37 research outputs found
Curated disease-causing genes for bleeding, thrombotic, and platelet disorders: Communication from the SSC of the ISTH
No full textsponsorship: NHLBI NIH HHS|R01 HL141424, NHLBI NIH HHS|R01 HL102482status: Publishe
Publisher Correction: Whole-genome sequencing of a sporadic primary immunodeficiency cohort (Nature, (2020), 583, 7814, (90-95), 10.1038/s41586-020-2265-1)
No full text\ua9 2020, The Author(s), under exclusive licence to Springer Nature Limited. An amendment to this paper has been published and can be accessed via a link at the top of the paper
Erratum to: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data (Scientific Reports, (2018), 8, 1, (1300), 10.1038/s41598-017-14403-y)
No full text\ua9 2018, The Author(s). A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper
Enhancing Survival of Mothers and Their Newborns in Tanzania
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The main purpose of the present studies was to examine the problem of maternal and perinantal mortality in an upcountry region of a low-income country. This was done by estimating the magnitude of maternal and perinatal mortality, both in the hospital and in the community, through elucidating the underlying causes of maternal and perinatal mortality, and by initiating low-cost interventions and monitoring mechanisms in order to enhance the survival of mothers and their newborns, in Kigoma, Tanzania. To utilize all available evidence to register the causes, contributory factors and real magnitude of maternal in a regional hospital as well as to estimate the magnitude of maternal mortality in the community. To formulate low-cost interventions to address the identified contributing factors to maternal mortality and to follow these interventions over time. To perform regular audits of the causes of maternal mortality in order to elucidate avoidance causes. To monitor and adjust the interventions during the study period, while assessing the impact of these interventions. To investigate the suspected causes of obstetric risk knowledge among community members, health workers, and traditional birth attendants. To assess the utilization of the simple “three phases of delay model” in the audit of maternal and perinatal mortality. A retrospective analysis of mortality in the hospital setting utilizing all available evidence was undertaken for three years, 1984-1987. The magnitude, causes and contributory factors to maternal mortality were examined in the in the hospital setting. This led to the formulation of 22 specific, low –cost interventions, which utilized local resources. These interventions were followed-up for a period of 7years. Monitoring was conducted through monthly audit-oriented meetings. Maternal mortality in the in the community being served by the hospital was assessed utilizing the “sisterhood method”, followed by an assessment of perceptions of obstetric risk among community members, health workers and peripheral staff in order to evaluate factors contributing to futher non-reduction of maternal mortality in the hospital. Finally an assessment utilizing the three phases of delay methodology was conducted focusing on the reduction of maternal and perinatal mortality. There was gross underreporting of martenal death in the official statistics (849 against 350 per 100,000 live births, respectively). Major causes were haemorrhage , obstracted labour , infections and rupture of the uterus. Several other associated factors comprised lack of equipment, drug/blood and issues concerning staff and community distrust of the obstetric unit. The application of the 22 specific interventions saw a progressive reduction in the maternal mortality ratio (from 849 to 275 per 100,000 live birth) after the 7-year period (p<0.001). This was despite an increase in the number admissions to the unit (3,000 to 4,296 respectively). Also the fatality rate for the major causes of death was reduced from 9.2 to 3.1%. However, The community assessment undertaken in 2001 revealed the actual MMR at that time to be 447 (urban) and (rural) per 100,000. The result of the assessment in perceptions of obstetric risk revealed low knowledge among the community, staff and traditional birth attendants and that there was distrust in the health system. A final audit using the “ three phases of delay methodology” revealed that the major causes of perinatal and maternal deaths occurred in the health system. Maternal and perinatal mortality can be reduced through low-cost interventions available in most low-resource settings. Regular audit of maternal and perinatal deaths can be undertaken in the these settings. Low-cost methodology. T o be of value audits must be sustained and used as monitoring mechanisms for service delivery improvements and as managerial tools to reduce maternal and perinatal deaths the “three phases of delay model” is a simple and user-friendly method for the audit of both perinatal and maternal deaths. \u
Investigating genotype-phenotype relationship of extreme neuropathic pain disorders in a UK national cohort
