Publications by authors named "Eleanor Seaby"

30 Publications

  • Page 1 of 1

Strategies to Uplift Novel Mendelian Gene Discovery for Improved Clinical Outcomes.

Front Genet 2021 17;12:674295. Epub 2021 Jun 17.

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States.

Rare genetic disorders, while individually rare, are collectively common. They represent some of the most severe disorders affecting patients worldwide with significant morbidity and mortality. Over the last decade, advances in genomic methods have significantly uplifted diagnostic rates for patients and facilitated novel and targeted therapies. However, many patients with rare genetic disorders still remain undiagnosed as the genetic etiology of only a proportion of Mendelian conditions has been discovered to date. This article explores existing strategies to identify novel Mendelian genes and how these discoveries impact clinical care and therapeutics. We discuss the importance of data sharing, phenotype-driven approaches, patient-led approaches, utilization of large-scale genomic sequencing projects, constraint-based methods, integration of multi-omics data, and gene-to-patient methods. We further consider the health economic advantages of novel gene discovery and speculate on potential future methods for improved clinical outcomes.
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http://dx.doi.org/10.3389/fgene.2021.674295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248347PMC
June 2021

Treatment of Multisystem Inflammatory Syndrome in Children.

N Engl J Med 2021 07 16;385(1):11-22. Epub 2021 Jun 16.

From the Department of Infectious Disease, Section of Pediatric Infectious Disease (A.J.M., O.V., H.P., E.G.S., P.S., C.W., C.B., R.N., T.D., E.W., J.A.H., M.K., A.J.C., M.L.), and the Inflammation, Repair, and Development Section, National Heart and Lung Institute, Faculty of Medicine (D.M.), Imperial College London, the Department of Pediatrics, Imperial College Healthcare NHS Trust (R.N., E.W., J.A.H., A.J.C., M.L.), and the Department of Women and Children's Health, School of Life Course Sciences, King's College London, St. Thomas' Hospital (M.J.C.), London, and the Genomic Informatics Group, University of Southampton, Southampton (E.G.S.) - all in the United Kingdom; the Translational Genomics Group, Broad Institute of MIT and Harvard, Cambridge, MA (E.G.S.); the Department of Pediatrics, University of California, San Diego, and Rady Children's Hospital, San Diego (A.H.T.); the Department of Pediatrics and Pediatric Infectious Diseases, Sechenov University, Moscow (D.M.); Servicio de Infectología, Hospital Nacional de Niños Dr. Carlos Sáenz Herrera, Centro de Ciencias Médicas, Caja Costarricense de Seguro Social, San José, Costa Rica (R.U.-G.); and the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (C.H.).

Background: Evidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2.

Methods: We performed an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. We used inverse-probability weighting and generalized linear models to evaluate intravenous immune globulin (IVIG) as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were two primary outcomes: the first was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the second was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation.

Results: Data were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the World Health Organization criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33). The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the three groups.

Conclusions: We found no evidence that recovery from MIS-C differed after primary treatment with IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone, although significant differences may emerge as more data accrue. (Funded by the European Union's Horizon 2020 Program and others; BATS ISRCTN number, ISRCTN69546370.).
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http://dx.doi.org/10.1056/NEJMoa2102968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220965PMC
July 2021

Identification of novel locus associated with coronary artery aneurysms and validation of loci for susceptibility to Kawasaki disease.

Eur J Hum Genet 2021 Mar 26. Epub 2021 Mar 26.

Section of Paediatric Infectious Disease, Department of Infectious Disease, Imperial College London, London, UK.

Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13.
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http://dx.doi.org/10.1038/s41431-021-00838-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994355PMC
March 2021

De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis.

Am J Hum Genet 2021 02 27;108(2):357-367. Epub 2021 Jan 27.

Division of Pediatric Neurology and Developmental Medicine, Duke University Medical Center, Durham, NC 27710, USA.

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895901PMC
February 2021

Transcript expression-aware annotation improves rare variant interpretation.

Nature 2020 05 27;581(7809):452-458. Epub 2020 May 27.

