821 research outputs found
Clinical and molecular basis of transient neonatal diabetes mellitus in Brazilian children
No full textWe report a series of patients with transient neonatal diabetes mellitus (TNDM). Paternal uniparental isodisomy of chromosome 6 and heterozygous KCNJ11 and ABC88 mutation were the mutations found. This first reported series of Brazilian patients expands the geographical data on TNDM contributing to better understanding of its pathophysiology
Semi-automated unidirectional sequence analysis for mutation detection in a clinical diagnostic setting
No full textBACKGROUND: The past 10 years have seen an improvement in sequence data quality due to the introduction of capillary sequencers and new sequencing chemistries. In parallel, new software programs for automated mutation detection have been developed. We evaluated the sensitivity of semiautomated unidirectional sequence analysis for the detection of heterozygous base substitutions using the Mutation Surveyor software package.METHODS: Detection rates for heterozygous base substitutions in 29 genes by automated and visual inspection were compared. Examples of heterozygous bases not detected in one direction during bidirectional analysis were also sought through a national survey of United Kingdom (UK) genetics laboratories. Sequence quality was assessed in a consecutive cohort of 50 patients for whom the 39 exons of the ABCC8 gene had been sequenced in one direction.RESULTS: A total of 701 different heterozygous base substitutions were detected by the software with no false negatives (sensitivity >or=99.57%). Four examples of heterozygous bases missed in one direction during bidirectional analysis were reported. Two were detected using unidirectional analysis settings, and the other two bases had low-quality scores. Of the 1950 amplicons examined, 97.2% had a quality score >or=30 and an average PHRED-like score >or=50 for the defined region of interest, and 98.1% of the 323,650 bases had a PHRED score >40.CONCLUSIONS: We found no evidence to support a requirement for bidirectional sequencing. Semiautomated analysis of good quality unidirectional sequence data has high sensitivity and is suitable for heterozygote mutation scanning in clinical diagnostic laboratories. Further work is required to determine minimum quality parameters for semiautomated analysis.<br/
Rare disease genomic testing in the UK and Ireland:Promoting timely and equitable access
No full textPurpose and scope The aim of this position statement is to provide recommendations regarding the delivery of genomic testing to patients with rare disease in the UK and Ireland. The statement has been developed to facilitate timely and equitable access to genomic testing with reporting of results within commissioned turnaround times. Methods of statement development A 1-day workshop was convened by the UK Association for Clinical Genomic Science and attended by key stakeholders within the NHS Genomic Medicine Service, including clinical scientists, clinical geneticists and patient support group representatives. The aim was to identify best practice and innovations for streamlined, geographically consistent services delivering timely results. Attendees and senior responsible officers for genomic testing services in the UK nations and Ireland were invited to contribute. Results and conclusions We identified eight fundamental requirements and describe these together with key enablers in the form of specific recommendations. These relate to laboratory practice (proportionate variant analysis, bioinformatics pipelines, multidisciplinary team working model and test request monitoring), compliance with national guidance (variant classification, incidental findings, reporting and reanalysis), service development and improvement (multimodal testing and innovation through research, informed by patient experience), service demand, capacity management, workforce (recruitment, retention and development), and education and training for service users. This position statement was developed to provide best practice guidance for the specialist genomics workforce within the UK and Ireland but is relevant to any publicly funded healthcare system seeking to deliver timely rare disease genomic testing in the context of high demand and limited resources.</p
Clinical and genetic features of Argentinian children with diabetes-onset before 12 months of age: successful transfer from insulin to oral sulfonylurea