No full text\ua9 2023 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.The aims of our study were to use whole genome sequencing in a cross-sectional cohort of patients to identify new variants in genes implicated in neuropathic pain, to determine the prevalence of known pathogenic variants and to understand the relationship between pathogenic variants and clinical presentation. Patients with extreme neuropathic pain phenotypes (both sensory loss and gain) were recruited from secondary care clinics in the UK and underwent whole genome sequencing as part of the National Institute for Health and Care Research Bioresource Rare Diseases project. A multidisciplinary team assessed the pathogenicity of rare variants in genes previously known to cause neuropathic pain disorders and exploratory analysis of research candidate genes was completed. Association testing for genes carrying rare variants was completed using the gene-wise approach of the combined burden and variance-component test SKAT-O. Patch clamp analysis was performed on transfected HEK293T cells for research candidate variants of genes encoding ion channels. The results include the following: (i) Medically actionable variants were found in 12% of study participants (205 recruited), including known pathogenic variants: SCN9A(ENST00000409672.1): c.2544T>C, p.Ile848Thr that causes inherited erythromelalgia, and SPTLC1(ENST00000262554.2):c.340T>G, p.Cys133Tr variant that causes hereditary sensory neuropathy type-1. (ii) Clinically relevant variants were most common in voltage-gated sodium channels (Nav). (iii) SCN9A(ENST00000409672.1):c.554G>A, pArg185His variant was more common in non-freezing cold injury participants than controls and causes a gain of function of NaV1.7 after cooling (the environmental trigger for non-freezing cold injury). (iv) Rare variant association testing showed a significant difference in distribution for genes NGF, KIF1A, SCN8A, TRPM8, KIF1A, TRPA1 and the regulatory regions of genes SCN11A, FLVCR1, KIF1A and SCN9A between European participants with neuropathic pain and controls. (v) The TRPA1(ENST00000262209.4):c.515C>T, p.Ala172Val variant identified in participants with episodic somatic pain disorder demonstrated gain-of-channel function to agonist stimulation. Whole genome sequencing identified clinically relevant variants in over 10% of participants with extreme neuropathic pain phenotypes. The majority of these variants were found in ion channels. Combining genetic analysis with functional validation can lead to a better understanding as to how rare variants in ion channels lead to sensory neuron hyper-excitability, and how cold, as an environmental trigger, interacts with the gain-of-function NaV1.7 p.Arg185His variant. Our findings highlight the role of ion channel variants in the pathogenesis of extreme neuropathic pain disorders, likely mediated through changes in sensory neuron excitability and interaction with environmental triggers
Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome
No full textGray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease.sponsorship: M.C.S and J.H.C. are supported by Medical Research Council Clinical Research Training Fellowships (MR/R002363/1 and MR/P02002X/1). L.M. is supported by a studentship grant from the Rosetrees Trust. T.K.B. was supported by the NHSBT and the British Society for Haematology. D.S. was in part funded by an Isaac Newton Trust/Wellcome Trust Institutional Strategic Support Fund fellowship to M.F. L.K. and A.S. acknowledge support by the Ministerium fur Kultur und Wissenschaft des Landes Nordrhein-Westfalen, the Regierende Burgermeister von Berlin-inkl. Wissenschaft und Forschung, and the Bundesministerium fur Bildung und Forschung and A.S. is supported by the Deutsche Forschungsgemeinschaft (DFG, SFB 1116 and TR 240). L.B. was supported by a fellowship from Fondazione Umberto Veronesi. P.G. was supported by a Telethon Foundation Grant (GGP15063). K.F. is supported by the Research Council of the KULeuven (C14/19/096) and by unrestricted grants of the Swedish Orphan Biovitrum AB, Bayer, and CSL Behring. M.F. is supported by the British Heart Foundation (FS/18/53/33863). This work was performed by using resources provided by the Cambridge Service for Data Driven Discovery operated by the University of Cambridge Research Computing Service, provided by Dell EMC and Intel using Tier-2 funding from the Engineering and Physical Sciences Research Council (EP/P020259/1), and DiRAC funding from the Science and Technology Facilities Council.The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health and Social Care in England. This research was made possible through access to the data and findings generated by the 100 000 Genomes Project. The 100 000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100 000 Genomes Project is funded by the NIHR and NHS England. TheWellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100 000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. (Medical Research Council Clinical Research Training Fellowships|MR/R002363/1, Medical Research Council Clinical Research Training Fellowships|MR/P02002X/1, Rosetrees Trust, NHSBT, British Society for Haematology, Isaac Newton Trust/Wellcome Trust Institutional Strategic Support Fund fellowship, Ministerium fur Kultur und Wissenschaft des Landes Nordrhein-Westfalen, Regierende Burgermeister von Berlin-inkl. Wissenschaft und Forschung, Bundesministerium fur Bildung und Forschung, Deutsche Forschungsgemeinschaft (DFG)|SFB 1116, Deutsche Forschungsgemeinschaft (DFG)|TR 240, Fondazione Umberto Veronesi, Telethon Foundation|GGP15063, Research Council of the KULeuven|C14/19/096, Swedish Orphan Biovitrum AB, Bayer, CSL Behring, British Heart Foundation|FS/18/53/33863, Engineering and Physical Sciences Research Council|EP/P020259/1, Science and Technology Facilities Council, NIHR, NHS England, Wellcome Trust, Cancer Research UK, Medical Research Council, EPSRC|EP/P020259/1, MRC|MR/M008959/1, MRC|MR/P02002X/1, MRC|MR/R002363/1, MRC|MR/N00583X/1)status: Publishe
Investigating genotype-phenotype relationship of extreme neuropathic pain disorders in a national cohort: ’NIHR Bioresources Rare Disease – Neuropathic Pain Disorders’
No full textObjective: The aims of our study were to use whole genome sequencing in a cross-sectional cohort of patients to identify new variants in genes implicated in neuropathic pain, to determine prevalence of known pathogenic variants, and understand the relationship between pathogenic variants and clinical presentation.