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The acceleration of DNA sequencing in samples from patients and population studies has resulted in extensive catalogues of human genetic variation, but the interpretation of rare genetic variants remains problematic. A notable example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy individuals. Here, by manual curation of putative loss-of-function (pLoF) variants in haploinsufficient disease genes in the Genome Aggregation Database (gnomAD), we show that one explanation for this paradox involves alternative splicing of mRNA, which allows exons of a gene to be expressed at varying levels across different cell types. Currently, no existing annotation tool systematically incorporates information about exon expression into the interpretation of variants. We develop a transcript-level annotation metric known as the 'proportion expressed across transcripts', which quantifies isoform expression for variants. We calculate this metric using 11,706 tissue samples from the Genotype Tissue Expression (GTEx) project and show that it can differentiate between weakly and highly evolutionarily conserved exons, a proxy for functional importance. We demonstrate that expression-based annotation selectively filters 22.8% of falsely annotated pLoF variants found in haploinsufficient disease genes in gnomAD, while removing less than 4% of high-confidence pathogenic variants in the same genes. Finally, we apply our expression filter to the analysis of de novo variants in patients with autism spectrum disorder and intellectual disability or developmental disorders to show that pLoF variants in weakly expressed regions have similar effect sizes to those of synonymous variants, whereas pLoF variants in highly expressed exons are most strongly enriched among cases. Our annotation is fast, flexible and generalizable, making it possible for any variant file to be annotated with any isoform expression dataset, and will be valuable for the genetic diagnosis of rare diseases, the analysis of rare variant burden in complex disorders, and the curation and prioritization of variants in recall-by-genotype studies.
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http://dx.doi.org/10.1038/s41586-020-2329-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334198PMC
May 2020

The mutational constraint spectrum quantified from variation in 141,456 humans.

Nature 2020 05 27;581(7809):434-443. Epub 2020 May 27.

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.
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http://dx.doi.org/10.1038/s41586-020-2308-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334197PMC
May 2020

Challenges in the diagnosis and discovery of rare genetic disorders using contemporary sequencing technologies.

Brief Funct Genomics 2020 07;19(4):243-258

Next generation sequencing (NGS) has revolutionised rare disease diagnostics. Concomitant with advancing technologies has been a rise in the number of new gene disorders discovered and diagnoses made for patients and their families. However, despite the trend towards whole exome and whole genome sequencing, diagnostic rates remain suboptimal. On average, only ~30% of patients receive a molecular diagnosis. National sequencing projects launched in the last 5 years are integrating clinical diagnostic testing with research avenues to widen the spectrum of known genetic disorders. Consequently, efforts to diagnose genetic disorders in a clinical setting are now often shared with efforts to prioritise candidate variants for the detection of new disease genes. Herein we discuss some of the biggest obstacles precluding molecular diagnosis and discovery of new gene disorders. We consider bioinformatic and analytical challenges faced when interpreting next generation sequencing data and showcase some of the newest tools available to mitigate these issues. We consider how incomplete penetrance, non-coding variation and structural variants are likely to impact diagnostic rates, and we further discuss methods for uplifting novel gene discovery by adopting a gene-to-patient-based approach.
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http://dx.doi.org/10.1093/bfgp/elaa009DOI Listing
July 2020

Correction: Blood RNA analysis can increase clinical diagnostic rate and resolve variants of uncertain significance.

Genet Med 2020 Jun;22(6):1129

Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41436-020-0789-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272324PMC
June 2020

Blood RNA analysis can increase clinical diagnostic rate and resolve variants of uncertain significance.

Genet Med 2020 06 3;22(6):1005-1014. Epub 2020 Mar 3.

Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.

Purpose: Diagnosis of genetic disorders is hampered by large numbers of variants of uncertain significance (VUSs) identified through next-generation sequencing. Many such variants may disrupt normal RNA splicing. We examined effects on splicing of a large cohort of clinically identified variants and compared performance of bioinformatic splicing prediction tools commonly used in diagnostic laboratories.

Methods: Two hundred fifty-seven variants (coding and noncoding) were referred for analysis across three laboratories. Blood RNA samples underwent targeted reverse transcription polymerase chain reaction (RT-PCR) analysis with Sanger sequencing of PCR products and agarose gel electrophoresis. Seventeen samples also underwent transcriptome-wide RNA sequencing with targeted splicing analysis based on Sashimi plot visualization. Bioinformatic splicing predictions were obtained using Alamut, HSF 3.1, and SpliceAI software.

