Genetics update: monogenetics, polygene disorders and the quest for modifying genes

The genetic channelopathies are a broad collection of diseases. Many ion channel genes demonstrate wide phenotypic pleiotropy, but nonetheless concerted efforts have been made to characterise genotype-phenotype relationships. In this review we give an overview of the factors that influence genotype-phenotype relationships across this group of diseases as a whole, using specific individual channelopathies as examples. We suggest reasons for the limitations observed in these relationships. We discuss the role of ion channel variation in polygenic disease and highlight research that has contributed to unravelling the complex aetiological nature of these conditions. We focus specifically on the quest for modifying genes in inherited channelopathies, using the voltage-gated sodium channels as an example. Epilepsy related to genetic channelopathy is one area in which precision medicine is showing promise. We will discuss the successes and limitations of precision medicine in these conditions

The potential impact of genotype-driven precision medicine for children with epilepsy

Introduction: The development and application of next generation sequencing (NGS) technology has led to an exponential rise in the number of genes and genetic variants associated with epilepsy. The detection of highly penetrant and damaging variants in some patients can be sufficient to provide an adequate explanation for the entire disease process. Particularly high yields from such diagnostic genetic testing are observed in cohorts of children who present with early onset seizures. Obtaining a genetic diagnosis can be helpful to families in terms of informing further reproductive decisions, providing answers, and preventing further costly investigations. Evidence is emerging that certain anti-epileptic therapies may be more effective than others in specific genetic epilepsies. Aim: The aim of this thesis is to explore the potential for genetically-guided therapy for children with epilepsy. This will be primarily achieved through describing the epidemiology of the genetic epilepsies of childhood, and through researching the evidence-base for gene-specific therapy. Methods: This is a mixed methods study. In chapter 5 The epidemiology of early childhood genetic epilepsy is described using a prospective whole Scotland population based national cohort. This includes all children presenting under three years of age presenting with new onset epilepsy over a defined time period (May 2014 to May 2017, n =315). These children were tested on a panel of 104 epilepsy-associated genes. In chapter 6 the potential for Whole Genome Sequencing (WGS) to identify further genetic diagnoses in deeply-phenotyped families is then explored in a separate cohort of children presenting in the West of Scotland with severe or drug-resistant epilepsy (n = 79). In chapter 4, a systematic review approach is used to identify any epilepsy-associated genes for which evidence exists to support a specific therapeutic approach. The results from this review considered in both cohorts. Chapter 7 describes a new genetic epilepsy due to SMC1A truncation and explores the potential for specific therapy in this condition. Chapter 8 evaluates whether sub-analysis of genetic data within a randomised controlled trial can be harnessed to identify patients most likely to respond to therapy. Key results: Epilepsy affects 1 per 383 children before their third birthday. In 22% of these children a single-gene cause can be identified. For 80% per cent of single-gene diagnoses in this group of patients there is some evidence to support a specific therapeutic approach. Evidence is variable in quality and nature. Between 1 in 2,000 and 1 in 2,300 of all children born are likely to have a genetically determined epilepsy for which there is currently available some evidence for a specific treatment choice. The majority of currently achievable genetic diagnoses are concentrated in a small number of genes, with genetic diagnoses beyond the 20 most common being extremely individually rare. Evidence to support specific therapeutic approaches is generally lacking in these rarer genetic epilepsies, particularly in those not associated with ion channel dysfunction. A stronger evidence base is required, and to generate this this will demand wide collaboration, and rigorous study design, and open access to pharmacogenomic data

Does measurement technique explain the mismatch between European head size and WHO charts?

Objective To test whether different measuring techniques produce systematic differences in head size that could explain the large head circumferences found in Northern European children compared with the WHO standard. Design: Cross-sectional observational study. Setting: Scotland, UK. Patients: Study 1: 68 healthy children aged 0.4–18 months from mother and baby groups and a medical students teaching session. Study 2: 81 children aged 0.4 to 25 months from hospital wards and neonatal follow-up clinics. Interventions: Study 1: heads measured with plastic tape using both the WHO tight and UK loose technique. Study 2: heads measured using WHO research technique and a metal measuring tape and compared with routinely acquired measurements. Main outcome measures: Mean difference in head z-scores using WHO standard between the two methods. Results: The tight technique resulted in a mean (95% CI) z-score difference of 0.41 (0.27 to 0.54, p<0.001) in study 1 and 0.44 (0.36 to 0.53, p<0.001) in study 2. However, the mean WHO measurements in the healthy infants still produced a mean z-score that was two-third of a centile space (0.54 SD (0.28 to 0.79) p<0.001) above the 50th centile. Conclusion: The WHO measurement techniques produced significantly lower measures of head size, but average healthy Scottish children still had larger heads than the WHO standard using this method

Nathaniel Hawthorne: An oration delivered before the alumni of Bowdoin College, Brunswick, Maine, July 10, 1878

Sample paragraph: At the age of fourteen, Hawthorne came to reside with his mother in the house which her brothers had built for her on their new lands in Maine -- a large house, the walls of which are still standing, near the shores of Sebago Lake, in Raymond. He lived there several years, at different times, including some of the vacations of his college course. They were days of delight. With gun or fishing-rod in hand, he wandered at will through the unbroken forest, skirted the shores of the lake in his bouat, watching the lights and shadows on near and distant mountains, or, in winter, when the moonlight was on the ices, skated alone till midnight, building fires to chase the black shadows of the forest from the shores.https://digicom.bpl.lib.me.us/books_pubs/1125/thumbnail.jp

Eliciting third person perspectives in social work case discussions:A device for reflective supervision?