Methods: Patients with extreme neuropathic pain phenotypes (both sensory loss and gain) were recruited from secondary care clinics in the UK, and underwent whole genome sequencing as part of NIHR-Bioresource. A multi-disciplinary team assessed pathogenicity of rare variants in genes previously known to cause neuropathic pain disorders and exploratory analysis of research candidate genes was completed. Association testing for genes carrying rare variants was completed using the gene-wise approach of the combined burden and variance-component test SKAT-O. Patch clamp analysis was performed on transfected HEK293T cells for research candidate variants of genes encoding ion channels.
Results:
1) Medically actionable variants were found in 12% of study participants (205 recruited), including known pathogenic variants: SCN9A(ENST00000409672.1): c.2544T>C, p.Ile848Thr that causes inherited erythromelalgia, and SPTLC1(ENST00000262554.2):c.340T>G, p.Cys133Tr variant that causes hereditary sensory neuropathy type-1.
2) Clinically relevant variants were most common in voltage-gated sodium channels.
3) SCN9A(ENST00000409672.1):c.554G>A, pArg185His variant was more common in non-freezing cold injury participants than controls, and causes a gain of function of NaV1.7 after cooling (the environmental trigger for non-freezing cold injury).
4) Rare variant association testing showed a significant difference in distribution for genes NGF, KIF1A, SCN8A, TRPM8, KIF1A, TRPA1 and the regulatory regions of genes SCN11A, FLVCR1, KIF1A, and SCN9A between European participants with neuropathic pain and controls.
5) The TRPA1(ENST00000262209.4):c.515C>T, p.Ala172Val variant identified in participants with episodic somatic pain disorder demonstrated gain of channel function to agonist stimulation.
Conclusion: Whole genome sequencing identified clinically relevant variants in over 10% of participants with extreme neuropathic pain phenotypes. The majority of these variants were found in ion channels. Combining genetic analysis with functional validation can lead to better understanding as to how rare variants in ion channels lead to sensory neuron hyper-excitability, and how cold, as an environmental trigger, interacts with the gain of function NaV1.7 p.Arg185His variant. Our findings highlight the role of ion channel variants in the pathogenesis of extreme neuropathic pain disorders, likely mediated through changes in sensory neuron excitability and interaction with environmental triggers
Exploring the relevance of NUP93 variants in steroid-resistant nephrotic syndrome using next generation sequencing and a fly kidney model
No full textBackground: Variants in genes encoding nuclear pore complex (NPC) proteins are a newly identified cause of paediatric steroid-resistant nephrotic syndrome (SRNS). Recent reports describing NUP93 variants suggest these could be a significant cause of paediatric onset SRNS. We report NUP93 cases in the UK and demonstrate in vivo functional effects of Nup93 depletion in a fly (Drosophila melanogaster) nephrocyte model. Methods: Three hundred thirty-seven paediatric SRNS patients from the National cohort of patients with Nephrotic Syndrome (NephroS) were whole exome and/or whole genome sequenced. Patients were screened for over 70 genes known to be associated with Nephrotic Syndrome (NS). D. melanogaster Nup93 knockdown was achieved by RNA interference using nephrocyte-restricted drivers. Results: Six novel homozygous and compound heterozygous NUP93 variants were detected in 3 sporadic and 2 familial paediatric onset SRNS characterised histologically by focal segmental glomerulosclerosis (FSGS) and progressing to kidney failure by 12 months from clinical diagnosis. Silencing of the two orthologs of human NUP93 expressed in D. melanogaster, Nup93-1, and Nup93-2 resulted in significant signal reduction of up to 82% in adult pericardial nephrocytes with concomitant disruption of NPC protein expression. Additionally, nephrocyte morphology was highly abnormal in Nup93-1 and Nup93-2 silenced flies surviving to adulthood. Conclusion: We expand the spectrum of NUP93 variants detected in paediatric onset SRNS and demonstrate its incidence within a national cohort. Silencing of either D. melanogaster Nup93 ortholog caused a severe nephrocyte phenotype, signaling an important role for the nucleoporin complex in podocyte biology. Graphical Abstract: A higher resolution version of the Graphical abstract is available as Supplementary information[Figure not available: see fulltext.