No full textAims Neonatal diabetes mellitus (NDM) is a rare monogenic disorder, reported to affect less than 2 cases per 100,000 infants. There are two types, permanent (PNDM) and transient (TNDM). We describe our clinical experience in determining and comparing the genetic basis of diabetes in children with onset before 6 months versus those diagnosed between 6 and 12 months of age.Methods We reviewed medical records of children with diabetes diagnosed before 12 months of age. Genetic testing was performed in all cases.Results 12 patients were diagnosed with diabetes before 6 months of age (PNDM = 6; TNDM = 6), and 11 patients between 6 and 12 months (all with permanent diabetes). Among children with PNDM, we identified three different KCNJ11 mutations in 5 patients, and one novel ABCC8 mutation in a single patient. Among children with TNDM, we detected a KCNJ11 and ABCC8 mutation each in a single patient and methylation abnormalities at chromosome 6q24 in 4 patients.Among children with diabetes diagnosed between 6 and 12 months, 1 patient had an INS mutation and one patient was homozygous for an SLC19A2 mutation which confirmed a diagnosis of thiamine-responsive megaloblastic anaemia syndrome. Five of the patients with an ABCC8 or KCNJ11 mutation have successfully transferred from insulin to glibenclamide whist 1 child demonstrated a partial response to sulfonylurea treatment.Conclusions Investigating the underlying genetic basis of diabetes in children with onset before 1 year is useful for choosing the most efficient treatment, the basis of Personalized Medicine
What is the impact of teaching culturally diverse graphic novels on students of KS3 English? A Case Study
No full textGraphic novels are an increasingly popular choice for young readers, sparking debate about whether they are appropriate taught material in the secondary English classroom. Meanwhile, a separate debate has been focused on decolonising the English curriculum to be more representative of different identities, especially races. This interventionist case study examines how graphic novels could sit at the intersection of these two movements, diversifying both the characters and forms taught in the KS3 curriculum. The study reveals that graphic novels support student engagement, as pupils find them interesting, informative and easier to understand than traditional prose texts. Within the case study, students’ analytical writing on the graphic novel was more accurate and detailed than the responses they wrote to the prose text, aided by Moebius’s (1990) picturebook codes. The visual elements of the graphic novel not only supported comprehension, but also provided additional clues about characters and their lives; pupils seemed to connect more with the characters in the graphic novel. The study also proposes that cultural awareness could be improved through teaching graphic novels, although teaching a range of texts would promote this further. The author suggests that graphic novels are an untapped resource for the KS3 curriculum and encourages English teachers to trial them in their classrooms
[[alternative]]The Land Cultivation and Formation of the Regional Characteristics in Nan-Zi-Sian river mid-stream region During the Japanese-Ruled Period
No full text[[abstract]]This thesis study land cultivation process from Ch’ing dynasty to Japanese-Ruled Period in Nan-Zi-Sian river mid-stream region, on the frontier of Kaoshiuang .In order to restructure the regional characteristics, we selected the power of Japanese-Ruled government in Taiwan and private Japanese corporations project to Nan-Zi-Sian river mid-stream region as the research objects.
The land cultivation before Japanese-Ruled in Nan-Zi-Sian river mid-stream region, was a process of long-term interaction between Contonese(客家人) and plain aborigines, and that of construction of different life-style in both shores of Nan-Zi-Sian river mid-stream. Despite the fact that Nan-Zi-Sian river mid-stream region had been developed for a long time , the high limitation of unstable natural environment and the characteristic of traditional self-subsistent economy, which compelled the phenomena as individual isolated settlement and scattered space.
After 1895, the colonialists accelerated a new growth of development of land cultivation in the mid-stream region. Modern cane-sugar refinery , camphor and afforestation enterprises established in this area. Moreover, after private Japanese corporations invested in mid-stream region, they not only had changed the land-use of the hillside around this area , but had controlled the land operation and agricultural activities. A crowd relationship also change.
Under the powerful control of new style land cultivation and enterprise , many landowners and gentry appeared. They became local leaders. Local leaders almost took charge of leaders of important social and economic organizations. The important social and economic organizations became the formation of space of jiezhuangmin, the space of jingchaguan , and the space of buluomin.With agriculture , market ,school ,traffic and police system developed, Nan-Zi-Sian river mid-stream region greatly was structured. Finally, this area had changed the frontier and established tightly contact to other regions.