Reflective supervision is widely recommended as an effective way to support social workers to think about their practice and to make better decisions. Although previous research has proposed methods of pursuing reflective supervision, little is known about how supervisors attempt this in actual supervision meetings. One proposed method for supervisors is to elicit third person perspectives so that social workers can consider a situation from different points of view. In this article, we examine this method by analysing audio recordings of 12 supervision meetings from one local authority Children and Families Social Work team. Using Conversation Analysis (CA), we explore supervisors’ attempts to elicit other people’s perspectives, focusing on how such requests were formed and how the social worker responded. We found 35 instances of supervisors attempting to elicit third person perspectives and identified four different ways that supervisors designed these enquiries. Supervisors oriented to two concerns, based on whether they enquired about a perspective that was currently established or projected into the future, and whether the information was verifiable through speech or actions, or imagined based on the other person’s thoughts or understanding. We draw on CA work on epistemics and stance to show how these different approaches have implications for what the social worker is expected to know and how both speakers orient to the accountability of the social worker. We conclude by considering the epistemic friction between the design of these enquiries, the relevance of professional accountability and the possibilities for pursuing reflective supervision in practice

Falling admissions to hospital with febrile seizures in the UK

Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.Peer reviewedPostprin

Gene variant effects across sodium channelopathies predict function and guide precision therapy

Pathogenic variants in the voltage-gated sodium channel gene family lead to early onset epilepsies, neurodevelopmental disorders, skeletal muscle channelopathies, peripheral neuropathies and cardiac arrhythmias. Disease-associated variants have diverse functional effects ranging from complete loss-of-function to marked gain-of-function. Therapeutic strategy is likely to depend on functional effect. Experimental studies offer important insights into channel function but are resource intensive and only performed in a minority of cases. Given the evolutionarily conserved nature of the sodium channel genes, we investigated whether similarities in biophysical properties between different voltage-gated sodium channels can predict function and inform precision treatment across sodium channelopathies. We performed a systematic literature search identifying functionally assessed variants in any of the nine voltage-gated sodium channel genes until 28 April 2021. We included missense variants that had been electrophysiologically characterized in mammalian cells in whole-cell patch-clamp recordings. We performed an alignment of linear protein sequences of all sodium channel genes and correlated variants by their overall functional effect on biophysical properties. Of 951 identified records, 437 sodium channel-variants met our inclusion criteria and were reviewed for functional properties. Of these, 141 variants were epilepsy-associated (SCN1/2/3/8A), 79 had a neuromuscular phenotype (SCN4/9/10/11A), 149 were associated with a cardiac phenotype (SCN5/10A) and 68 (16%) were considered benign. We detected 38 missense variant pairs with an identical disease-associated variant in a different sodium channel gene. Thirty-five out of 38 of those pairs resulted in similar functional consequences, indicating up to 92% biophysical agreement between corresponding sodium channel variants (odds ratio = 11.3; 95% confidence interval = 2.8 to 66.9; P < 0.001). Pathogenic missense variants were clustered in specific functional domains, whereas population variants were significantly more frequent across non-conserved domains (odds ratio = 18.6; 95% confidence interval = 10.9-34.4; P < 0.001). Pore-loop regions were frequently associated with loss-of-function variants, whereas inactivation sites were associated with gain-of-function (odds ratio = 42.1, 95% confidence interval = 14.5-122.4; P < 0.001), whilst variants occurring in voltage-sensing regions comprised a range of gain- and loss-of-function effects. Our findings suggest that biophysical characterisation of variants in one SCN-gene can predict channel function across different SCN-genes where experimental data are not available. The collected data represent the first gain- versus loss-of-function topological map of SCN proteins indicating shared patterns of biophysical effects aiding variant analysis and guiding precision therapy. We integrated our findings into a free online webtool to facilitate functional sodium channel gene variant interpretation (http://SCN-viewer.broadinstitute.org).Peer reviewe

Spatial variation in avian bill size is associated with humidity in summer among Australian passerines