Results: Eighty-five variants (33%) were associated with abnormal splicing. The most frequent abnormality was upstream exon skipping (39/85 variants), which was most often associated with splice donor region variants. SpliceAI had greatest accuracy in predicting splicing abnormalities (0.91) and outperformed other tools in sensitivity and specificity.

Conclusion: Splicing analysis of blood RNA identifies diagnostically important splicing abnormalities and clarifies functional effects of a significant proportion of VUSs. Bioinformatic predictions are improving but still make significant errors. RNA analysis should therefore be routinely considered in genetic disease diagnostics.
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http://dx.doi.org/10.1038/s41436-020-0766-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272326PMC
June 2020

Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency.

Am J Hum Genet 2020 02 9;106(2):234-245. Epub 2020 Jan 9.

Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK.

Germline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation (5-methylcytosine [5mC]) of DNA is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has yet been delineated. Here, we describe in detail a Mendelian disorder caused by the disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. We identify and characterize 11 cases of human TET3 deficiency in eight families with the common phenotypic features of intellectual disability and/or global developmental delay; hypotonia; autistic traits; movement disorders; growth abnormalities; and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues; all but one such variant occur within the catalytic domain, and most display hypomorphic function in an assay of catalytic activity. TET3 deficiency and other Mendelian disorders of the epigenetic machinery show substantial phenotypic overlap, including features of intellectual disability and abnormal growth, underscoring shared disease mechanisms.
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http://dx.doi.org/10.1016/j.ajhg.2019.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010978PMC
February 2020

The Career Impact of the National Undergraduate Neuroanatomy Competition.

World Neurosurg 2020 Jan 25;133:e535-e539. Epub 2019 Sep 25.

Centre for Learning Anatomical Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

Background: Neurosurgery is a notoriously difficult career to enter and requires medical students to engage in extracurricular activities to demonstrate their commitment to the specialty. The National Undergraduate Neuroanatomy Competition (NUNC) was established in 2013 as a means for students to display this commitment as well as academic ability.

Methods: A bespoke 22-item questionnaire was designed to determine career outcomes and the role of competition attendance in job applications. It was distributed using the SurveyMonkey website to the 87 attendees at the 2013 and 2014 competitions.

Results: Responses were received by 40 competitors (response rate, 46.0%). Twenty-four responders (60.0%) intended to pursue a career in either neurosurgery (n = 18) or neurology (n = 6). This included 10 responders (25.0%) who had successfully entered either neurosurgery (n = 9) or neurology (n = 1). The performance of these 10 was significantly better than the other responders (57.0 ± 13.6% vs. 46.5 ± 13.5% [n = 30]; P = 0.036). Seventeen responders (42.5%) either included their attendance at NUNC in a post-Foundation job application or intend to.

Conclusions: The NUNC provides the opportunity for medical students to demonstrate their interest in neurosurgery. It has the potential to be used as a tool for recognizing medical students suitable for neurosurgery training.
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http://dx.doi.org/10.1016/j.wneu.2019.09.086DOI Listing
January 2020

Identification of disease-associated loci using machine learning for genotype and network data integration.

Bioinformatics 2019 12;35(24):5182-5190

Department of Life Sciences, Centre for Integrative Systems Biology and Bioinformatics, Imperial College London, London SW7 2AZ, UK.

Motivation: Integration of different omics data could markedly help to identify biological signatures, understand the missing heritability of complex diseases and ultimately achieve personalized medicine. Standard regression models used in Genome-Wide Association Studies (GWAS) identify loci with a strong effect size, whereas GWAS meta-analyses are often needed to capture weak loci contributing to the missing heritability. Development of novel machine learning algorithms for merging genotype data with other omics data is highly needed as it could enhance the prioritization of weak loci.