Genomic variant sharing: a position statement
No full textSharing de-identified genetic variant data is essential for the practice of genomic medicine and is demonstrably beneficial to patients. Robust genetic diagnoses that inform medical management cannot be made accurately without reference to genetic test results from other patients, as well as population controls. Errors in this process can result in delayed, missed or erroneous diagnoses, leading to inappropriate or missed medical interventions for the patient and their family. The benefits of sharing individual genetic variants, and the harms of not sharing them, are numerous and well-established. Databases and mechanisms already exist to facilitate deposition and sharing of pseudonomised genetic variants, but clarity and transparency around best practice is needed to encourage widespread use, prevent inconsistencies between different communities, maximise individual privacy and ensure public trust. We therefore recommend that widespread sharing of a small number of individual genetic variants associated with limited clinical information should become standard practice in genomic medicine. Information robustly linking genetic variants with specific conditions is fundamental biological knowledge, not personal information, and therefore should not require consent to share. For additional case-level detail about individual patients or more extensive genomic information, which is often essential for clinical interpretation, it may be more appropriate to use a controlled-access model for data sharing, with the ultimate aim of making as much information as open and de-identified as possible with appropriate consent.</ns4:p
New insights into autoimmune mediated neonatal diabetes
No full textMonogenic autoimmune diseases are highly variable syndromes that usually have onset in the first year of life and are often fatal in early childhood. Identifying monogenic autoimmune diabetes is important as it can have implications for medical management of patients, informs families and clinicians of prognosis and recurrence risk, and gives insights into beta-cell autoimmunity and immune tolerance.
The first section of this thesis introduces monogenic autoimmune disease, with focus on the conditions that have autoimmune endocrine disorders as part of their clinical phenotype. The following section details the methodologies used throughout this thesis.
In chapter 1, we used a type 1 diabetes genetic risk score (T1D-GRS) based on the top 10 risk alleles for T1D to identify patients with monogenic autoimmunity from patients with early-onset polygenic diabetes and additional autoimmunity. We showed that the T1D-GRS was highly discriminatory of monogenic autoimmunity, especially when combined with age of onset (ROC-AUC 0.88). We also identified 16 families for gene discovery studies. Furthermore, this work shows that polygenic risk for the development of T1D does not affect the development of diabetes in monogenic autoimmunity.
Chapter 2 describes the genetic and phenotypic information for the largest cohort of patients with IPEX syndrome, caused by hemizygous mutations in FOXP3, reported to date (n=48). We analysed this data to determine if there were any genotypic or clinical characteristics of IPEX syndrome that could predict prognosis. We did not find evidence of phenotype-genotype relationships and showed that presenting feature did not predict prognosis. Medical management of IPEX syndrome cannot, therefore, be based on genotype or presentation.
In chapter 3 we employed whole exome sequencing to look for causal variant(s) in a patient with diabetes (diagnosed aged 7 weeks) and autoimmune lymphoproliferative disease. This identified recessively inherited causative variants in LRBA. We then used targeted next generation sequencing (NGS) to screen a large cohort of patients (n=169) and identified an additional 8 probands and an affected family member. This confirms the role of LRBA as a neonatal diabetes gene, bringing the total number of genes to 25.
In chapter 4, we assessed if immunoglobulin E (IgE) could be useful to identify patients with early-onset multisystem autoimmune disease caused by gain of function (GOF) STAT3 mutations. We showed that serum IgE was below the lower limit of the normal reference range (2KU/L) in all patients with STAT3 GOF (n=6), giving this threshold a sensitivity of 100% (95% CI: 54.1 – 100) and specificity 97.2% (95% CI: 96.2-97.9). We also found that IgE in patients with IPEX (n=16) was significantly higher than those with STAT3 GOF (p=0.002) suggesting it could be useful to identify IPEX from STAT3 GOF in non-consanguineous males with early-onset autoimmunity.
The final concluding section summarises the key findings of each chapter, the impact of these findings and suggests future avenues for research.
Identifying monogenic autoimmunity has enabled prenatal diagnoses, given families and clinicians knowledge on recurrence risk, and could enable targeted therapies to be employed. This body of work will enable better discrimination of monogenic autoimmunity from polygenic clustering of early-onset autoimmunity, and gives insights into the factors that determine disease phenotype and clinical course in monogenic autoimmunity. Gene discovery on the remaining patients will give new insights into the mechanisms of beta-cell autoimmunity and the regulation of the adaptive immune system and maintenance of immune tolerance.Wellcome Trus
Transpositions: Reflections on Friendship and Nine Days in October with Peter Beilharz and Sian Supski
No full textIn this essay, the author uses the idea of transposition to reflect on Peter Beilharz and Sian Supski\u27s historic visit to Eastern Michigan University and southeast Michigan in October 2024. Transposition is used to deprivatize Robbins\u27s reflections to consider broader and more generalizable concerns relative to pedagogy and educational philosophy. Further, transposition, in this regard, provided a way to reflect on the (increased) importance of friendship in academia.