Background: Climate imposes multiple selection pressures on animal morphology. Allen&rsquo;s Rule proposes thatgeographic variation in the appendage size of endotherms, relative to body size, is linked to climatic variation,thereby facilitating heat exchange and body temperature regulation. Thus relatively larger appendages tend to befound in animals in warmer climates. Despite growing understanding of the role of the avian bill as an organ forheat exchange, few studies have tested the ecological significance of bill size for heat dissipation across speciesand environmental gradients. Amongst those that have, most have focused on the relationship with ambienttemperature, but there is growing evidence that humidity also has a strong influence on heat dissipation. Inparticular, increasing humidity reduces the potential for evaporative cooling, favouring radiative and convectiveheat loss via the bill, and hence potentially favouring larger bills in humid environments. Here, we usedphylogenetically-controlled analyses of the bill morphology of 36 species of Australian passerines to explore therelationship between bill size and multiple aspects of climate.Results: Humidity during the hot summer months (December-February) was positively associated with relative billsurface area across species. There was no overall association between bill size and summer temperatures per se, butthe association with humidity was mediated by temperature, with a significant interaction indicating strongerassociations with humidity at cooler summer temperatures. This is consistent with the idea that larger bills maybecome disadvantageous in humid conditions as ambient temperature approaches body temperature. Relative billsize was similar among closely related species, with phylogeny explaining 63.3% of the variance, and there wassignificant variation among species in their response to humidity. However, the relationship between relative billsize and humidity was not associated with phylogeny.Conclusions: Our results are consistent with the idea that body temperature regulation underlies continent-widepatterns of bill size variation in a broad range of Australian passerines, and suggests that Allen&rsquo;s Rule may apply tohumidity gradients as well as temperature gradients. They add to growing evidence that a narrow focus ontemperature alone in studies of responses to climate change may limit our understanding of species&rsquo; sensitivities toclimatic variation, and of their capacity to adapt

'To live and die [for] Dixie': Irish civilians and the Confederate States of America

Around 20,000 Irishmen served in the Confederate army in the Civil War. As a result, they left behind, in various Southern towns and cities, large numbers of friends, family, and community leaders. As with native-born Confederates, Irish civilian support was crucial to Irish participation in the Confederate military effort. Also, Irish civilians served in various supporting roles: in factories and hospitals, on railroads and diplomatic missions, and as boosters for the cause. They also, however, suffered in bombardments, sieges, and the blockade. Usually poorer than their native neighbours, they could not afford to become 'refugees' and move away from the centres of conflict. This essay, based on research from manuscript collections, contemporary newspapers, British Consular records, and Federal military records, will examine the role of Irish civilians in the Confederacy, and assess the role this activity had on their integration into Southern communities. It will also look at Irish civilians in the defeat of the Confederacy, particularly when they came under Union occupation. Initial research shows that Irish civilians were not as upset as other whites in the South about Union victory. They welcomed a return to normalcy, and often 'collaborated' with Union authorities. Also, Irish desertion rates in the Confederate army were particularly high, and I will attempt to gauge whether Irish civilians played a role in this. All of the research in this paper will thus be put in the context of the Drew Gilpin Faust/Gary Gallagher debate on the influence of the Confederate homefront on military performance. By studying the Irish civilian experience one can assess how strong the Confederate national experiment was. Was it a nation without a nationalism

Rates, causes and predictors of all-cause and avoidable mortality in 163 686 children and young people with and without intellectual disabilities:A record linkage national cohort study

Objectives: To investigate mortality rates and associated factors, and avoidable mortality in children/young people with intellectual disabilities. Design: Retrospective cohort; individual record-linked data between Scotland’s 2011 Census and 9.5 years of National Records for Scotland death certification data. Setting: General community. Participants: Children and young people with intellectual disabilities living in Scotland aged 5–24 years, and an age-matched comparison group. Main outcome measures: Deaths up to 2020: age of death, age-standardised mortality ratios (age-SMRs); causes of death including cause-specific age-SMRs/sex-SMRs; and avoidable deaths. Results: Death occurred in 260/7247 (3.6%) children/young people with intellectual disabilities (crude mortality rate=388/100 000 person-years) and 528/156 439 (0.3%) children/young people without intellectual disabilities (crude mortality rate=36/100 000 person-years). SMRs for children/young people with versus those without intellectual disabilities were 10.7 for all causes (95% CI 9.47 to 12.1), 5.17 for avoidable death (95% CI 4.19 to 6.37), 2.3 for preventable death (95% CI 1.6 to 3.2) and 16.1 for treatable death (95% CI 12.5 to 20.8). SMRs were highest for children (27.4, 95% CI 20.6 to 36.3) aged 5–9 years, and lowest for young people (6.6, 95% CI 5.1 to 8.6) aged 20–24 years. SMRs were higher in more affluent neighbourhoods. Crude mortality incidences were higher for the children/young people with intellectual disabilities for most International Statistical Classification of Diseases and Related Health Problems, 10th Revision chapters. The most common underlying avoidable causes of mortality for children/young people with intellectual disabilities were epilepsy, aspiration/reflux/choking and respiratory infection, and for children/young people without intellectual disabilities were suicide, accidental drug-related deaths and car accidents. Conclusion: Children with intellectual disabilities had significantly higher rates of all-cause, avoidable, treatable and preventable mortality than their peers. The largest differences were for treatable mortality, particularly at ages 5–9 years. Interventions to improve healthcare to reduce treatable mortality should be a priority for children/young people with intellectual disabilities. Examples include improved epilepsy management and risk assessments, and coordinated multidisciplinary actions to reduce aspiration/reflux/choking and respiratory infection. This is necessary across all neighbourhoods