Ethical preparedness in genomic medicine: how NHS clinical scientists navigate ethical issues.

Much has been published about the ethical issues encountered by clinicians in genetics/genomics, but those experienced by clinical laboratory scientists are less well described. Clinical laboratory scientists now frequently face navigating ethical problems in their work, but how they should be best supported to do this is underexplored. This lack of attention is also reflected in the ethics tools available to clinical laboratory scientists such as guidance and deliberative ethics forums, developed primarily to manage issues arising within the clinic.We explore what ethical issues are being experienced by clinical scientists, how they think such issues could be best analysed and managed, and whether their practice might be enhanced by more situated approaches to ethics deliberation and practice such as ethical preparedness. From thematic analysis of cases presented by clinical scientists at a specially convened meeting of the UK Genethics Forum, we derived three main ethical themes: (1) the redistribution of labour and responsibilities resulting from the practice of genomic medicine; (2) the interpretation and certainty of results and (3) the proposal that better standardisation and consistency of ethical approaches (for example, more guidelines and policy) could resolve some of the challenges arising.We argue that although standardisation is important for promoting shared understandings of good (including ethical) practice, supplementary approaches to enhance and sustain ethical preparedness will be important to help clinical scientists and others in the recently expanded genetic/genomic medicine environment foster quality ethical thinking.

BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome.

INTRODUCTION: KCTD15 encodes an oligomeric BTB domain protein reported to inhibit neural crest formation through repression of Wnt/beta-catenin signalling, as well as transactivation by TFAP2. Heterozygous missense variants in the closely related paralogue KCTD1 cause scalp-ear-nipple syndrome. METHODS: Exome sequencing was performed on a two-generation family affected by a distinctive phenotype comprising a lipomatous frontonasal malformation, anosmia, cutis aplasia of the scalp and/or sparse hair, and congenital heart disease. Identification of a de novo missense substitution within KCTD15 led to targeted sequencing of DNA from a similarly affected sporadic patient, revealing a different missense mutation. Structural and biophysical analyses were performed to assess the effects of both amino acid substitutions on the KCTD15 protein. RESULTS: A heterozygous c.310G>C variant encoding p.(Asp104His) within the BTB domain of KCTD15 was identified in an affected father and daughter and segregated with the phenotype. In the sporadically affected patient, a de novo heterozygous c.263G>A variant encoding p.(Gly88Asp) was present in KCTD15. Both substitutions were found to perturb the pentameric assembly of the BTB domain. A crystal structure of the BTB domain variant p.(Gly88Asp) revealed a closed hexameric assembly, whereas biophysical analyses showed that the p.(Asp104His) substitution resulted in a monomeric BTB domain likely to be partially unfolded at physiological temperatures. CONCLUSION: BTB domain substitutions in KCTD1 and KCTD15 cause clinically overlapping phenotypes involving craniofacial abnormalities and cutis aplasia. The structural analyses demonstrate that missense substitutions act through a dominant negative mechanism by disrupting the higher order structure of the KCTD15 protein complex.

Getting rights right: implementing 'Martha's Rule'.

The UK government has recently committed to adopting a new policy-dubbed 'Martha's Rule'-which has been characterised as providing patients the right to rapidly access a second clinical opinion in urgent or contested cases. Support for the rule emerged following the death of Martha Mills in 2021, after doctors failed to admit her to intensive care despite concerns raised by her parents. We argue that framing this issue in terms of patient rights is not productive, and should be avoided. Insofar as the ultimate goal of Martha's Rule is the provision of a clinical service that protects patient safety, an approach that focuses on the obligations of the health system-rather than the individual rights of patients-will better serve this goal. We outline an alternative approach that situates rapid clinical review as part of a suite of services aimed at enhancing and protecting patient care. This approach would make greater progress towards addressing the difficult systemic issues that Martha's Rule does not, while also better engaging with the constraints of clinical practice.

Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.

Ethical issues in Nipah virus control and research: addressing a neglected disease.

