse outcomes increased across all grades of CFS from 4 to 9.CONCLUSIONS: Age and frailty are independently associated with adverse outcomes in COVID-19. Risk of increased care needs was also increased in survivors of COVID-19 with frailty or older age