Results: We developed cNMTF (corrected non-negative matrix tri-factorization), an integrative algorithm based on clustering techniques of biological data. This method assesses the inter-relatedness between genotypes, phenotypes, the damaging effect of the variants and gene networks in order to identify loci-trait associations. cNMTF was used to prioritize genes associated with lipid traits in two population cohorts. We replicated 129 genes reported in GWAS world-wide and provided evidence that supports 85% of our findings (226 out of 265 genes), including recent associations in literature (NLGN1), regulators of lipid metabolism (DAB1) and pleiotropic genes for lipid traits (CARM1). Moreover, cNMTF performed efficiently against strong population structures by accounting for the individuals' ancestry. As the method is flexible in the incorporation of diverse omics data sources, it can be easily adapted to the user's research needs.

Availability And Implementation: An R package (cnmtf) is available at https://lgl15.github.io/cnmtf_web/index.html.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954643PMC
December 2019

Autosomal dominant tubulointerstitial kidney disease-UMOD is the most frequent non polycystic genetic kidney disease.

BMC Nephrol 2018 10 30;19(1):301. Epub 2018 Oct 30.

Wessex Kidney Centre, Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Southwick Hill Road, Cosham, Portsmouth, PO6 3LY, UK.

Background: Autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by mutations in the UMOD gene (ADTKD-UMOD) is considered rare and often remains unrecognised. We aimed to establish the prevalence of genetic kidney diseases, ADTKD and ADTKD-UMOD in adult chronic kidney disease (CKD) patients, and to investigate characteristic features.

Methods: We sent questionnaires on family history to all patients with CKD stages 3-5 in our tertiary renal centre to identify patients with inherited renal disease. Details on clinical and family history were obtained from patient interviews and clinical records. Sanger sequencing of the UMOD gene was performed from blood or saliva samples.

Results: 2027 of 3770 sent questionnaires were returned. 459 patients reported a family history, which was consistent with inherited kidney disease in 217 patients. 182 non-responders with inherited kidney diseases were identified through a database search. Of these 399 individuals, 252 had autosomal dominant polycystic kidney disease (ADPKD), 28 had ADTKD, 25 had Alports, and 44 were unknown, resulting in 11% of CKD 3-5 patients and 19% of end-stage renal disease patients with genetic kidney diseases. Of the unknown, 40 were genotyped, of whom 31 had findings consistent with ADTKD. 30% of unknowns and 39% of unknowns with ADTKD had UMOD mutations. Altogether, 35 individuals from 18 families were found to have ten distinct UMOD mutations (three novel), making up 1% of patients with CKD 3-5, 2% of patients with end-stage renal disease, 9% of inherited kidney diseases and 56% with ADTKD. ADTKD-UMOD was the most common genetic kidney disease after ADPKD with a population prevalence of 9 per million. Less proteinuria and haematuria, but not hyperuricaemia or gout were predictive of ADTKD-UMOD. The main limitations of the study are the single-centre design and a predominantly Caucasian population.

Conclusions: The prevalence of genetic kidney diseases and ADTKD-UMOD is significantly higher than previously described. Clinical features poorly predicted ADTKD-UMOD, highlighting the need for genetic testing guided by family history alone.
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http://dx.doi.org/10.1186/s12882-018-1107-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208030PMC
October 2018

The Efficacy of Frontline Near-Peer Teaching in a Modern Medical Curriculum.

Anat Sci Educ 2019 May 17;12(3):236-244. Epub 2018 Oct 17.

Centre for Learning Anatomical Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

Within medical education a reduction in curriculum time for subjects, such as anatomy puts pressure on educators to ensure the same learning outcomes are conveyed in less time. This has the potential to impact negatively on student experience. Near-peer teaching (NPT) is often praised as an effective revision tool, but its use as a frontline teaching resource remains unreported. The study explores the potential for NPT to promote delivery of learning outcomes and maximize student experience within a neuroanatomy module for second year medical students. The study occurred in three educational settings, (1) frontline NPT of cranial nerves, (2) revision session NPT of cranial nerves, and (3) NPT alongside faculty staff in laboratory-based neuroanatomy practical exercises. For the first and second components, knowledge was measured using a pre- and post-session test and student perception was ascertained with a questionnaire. For the third component, student perception was assessed with an end-of-module survey. The results show that overall, NPT was well received by learners. A significant knowledge gain was seen between the pre- and post-session test of the frontline NPT session. The study presents evidence in favor of using NPTs to supplement the delivery of learning outcomes in a time and resource constrained curriculum. In particular, for the effective delivery of frontline material. Anat Sci Educ 0: 1-9. © 2018 American Association of Anatomists.
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http://dx.doi.org/10.1002/ase.1827DOI Listing
May 2019

The benefits of being a near-peer teacher.