Nipah virus is a priority pathogen that is receiving increasing attention among scientists and in work on epidemic preparedness. Despite this trend, there has been almost no bioethical work examining ethical considerations surrounding the epidemiology, prevention, and treatment of Nipah virus or research that has already begun into animal and human vaccines. In this paper, we advance the case for further work on Nipah virus disease in public health ethics due to the distinct issues it raises concerning communication about the modes of transmission, the burdens of public health surveillance, the recent use of stringent public health measures during epidemics, and social or religious norms intersecting with preventive measures. We also advance the case for further work on Nipah virus disease in research ethics, given ethical issues surrounding potential vaccine trials for a high-fatality disease with sporadic spillover events, the different local contexts where trials may occur, and the potential use of unproven therapeutics during outbreaks. Further bioethics work may help to ensure that research and public health interventions for Nipah virus disease are ethically acceptable and more likely to be effective.

Clinical exome sequencing efficacy and phenotypic expansions involving anomalous pulmonary venous return.

Anomalous pulmonary venous return (APVR) frequently occurs with other congenital heart defects (CHDs) or extra-cardiac anomalies. While some genetic causes have been identified, the optimal approach to genetic testing in individuals with APVR remains uncertain, and the etiology of most cases of APVR is unclear. Here, we analyzed molecular data from 49 individuals to determine the diagnostic yield of clinical exome sequencing (ES) for non-isolated APVR. A definitive or probable diagnosis was made for 8 of those individuals yielding a diagnostic efficacy rate of 16.3%. We then analyzed molecular data from 62 individuals with APVR accrued from three databases to identify novel APVR genes. Based on data from this analysis, published case reports, mouse models, and/or similarity to known APVR genes as revealed by a machine learning algorithm, we identified 3 genes-EFTUD2, NAA15, and NKX2-1-for which there is sufficient evidence to support phenotypic expansion to include APVR. We also provide evidence that 3 recurrent copy number variants contribute to the development of APVR: proximal 1q21.1 microdeletions involving RBM8A and PDZK1, recurrent BP1-BP2 15q11.2 deletions, and central 22q11.2 deletions involving CRKL. Our results suggest that ES and chromosomal microarray analysis (or genome sequencing) should be considered for individuals with non-isolated APVR for whom a genetic etiology has not been identified, and that genetic testing to identify an independent genetic etiology of APVR is not warranted in individuals with EFTUD2-, NAA15-, and NKX2-1-related disorders.

Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions.

While common obesity accounts for an increasing global health burden, its monogenic forms have taught us underlying mechanisms via more than 20 single-gene disorders. Among these, the most common mechanism is central nervous system dysregulation of food intake and satiety, often accompanied by neurodevelopmental delay (NDD) and autism spectrum disorder. In a family with syndromic obesity, we identified a monoallelic truncating variant in POU3F2 (alias BRN2) encoding a neural transcription factor, which has previously been suggested as a driver of obesity and NDD in individuals with the 6q16.1 deletion. In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity. Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperphagia during childhood. Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation. In a cohort with common non-syndromic obesity, we independently observed a negative correlation of POU3F2 gene expression with BMI, suggesting a role beyond monogenic obesity. In summary, we propose deleterious intragenic variants of POU3F2 to cause transcriptional dysregulation associated with hyperphagic obesity of adolescent onset with variable NDD.

Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland.

