Phenotypic profiling in subjects heterozygous for 1 of 2 rare variants in the hypophosphatasia gene (ALPL)

CONTEXT: Hypophosphatasia (HPP) is a syndrome marked by low serum alkaline phosphatase (AlkP) activity as well as musculoskeletal and/or dental disease. While the majority of subjects with HPP carry a pathogenic variant in the METHODS: Through BioVU, a DNA biobank that pairs individuals\u27 genetic information with their de-identified medical records, we identified subjects with 2 rare variants with distinct reported clinical phenotypes (p.D294A and p.T273M). We then performed a manual review of these subjects\u27 de-identified medical records along with computational modeling of protein structure to construct a genetic, biochemical and clinical phenotype for each subject and variant. RESULTS: Twenty subjects with the p.D294A variant and 17 with the p.T273M variant had sufficient data for analysis. Among subjects in our cohort with the p.D294A variant, 6 (30.0%) had both clinical bone disease and serum AlkP activity below 40 IU/L while 4 subjects (23.5%) with the p.T273M variant met the same criteria despite the distinct clinical phenotypes of these variants. CONCLUSIONS: Given the loose genotype/phenotype correlation in HPP seen in our cohort, clinical context is crucial for the interpretation of genetic test results to guide clinical care in this population. Otherwise, over- or under-diagnosis may occur, resulting in misidentification of those who may benefit from additional screening and perhaps pharmacologic intervention

Loss of Krüppel-like factor 9 deregulates both physiological gene expression and development

Abstract Krüppel-like factor 9 (Klf9) is a ubiquitously expressed transcription factor that is a feedforward regulator of multiple stress-responsive and endocrine signaling pathways. We previously described how loss of Klf9 function affects the transcriptome of zebrafish larvae sampled at a single time point 5 days post-fertilization (dpf). However, klf9 expression oscillates diurnally, and the sampled time point corresponded to its expression nadir. To determine if the transcriptomic effects of the klf9 −/− mutation vary with time of day, we performed bulk RNA-seq on 5 dpf zebrafish embryos sampled at three timepoints encompassing the predawn peak and midmorning nadir of klf9 expression. We found that while the major effects of the klf9 −/− mutation that we reported previously are robust to time of day, the mutation has additional effects that manifest only at the predawn time point. We used a published single-cell atlas of zebrafish development to associate the effects of the klf9 −/− mutation with different cell types and found that the mutation increased mRNA associated with digestive organs (liver, pancreas, and intestine) and decreased mRNA associated with differentiating neurons and blood. Measurements from confocally-imaged larvae suggest that overrepresentation of liver mRNA in klf9 −/− mutants is due to development of enlarged livers

Digital heritage interpretation: a conceptual framework

© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group. ‘Heritage Interpretation’ has always been considered as an effective learning, communication and management tool that increases visitors’ awareness of and empathy to heritage sites or artefacts. Yet the definition of ‘digital heritage interpretation’ is still wide and so far, no significant method and objective are evident within the domain of ‘digital heritage’ theory and discourse. Considering ‘digital heritage interpretation’ as a process rather than as a tool to present or communicate with end-users, this paper presents a critical application of a theoretical construct ascertained from multiple disciplines and explicates four objectives for a comprehensive interpretive process. A conceptual model is proposed and further developed into a conceptual framework with fifteen considerations. This framework is then implemented and tested on an online platform to assess its impact on end-users’ interpretation level. We believe the presented interpretive framework (PrEDiC) will help heritage professionals and media designers to develop interpretive heritage project