Clin Teach 2018 10 23;15(5):403-407. Epub 2018 Mar 23.

Centre for Learning Anatomical Sciences, Faculty of Medicine, Southampton General Hospital, Southampton, UK.

Background: Near-peer teaching is used in anatomy education because of its benefits to the learner, teacher and faculty members. Despite the range of reports focusing on the learner, the advantages for the teacher, which are thought to include communication skills, subject knowledge and employability, are only beginning to be explored.

Method: A questionnaire was distributed to the teachers involved in anatomy near-peer teaching at the University of Southampton and Brighton and Sussex Medical School (BSMS). This questionnaire was designed using a rating scale of 0-10 to assess teacher perspectives on their level of knowledge, teaching skills and enjoyment of teaching. Free-text responses determined the teachers' motivation and perceived benefits from the teaching.

Results: Twenty-eight questionnaires were gathered (54.9% response rate), including 20 from Southampton and eight from BSMS. Long-term knowledge retention and better understanding of the material were rated 8.1 and 7.9 out of 10, respectively. Eight responses were from currently practising doctors, who rated how much they now use their teaching skills as doctors as 8.9 out of 10. Of the eight doctors, seven gained points for their foundation programme applications as a direct result of near-peer teaching. The most common motivator for engaging in teaching was to improve subject matter knowledge and the most common benefit was improved communication skills. There are numerous advantages to being a near-peer teacher in medical school DISCUSSION: There are numerous advantages to being a near-peer teacher in medical school, which include knowledge improvement, transferrable professional skills and employability. These initial results support the hypothesised benefits to the teachers and provide a foundation for further longitudinal studies.
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http://dx.doi.org/10.1111/tct.12784DOI Listing
October 2018

Inactivation of AMMECR1 is associated with growth, bone, and heart alterations.

Hum Mutat 2018 02 14;39(2):281-291. Epub 2017 Dec 14.

Department of Pharmacology, Universidade Federal de São Paulo, São Paulo, Brazil.

We report five individuals with loss-of-function of the X-linked AMMECR1: a girl with a balanced X-autosome translocation and inactivation of the normal X-chromosome; two boys with maternally inherited and de novo nonsense variants; and two half-brothers with maternally inherited microdeletion variants. They present with short stature, cardiac and skeletal abnormalities, and hearing loss. Variants of unknown significance in AMMECR1 in four male patients from two families with partially overlapping phenotypes were previously reported. AMMECR1 is coexpressed with genes implicated in cell cycle regulation, five of which were previously associated with growth and bone alterations. Our knockdown of the zebrafish orthologous gene resulted in phenotypes reminiscent of patients' features. The increased transcript and encoded protein levels of AMMECR1L, an AMMECR1 paralog, in the t(X;9) patient's cells indicate a possible partial compensatory mechanism. AMMECR1 and AMMECR1L proteins dimerize and localize to the nucleus as suggested by their nucleic acid-binding RAGNYA folds. Our results suggest that AMMECR1 is potentially involved in cell cycle control and linked to a new syndrome with growth, bone, heart, and kidney alterations with or without elliptocytosis.
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http://dx.doi.org/10.1002/humu.23373DOI Listing
February 2018

Thrombotic microangiopathy following haematopoietic stem cell transplant.

Pediatr Nephrol 2018 09 9;33(9):1489-1500. Epub 2017 Oct 9.

Southampton Children's Hospital and Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK.

Thrombotic microangiopathy is a potentially lethal complication of haematopoietic stem cell (bone marrow) transplantation. The pathophysiology is incompletely understood, although endothelial damage appears to be central. Platelet activation, neutrophil extracellular traps and complement activation appear to play key roles. Diagnosis may be difficult and universally accepted diagnostic criteria are not available. Treatment remains controversial. In some cases, withdrawal of calcineurin inhibitors is adequate. Rituximab and defibrotide also appear to have been used successfully. In severe cases, complement inhibitors such as eculizumab may play a valuable role. Further research is required to define the pathophysiology and determine both robust diagnostic criteria and the optimal treatment.
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http://dx.doi.org/10.1007/s00467-017-3803-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061668PMC
September 2018

Unexpected Findings in a Child with Atypical Hemolytic Uremic Syndrome: An Example of How Genomics Is Changing the Clinical Diagnostic Paradigm.