BACKGROUND: Pediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genomewide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits. METHODS: We conducted a large-scale sequencing study involving more than 13,500 families with probands with severe, probably monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services in the United Kingdom and Ireland. Standardized phenotypic data were collected, and exome sequencing and microarray analyses were performed to investigate novel genetic causes. We developed an iterative variant analysis pipeline and reported candidate variants to clinical teams for validation and diagnostic interpretation to inform communication with families. Multiple regression analyses were performed to evaluate factors affecting the probability of diagnosis. RESULTS: A total of 13,449 probands were included in the analyses. On average, we reported 1.0 candidate variant per parent-offspring trio and 2.5 variants per singleton proband. Using clinical and computational approaches to variant classification, we made a diagnosis in approximately 41% of probands (5502 of 13,449). Of 3599 probands in trios who received a diagnosis by clinical assertion, approximately 76% had a pathogenic de novo variant. Another 22% of probands (2997 of 13,449) had variants of uncertain significance in genes that were strongly linked to monogenic developmental disorders. Recruitment in a parent-offspring trio had the largest effect on the probability of diagnosis (odds ratio, 4.70; 95% confidence interval [CI], 4.16 to 5.31). Probands were less likely to receive a diagnosis if they were born extremely prematurely (i.e., 22 to 27 weeks' gestation; odds ratio, 0.39; 95% CI, 0.22 to 0.68), had in utero exposure to antiepileptic medications (odds ratio, 0.44; 95% CI, 0.29 to 0.67), had mothers with diabetes (odds ratio, 0.52; 95% CI, 0.41 to 0.67), or were of African ancestry (odds ratio, 0.51; 95% CI, 0.31 to 0.78). CONCLUSIONS: Among probands with severe, probably monogenic, difficult-to-diagnose developmental disorders, multimodal analysis of genomewide data had good diagnostic power, even after previous attempts at diagnosis. (Funded by the Health Innovation Challenge Fund and Wellcome Sanger Institute.).

Online Courses Provide Robust Learning Gains and Improve Learner Confidence in the Foundational Biomedical Sciences.

The early stages of medical school involve education in a number of foundational biomedical sciences including genetics, immunology, and physiology. However, students entering medical school may have widely varying levels of background in these areas due to differences in the availability and quality of prior education on these topics. Even students who have recently taken formal courses in these subjects may not feel confident in their level of preparation, leading to anxiety for early-stage medical students. These differences can make it difficult for instructors to create meaningful learning experiences that are appropriate for all students. Additionally, actual or perceived differences in preparation may lead fewer students from diverse backgrounds to apply to medical school. Therefore, creating an efficient and scalable way to increase students' knowledge and confidence in these topics addresses an important need for many medical schools. We recorded pre- and post-course quiz scores for 9790 individuals who completed HMX online courses, developed in accordance with evidence-based learning practices and covering the fundamentals of biochemistry, genetics, immunology, pharmacology, and physiology. Each question was accompanied by a Likert scale question to assess the learner's confidence in their answer. Learners' median post-course quiz performance and self-assessed confidence significantly increased relative to pre-course quiz performance for each course. Improvements were consistent across US-based medical schools, non-US medical schools, and course runs open to the public. This indicates that online courses created using evidence-based learning practices can lead to significant increases in knowledge and confidence for many learners, helping prepare them for further medical education. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-022-01660-4.

Work-Up and Outcome of Hepatic Resection for Peri-Hilar Cholangiocarcinoma (PH-CCA) without Staging Laparoscopy.

Background: This study reports the outcome of a work-up programme for resection of peri-hilar cholangiocarcinoma (PH-CCA) without the use of staging laparoscopy. Methods: This is a clinical case cohort series of patients undergoing surgical resection of PH-CCA without the use of staging laparoscopy in the work-up algorithm. During the 13 years from 1 January 2009 to 1 January 2022, 32 patients underwent laparotomy for planned surgical resection of PH-CCA. Data were collected on demographic profile, admission biochemistry, radiology, pre-operative intervention, operation and outcome, together with post-operative complications and disease-free and overall survival. Results: All patients underwent pre-operative contrast-enhanced CT. Twenty-four (75%) underwent pre-operative MR. Twenty-three (72%) underwent pre-operative biliary drainage. Twenty-nine patients (91%) had either type III or IV peri-hilar cholangiocarcinoma. One patient (3%) in this series underwent a non-resectional laparotomy. Twenty-nine (91%) had a final histopathological diagnosis of PH-CCA. One further patient had a final diagnosis of an intraductal papillary neoplasm of the biliary tree (IPNB) with high-grade dysplasia but no invasive cancer. Eleven patients (36%) received chemotherapy after surgery. The median (95% CI) time to recurrence was 14 (7-31) months. The median survival was 25 (18-upper limit not reached) months. Conclusion: This cohort of 32 patients undergoing attempted resection for PH-CCA without the use of staging laparoscopy in the work-up algorithm indicates that with careful attention to patient fitness and cross-sectional and interventional radiologic/endoscopic imaging, a very low non-therapeutic laparotomy rate of 3% can be achieved and sustained.