Keywords: transposition, translation, friendshi
Identification of hepatocyte nuclear factor 1β-associated disease
No full textHeterozygous mutations and deletions of the gene that encodes the transcription factor hepatocyte nuclear factor 1β (HNF1B) are the commonest known monogenic cause of developmental kidney disease. However, diagnosis remains challenging due to phenotypic variability and frequent absence of a family history. There is also no consensus as to when HNF1B genetic testing should be performed. This thesis includes work looking at the identification of HNF1B-associated disease.
An HNF1B score was developed in 2014 to help select appropriate patients for genetic testing. The aim in chapter 2 was to test the clinical utility of this score in a large number of referrals for HNF1B genetic testing to the UK diagnostic testing service for the HNF1B gene. An HNF1B score was assigned for 686 referrals using clinical information available at the time of testing; performance of the score was evaluated by receiver-operating characteristic curve analysis. Although the HNF1B score discriminated between patients with and without a mutation/deletion reasonably well, the negative predictive value of 85% reduces its clinical utility.
HNF1B-associated disease is due to an approximate 1.3 Mb deletion of chromosome 17q12 in about 50% of individuals. This deletion includes HNF1B plus 14 additional genes and has been linked to an increased risk of neurodevelopmental disorders, such as autism. The aim in chapter 3 was to compare the neurodevelopmental phenotype of patients with either an HNF1B intragenic mutation or 17q12 deletion to determine whether haploinsufficiency of the HNF1B gene is responsible for this aspect of the phenotype. Brief behavioural screening showed high levels of psychopathology and impact in children with a deletion. 8/20 (40%) patients with a deletion had a clinical diagnosis of a neurodevelopmental disorder compared to 0/18 with a mutation, P=0.004. 17q12 deletions were also associated with more autistic traits. Two independent clinical geneticists were able to predict the presence of a deletion with a sensitivity of 83% and specificity of 79% when assessing facial dysmorphic features as a whole. These results demonstrate that the 17q12 deletion but not HNF1B intragenic mutations are associated with neurodevelopmental disorders; we conclude that the HNF1B gene is not involved in the neurodevelopmental phenotype of these patients.
Extra-renal phenotypes frequently occur in HNF1B-associated disease, including diabetes mellitus and pancreatic hypoplasia. Faecal elastase-1 levels have only been reported in a small number of individuals, the majority of which have diabetes. In chapter 4 we measured faecal elastase-1 in patients with an HNF1B mutation or deletion regardless of diabetes status and assessed the degree of symptoms associated with pancreatic exocrine deficiency. We found that faecal elastase-1 deficiency is a common feature of HNF1B-associated renal disease even when diabetes is not present and pancreatic exocrine deficiency may be more symptomatic than previously suggested. Faecal elastase-1 should be measured in all patients with a known HNF1B molecular abnormality complaining of chronic abdominal pain, loose stools or unintentional weight loss.
Hypomagnesaemia is a common feature of HNF1B-associated disease and is due to renal magnesium wasting. The aim in chapter 5 was to measure both serum and urine magnesium and calcium levels in individuals with an HNF1B molecular defect and compare to a cohort of patients followed up in a general nephrology clinic in order to assess their potential as biomarkers for HNF1B-associated disease. The results of this pilot study show that using a cut-off for serum magnesium of ≤0.75 mmol/L was 100% sensitive and 87.5% specific for the presence of an HNF1B mutation/deletion. All individuals in the HNF1B cohort had hypermagnesuria with fractional excretion of magnesium >4%; a cut-off of ≥4.1% was 100% sensitive and 71% specific. This suggests serum magnesium levels and fractional excretion of magnesium are highly sensitive biomarkers for HNF1B-associated renal disease; if these results are confirmed in a larger study of patients with congenital anomalies of the kidneys or urinary tract they could be implemented as cheap screening tests for HNF1B genetic testing in routine clinical care.Medical Research Counci
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