Front Pediatr 2017 22;5:113. Epub 2017 May 22.

Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.

is a tumor suppressor gene on chromosome 11 encoding a multivalent adaptor protein with E3 ubiquitin ligase activity. Germline mutations are dominant. Pathogenic mutations result in a phenotype that overlaps Noonan syndrome (1). Some patients with mutations go on to develop juvenile myelomonocytic leukemia (JMML), an aggressive malignancy that usually necessitates bone marrow transplantation. Using whole exome sequencing methods, we identified a known mutation in in a 4-year-old Caucasian boy with atypical hemolytic uremic syndrome, moyamoya phenomenon, and dysmorphology consistent with a mild Noonan-like phenotype. Exome data revealed loss of heterozygosity across chromosome 11q consistent with JMML but in the absence of clinical leukemia. Our finding challenges conventional clinical diagnostics since we have identified a pathogenic variant in the gene previously only ascertained in children presenting with leukemia. The increasing affordability of expansive sequencing is likely to increase the scope of clinical profiles observed for previously identified pathogenic variants and calls into question the interpretability and indications for clinical management.
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http://dx.doi.org/10.3389/fped.2017.00113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438966PMC
May 2017

: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis.

J Med Genet 2017 04 3;54(4):269-277. Epub 2016 Nov 3.

Human Genetics & Genomic Medicine, University of Southampton, Duthie Building (Mailpoint 808), Southampton General Hospital, Southampton, UK.

Background: Deletions in the Xq22.3-Xq23 region, inclusive of , have been associated with a contiguous gene deletion syndrome characterised by lport syndrome with intellectual disability (ental retardation), idface hypoplasia and lliptocytosis (AMME). The extrarenal biological and clinical significance of neighbouring genes to the Alport locus has been largely speculative. We sought to discover a genetic cause for two half-brothers presenting with nephrocalcinosis, early speech and language delay and midface hypoplasia with submucous cleft palate and bifid uvula.

Methods: Whole exome sequencing was undertaken on maternal half-siblings. In-house genomic analysis included extraction of all shared variants on the X chromosome in keeping with X-linked inheritance. Patient-specific mutants were transfected into three cell lines and microscopically visualised to assess the nuclear expression pattern of the mutant protein.

Results: In the affected half-brothers, we identified a hemizygous novel non-synonymous variant of unknown significance in (c.G530A; p.G177D), a gene residing in the AMME disease locus. Transfected cell lines with the p.G177D mutation showed aberrant nuclear localisation patterns when compared with the wild type. Blood films revealed the presence of elliptocytes in the older brother.

Conclusions: Our study shows that a single missense mutation in causes a phenotype of midface hypoplasia, mild intellectual disability and the presence of elliptocytes, previously reported as part of a contiguous gene deletion syndrome. Functional analysis confirms mutant-specific protein dysfunction. We conclude that is a critical gene in the pathogenesis of AMME, causing midface hypoplasia and elliptocytosis and contributing to early speech and language delay, infantile hypotonia and hearing loss, and may play a role in dysmorphism, nephrocalcinosis and submucous cleft palate.
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http://dx.doi.org/10.1136/jmedgenet-2016-104100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502304PMC
April 2017

Deleterious coding variants in multi-case families with non-syndromic cleft lip and/or palate phenotypes.

Sci Rep 2016 07 26;6:30457. Epub 2016 Jul 26.

Department of Biomedical Sciences, Medical School, Universidad de La Sabana, Bogota, Colombia.