Initiation of an Emulsion Microinfusion: Flow Direction Influences Delivery Onset Rate.

Critically ill and anesthetized patients commonly receive life-sustaining medications by pump-driven continuous intravenous infusion. Microinfusion refers to delivering concentrated drugs with low flow carriers to conserve fluid administration. Most infused medications are water-soluble. Delivery onset lag times have been identified for microinfusions of water-soluble drugs or experimental surrogates. Drugs may be formulated as emulsions. Initiation of emulsion microinfusions has not been described. We tested in vitro the hypothesis that an emulsion's physical characteristics would influence its microinfusion delivery onset. We adapted an established in vitro model of pump-driven continuous intravenous microinfusion to compare the delivery of methylene blue as a surrogate for water-soluble drugs and a 10% lipid emulsion as a surrogate for a drug formulated as an emulsion. The drug surrogates joined the carrier with carrier flow vertically upwards, vertically downwards or horizontally. We measured the times to 5%, 50% and 95% of plateau delivery. Emulsion entry into a vertical (upwards) carrier flow resulted in a rapid initial emulsion delivery exceeding predictions of delivery models. Emulsion entry into both horizontal and vertical (downwards) carrier flows resulted in long lag times to steady state. Methylene blue delivery was unaffected by carrier flow orientation. Initiating microinfusion emulsion delivery with upward flow can result in a relative bolus, whereas long delivery lags would be expected with horizontal or downwards flow. An emulsion might carry a high potency drug having significant physiologic effects, e. g. clevidipine. Unrecognized, differences in initial emulsion delivery kinetics depending on carrier flow orientation may have clinical implications for both efficacy and safety.

Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies.

TUBA1A tubulinopathy is a rare neurodevelopmental disorder associated with brain malformations as well as early-onset and intractable epilepsy. As pathomechanisms and genotype-phenotype correlations are not completely understood, we aimed to provide further insights into the phenotypic and genetic spectrum. We here present a multicenter case series of ten unrelated individuals from four European countries using systematic MRI re-evaluation, protein structure analysis, and prediction score modeling. In two cases, pregnancy was terminated due to brain malformations. Amongst the eight living individuals, the phenotypic range showed various severity. Global developmental delay and severe motor impairment with tetraparesis was present in 63% and 50% of the subjects, respectively. Epilepsy was observed in 75% of the cases, which showed infantile onset in 83% and a refractory course in 50%. One individual presented a novel TUBA1A-associated electroclinical phenotype with evolvement from early myoclonic encephalopathy to continuous spike-and-wave during sleep. Neuroradiological features comprised a heterogeneous spectrum of cortical and extracortical malformations including rare findings such as cobblestone lissencephaly and subcortical band heterotopia. Two individuals developed hydrocephalus with subsequent posterior infarction. We report four novel and five previously published TUBA1A missense variants whose resulting amino acid substitutions likely affect longitudinal, lateral, and motor protein interactions as well as GTP binding. Assessment of pathogenic and benign variant distributions in synopsis with prediction scores revealed sections of variant enrichment and intolerance to missense variation. We here extend the clinical, neuroradiological, and genetic spectrum of TUBA1A tubulinopathy and provide insights into residue-specific pathomechanisms and genotype-phenotype correlations.

Further delineation of phenotypic spectrum of SCN2A-related disorder.

SCN2A-related disorders include intellectual disability, autism spectrum disorder, seizures, episodic ataxia, and schizophrenia. In this study, the phenotype-genotype association in SCN2A-related disorders was further delineated by collecting detailed clinical and molecular characteristics. Using previously proposed genotype-phenotype hypotheses based on variant function and position, the potential of phenotype prediction from the variants found was examined. Patients were identified through the Deciphering Developmental Disorders study and gene matching strategies. Phenotypic information and variant interpretation evidence were collated. Seventeen previously unreported patients and five patients who had been previously reported (but with minimal phenotypic and segregation data) were included (10 males, 12 females; median age 10.5 years). All patients had developmental delays and the majority had intellectual disabilities. Seizures were reported in 15 of 22 (68.2%), four of 22 (18.2%) had autism spectrum disorder and no patients were reported with episodic ataxia. The majority of variants were de novo. One family had presumed gonadal mosaicism. The correlation of the use of sodium channel-blocking antiepileptic drugs with phenotype or genotype was variable. These data suggest that variant type and position alone can provide some predictive information about the phenotype in a proportion of cases, but more precise assessment of variant function is needed for meaningful phenotype prediction.

Ethical Issues in Genetics and Infectious Diseases Research: An Interdisciplinary Expert Review.

PURPOSE: Research in genetics and infectious diseases (ID) presents novel configurations of ethical, legal, and social issues (ELSIs) related to the intersection of genetics with public health regulations and the control of transmissible diseases. Such research includes work both in pathogen genetics and on the ways that human genetics affect responses to ID. This paper identifies and systematizes the unique issues at this intersection, based on an interdisciplinary expert review. BASIC PROCEDURES: This paper presents results of a formal issue-spotting exercise among twenty experts in public health, law and genomics, biobanking, genetic epidemiology, ID medicine and public health, philosophy, ethics and ID, ethics and genomics, and law and ID. The focus of the exercise was on the collection, storage, and sharing of genetic information relating to ID. MAIN FINDINGS: The issue-spotting exercise highlighted the following ELSIs: risks in reporting to government authorities, return of individual research results, and resource allocation - each taking on specific configurations based on the balance between public health and individual privacy/protection. PRINCIPAL CONCLUSIONS: The public health implications of interactions between genomics and ID frame considerations for equity and justice. In the context of the COVID-19 pandemic, these issues are especially pressing.

Maternal obesity and baseline vitamin D insufficiency alter the response to vitamin D supplementation: a double-blind, randomized trial in pregnant women.

BACKGROUND: The achievement of target 25-hydroxyvitamin D [25(OH)D] concentrations in pregnancy may be altered by maternal obesity. OBJECTIVE: The authors examined the effects of maternal supplementation of 10 µg compared with 20 µg vitamin D3/d on maternal and umbilical cord 25(OH)D. The secondary aim was to investigate the influence of maternal BMI (in kg/m2) on the response of the primary outcomes. METHODS: The authors performed a 2-arm parallel double-blind randomized trial with 240 pregnant women recruited throughout the year in Northern Ireland. Women were stratified by BMI to receive 10 or 20 µg vitamin D3/d from 12 gestational wk (GW) until delivery. Maternal blood samples collected at 12, 28, and 36 GW and from the umbilical cord were analyzed for total serum 25(OH)D. A total of 166 women completed the study. RESULTS: Mean ± SD 25(OH)D at 36 GW was 80.8 ± 28.2 compared with 94.4 ± 33.2 nmol/L (P < 0.001) (10 compared with 20 µg vitamin D3/d, respectively). In those classified with 25(OH)D <50 nmol/L at baseline and assigned 10 µg vitamin D3/d, mean 25(OH)D concentrations remained <50 nmol/L at 36 GW, whereas those <50 nmol/L at baseline and assigned 20 µg vitamin D3/d, had mean 25(OH)D concentrations ≥50 nmol/L at 28 and 36 GW. In women with obesity and 25(OH)D <50 nmol/L at baseline, the related mean umbilical cord 25(OH)D was deficient (<25 nmol/L) in both treatment groups, whereas those with obesity and 25(OH)D ≥50 nmol/L at baseline had an average umbilical cord 25(OH)D between 25 and 50 nmol/L in both treatment groups. CONCLUSIONS: Supplementation of 20 µg vitamin D3/d is needed to attain maternal and umbilical cord 25(OH)D concentrations ≥50 nmol/L on average, in those who start pregnancy with low 25(OH)D concentrations (<50 nmol/L). Under current recommendations, women with obesity and low 25(OH)D in early pregnancy are particularly vulnerable to maintaining a low 25(OH)D concentration throughout pregnancy and having an infant born with deficient 25(OH)D concentrations. This trial was registered at ClinicalTrials.gov as NCT02713009.