Nonsyndromic Cleft Lip and/or Palate (NSCLP) is regarded as a multifactorial condition in which clefting is an isolated phenotype, distinguished from the largely monogenic, syndromic forms which include clefts among a spectrum of phenotypes. Nonsyndromic clefting has been shown to arise through complex interactions between genetic and environmental factors. However, there is increasing evidence that the broad NSCLP classification may include a proportion of cases showing familial patterns of inheritance and contain highly penetrant deleterious variation in specific genes. Through exome sequencing of multi-case families ascertained in Bogota, Colombia, we identify 28 non-synonymous single nucleotide variants that are considered damaging by at least one predictive score. We discuss the functional impact of candidate variants identified. In one family we find a coding variant in the MSX1 gene which is predicted damaging by multiple scores. This variant is in exon 2, a highly conserved region of the gene. Previous sequencing has suggested that mutations in MSX1 may account for ~2% of NSCLP. Our analysis further supports evidence that a proportion of NSCLP cases arise through monogenic coding mutations, though further work is required to unravel the complex interplay of genetics and environment involved in facial clefting.
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http://dx.doi.org/10.1038/srep30457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960602PMC
July 2016

Mutations specific to the Rac-GEF domain of cause intellectual disability and microcephaly.

J Med Genet 2016 Nov 14;53(11):735-742. Epub 2016 Jul 14.

Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.

Background: Neurodevelopmental disorders have challenged clinical genetics for decades, with over 700 genes implicated and many whose function remains unknown. The application of whole-exome sequencing is proving pivotal in closing the genotype/phenotype gap through the discovery of new genes and variants that help to unravel the pathogenic mechanisms driving neuropathogenesis. One such discovery includes , a gene recently implicated in neurodevelopmental delay. Trio is a Dbl family guanine nucleotide exchange factor (GEF) and a major regulator of neuronal development, controlling actin cytoskeleton dynamics by activating the GTPase Rac1.

Methods: Whole-exome sequencing was undertaken on a family presenting with global developmental delay, microcephaly and mild dysmorphism. Father/daughter exome analysis was performed, followed by confirmatory Sanger sequencing and segregation analysis on four individuals. Three further patients were recruited through the deciphering developmental disorders (DDD) study. Functional studies were undertaken using patient-specific Trio protein mutations.

Results: We identified a frameshift deletion in that segregated autosomal dominantly. By scrutinising data from DDD, we further identified three unrelated children with a similar phenotype who harboured de novo missense mutations in . Biochemical studies demonstrated that in three out of four families, the Trio mutations led to a markedly reduced Rac1 activation.

Conclusions: We describe an inherited global developmental delay phenotype associated with a frameshift deletion in . Additionally, we identify pathogenic de novo missense mutations in associated with the same consistent phenotype, intellectual disability, microcephaly and dysmorphism with striking digital features. We further functionally validate the importance of the GEF domain in Trio protein function. Our study demonstrates how genomic technologies are yet again proving prolific in diagnosing and advancing the understanding of neurodevelopmental disorders.
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http://dx.doi.org/10.1136/jmedgenet-2016-103942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264232PMC
November 2016

Progressive myoclonic epilepsy with Fanconi syndrome.

JRSM Open 2016 Jun 6;7(6):2054270415623145. Epub 2016 Jun 6.

Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.

This report illustrates the difficulties in diagnosing complex cases and demonstrates how whole exome sequencing can resolve complex phenotypes.
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http://dx.doi.org/10.1177/2054270415623145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900196PMC
June 2016

Genome-wide Association Studies in Infectious Diseases.

Pediatr Infect Dis J 2016 07;35(7):802-4

From the Section for Paediatric Infectious Diseases, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom.

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http://dx.doi.org/10.1097/INF.0000000000001183DOI Listing
July 2016

Can medical students accurately predict their learning? A study comparing perceived and actual performance in neuroanatomy.

Anat Sci Educ 2016 Oct 1;9(5):488-95. Epub 2016 Apr 1.

Centre for Learning Anatomical Sciences, University of Southampton, Southampton, United Kingdom.

It is important that clinicians are able to adequately assess their level of knowledge and competence in order to be safe practitioners of medicine. The medical literature contains numerous examples of poor self-assessment accuracy amongst medical students over a range of subjects however this ability in neuroanatomy has yet to be observed. Second year medical students attending neuroanatomy revision sessions at the University of Southampton and the competitors of the National Undergraduate Neuroanatomy Competition were asked to rate their level of knowledge in neuroanatomy. The responses from the former group were compared to performance on a ten item multiple choice question examination and the latter group were compared to their performance within the competition. In both cohorts, self-assessments of perceived level of knowledge correlated weakly to their performance in their respective objective knowledge assessments (r = 0.30 and r = 0.44). Within the NUNC, this correlation improved when students were instead asked to rate their performance on a specific examination within the competition (spotter, rS = 0.68; MCQ, rS = 0.58). Despite its inherent difficulty, medical student self-assessment accuracy in neuroanatomy is comparable to other subjects within the medical curriculum. Anat Sci Educ 9: 488-495. © 2016 American Association of Anatomists.
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http://dx.doi.org/10.1002/ase.1601DOI Listing
October 2016

Exome sequencing explained: a practical guide to its clinical application.

Brief Funct Genomics 2016 Sep 9;15(5):374-84. Epub 2015 Dec 9.

Next-generation sequencing has catapulted healthcare into a revolutionary genomics era. One such technology, whole-exome sequencing, which targets the protein-coding regions of the genome, has proven success in identifying new causal mutations for diseases of previously unknown etiology. With a successful diagnostic rate approaching 25% for rare disease in recent studies, its clinical utility is becoming increasingly popular. However, the interpretation of whole-exome sequencing data requires expertise in genomic informatics and clinical medicine to ensure the accurate and safe reporting of findings back to the bedside. This is challenged by vast amounts of sequencing data harbouring approximately 25 000 variants per sequenced individual. Computational strategies and fastidious filtering frameworks are thus required to extricate candidate variants in a sea of common polymorphisms. Once prioritized, identified variants require intensive scrutiny at a biological level, and require judicious assessment alongside the clinical phenotype. In the final step, all evidence is collated and documented alongside pathogenicity guidelines to produce an exome report that returns to the clinic. This review provides a practical guide for clinicians and genomic informaticians on the clinical application of whole-exome sequencing. We address sequencing capture and methodology, quality control parameters at different stages of sequencing analysis and propose an exome data filtering strategy that includes primary filtering (for the removal of probable benign variants) and secondary filtering for the prioritization of remaining candidates.
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http://dx.doi.org/10.1093/bfgp/elv054DOI Listing
September 2016

Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis.

Nephrol Dial Transplant 2016 06 7;31(6):961-70. Epub 2015 Sep 7.

Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.

Background: Multiple genes underlying focal segmental glomerulosclerosis (FSGS) and/or steroid-resistant nephrotic syndrome (SRNS) have been identified, with the recent inclusion of collagen IV mutations responsible for Alport disease (AD) or thin basement membrane nephropathy (TBMN). We aimed to investigate the distribution of gene mutations in adult patients with primary FSGS/SRNS by targeted next generation sequencing (NGS).

Methods: Eighty-one adults from 76 families were recruited; 24 families had a history of renal disease. A targeted NGS panel was designed and applied, covering 39 genes implicated in FSGS/SRNS including COL4A3-5.

Results: Confirmed pathogenic mutations were found in 10 patients (6 with family history) from 9 families (diagnostic rate 12%). Probably pathogenic mutations were identified in an additional six patients (combined diagnostic rate 20%). Definitely pathogenic mutations were identified in 22% of patients with family history and 10% without. Mutations in COL4A3-5 were present in eight patients from six families, representing 56% of definitely pathogenic mutations, and establishing a diagnosis of AD in six patients and TBMN in two patients. Collagen mutations were identified in 38% of families with familial FSGS, and 3% with sporadic FSGS, with over half the mutations occurring in COL4A5. Patients with collagen mutations were younger at presentation and more likely to have family history, haematuria and glomerular basement membrane abnormalities.

Conclusions: We show that collagen IV mutations, including COL4A5, frequently underlie FSGS and should be considered, particularly with a positive family history. Targeted NGS improves diagnostic efficiency by investigating many candidate genes in parallel.
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http://dx.doi.org/10.1093/ndt/gfv325DOI Listing
June 2016

Bullous herpes zoster.

J Pediatr 2014 Mar 16;164(3):667. Epub 2013 Nov 16.

Infectious Diseases Unit, Department of General Medicine, The Royal Children's Hospital, Melbourne, Parkville, Victoria, Australia.

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http://dx.doi.org/10.1016/j.jpeds.2013.10.026DOI Listing
March 2014
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