Heterozygous variants in SPTBN1 cause intellectual disability and autism.

Spectrins are common components of cytoskeletons, binding to cytoskeletal elements and the plasma membrane, allowing proper localization of essential membrane proteins, signal transduction, and cellular scaffolding. Spectrins are assembled from α and ß subunits, encoded by SPTA1 and SPTAN1 (α) and SPTB, SPTBN1, SPTBN2, SPTBN4, and SPTBN5 (ß). Pathogenic variants in various spectrin genes are associated with erythroid cell disorders (SPTA1, SPTB) and neurologic disorders (SPTAN1, SPTBN2, and SPTBN4), but no phenotypes have been definitively associated with variants in SPTBN1 or SPTBN5. Through exome sequencing and case matching, we identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities). Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset. Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis. Our findings support the essential roles of SPTBN1 in human neurodevelopment and expand the knowledge of human spectrinopathy disorders.

A Call to Action: Preventing Opioid and Substance Abuse in South Florida Youth.

Description The opioid crisis poses a substantial threat to youth throughout the nation. This crisis has been exacerbated by the COVID-19 pandemic, reversing some of the positive national trends in the fight against the opioid epidemic. Some risk factors for youth opioid use have been identified nationally. The South Florida tri-county region of Miami-Dade, Broward and Palm Beach is a culturally distinct region which may not follow national trends and likely has unique risk and protective factors. To address the concerning spike in youth opioid use in South Florida, a community coalition was formed to identify factors unique to South Florida and create a plan for early awareness and prevention.

Expanding the molecular spectrum and the neurological phenotype related to CAMTA1 variants.

The CAMTA1-associated phenotype was initially defined in patients with intragenic deletions and duplications who showed nonprogressive congenital ataxia, with or without intellectual disability. Here, we describe 10 individuals with CAMTA1 variants: nine previously unreported (likely) pathogenic variants comprising one missense, four frameshift and four nonsense variants, and one missense variant of unknown significance. Six patients were diagnosed following whole exome sequencing and four individuals with exome-based targeted panel analysis. Most of them present with developmental delay, manifesting in speech and motor delay. Other frequent findings are hypotonia, cognitive impairment, cerebellar dysfunction, oculomotor abnormalities, and behavioral problems. Feeding problems occur more frequently than previously observed. In addition, we present a systematic review of 19 previously published individuals with causal variants, including copy number, truncating, and missense variants. We note a tendency of more severe cognitive impairment and recurrent dysmorphic features in individuals with a copy number variant. Pathogenic variants are predominantly observed in and near the N- and C- terminal functional domains. Clinical heterogeneity is observed, but 3'-terminal variants seem to associate with less pronounced cerebellar dysfunction.

SARS-CoV-2 challenge studies: ethics and risk minimisation.

COVID-19 poses an exceptional threat to global public health and well-being. Recognition of the need to develop effective vaccines at unprecedented speed has led to calls to accelerate research pathways ethically, including by conducting challenge studies (also known as controlled human infection studies (CHIs)) with SARS-CoV-2 (the virus which causes COVID-19). Such research is controversial, with concerns being raised about the social, legal, ethical and clinical implications of infecting healthy volunteers with SARS-CoV-2 for research purposes. Systematic risk evaluations are critical to inform assessments of the ethics of any proposed SARS-CoV-2 CHIs. Such evaluations will necessarily take place within a rapidly changing and at times contested epidemiological landscape, in which differing criteria for the ethical acceptability of research risks have been proposed. This paper critically reviews two such criteria and evaluates whether the use of effective treatment should be a necessary condition for the ethical acceptability of SARS-CoV-2 CHIs, and whether the choice of study sites should be influenced by COVID-19 incidence levels. The paper concludes that ethical evaluations of proposed SARS-CoV-2 CHIs should be informed by rigorous, consultative and holistic approaches to systematic risk assessment.