First Genotype-Phenotype Study in TBX4 Syndrome: Gain-of-Function Mutations Causative for Lung Disease.
No full textRationale: Despite the increased recognition of TBX4 (T-BOX transcription factor 4)-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights. Objectives: To compile and functionally characterize all TBX4 variants reported to date and undertake a comprehensive genotype-phenotype analysis. Methods: We assembled a multicenter cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with patients with PAH with BMPR2 (Bone Morphogenetic Protein Receptor type 2) causal variants (n = 162) or no identified variants in PAH-associated genes (n = 741) genotyped via the National Institute for Health Research BioResource-Rare Diseases. Measurements and Main Results: Functional assessment of TBX4 missense variants led to the novel finding of gain-of-function effects associated with older age at diagnosis of lung disease compared with loss-of-function effects (P = 0.038). Variants located in the T-BOX and nuclear localization domains were associated with earlier presentation (P = 0.005) and increased incidence of interstitial lung disease (P = 0.003). Event-free survival (death or transplantation) was shorter in the T-BOX group (P = 0.022), although age had a significant effect in the hazard model (P = 0.0461). Carriers of TBX4 variants were diagnosed at a younger age (P < 0.001) and had worse baseline lung function (FEV1, FVC) (P = 0.009) than the BMPR2 and no identified causal variant groups. Conclusions: We demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain of function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains
Investigating genotype-phenotype relationship of extreme neuropathic pain disorders in a UK national cohort
No full textThe aims of our study were to use whole genome sequencing in a cross-sectional cohort of patients to identify new variants in genes implicated in neuropathic pain, to determine the prevalence of known pathogenic variants and to understand the relationship between pathogenic variants and clinical presentation. Patients with extreme neuropathic pain phenotypes (both sensory loss and gain) were recruited from secondary care clinics in the UK and underwent whole genome sequencing as part of the National Institute for Health and Care Research Bioresource Rare Diseases project. A multidisciplinary team assessed the pathogenicity of rare variants in genes previously known to cause neuropathic pain disorders and exploratory analysis of research candidate genes was completed. Association testing for genes carrying rare variants was completed using the gene-wise approach of the combined burden and variance-component test SKAT-O. Patch clamp analysis was performed on transfected HEK293T cells for research candidate variants of genes encoding ion channels. The results include the following: (i) Medically actionable variants were found in 12% of study participants (205 recruited), including known pathogenic variants: SCN9A(ENST00000409672.1): c.2544T>C, p.Ile848Thr that causes inherited erythromelalgia, and SPTLC1(ENST00000262554.2):c.340T>G, p.Cys133Tr variant that causes hereditary sensory neuropathy type-1. (ii) Clinically relevant variants were most common in voltage-gated sodium channels (Nav). (iii) SCN9A(ENST00000409672.1):c.554G>A, pArg185His variant was more common in non-freezing cold injury participants than controls and causes a gain of function of NaV1.7 after cooling (the environmental trigger for non-freezing cold injury). (iv) Rare variant association testing showed a significant difference in distribution for genes NGF, KIF1A, SCN8A, TRPM8, KIF1A, TRPA1 and the regulatory regions of genes SCN11A, FLVCR1, KIF1A and SCN9A between European participants with neuropathic pain and controls. (v) The TRPA1(ENST00000262209.4):c.515C>T, p.Ala172Val variant identified in participants with episodic somatic pain disorder demonstrated gain-of-channel function to agonist stimulation. Whole genome sequencing identified clinically relevant variants in over 10% of participants with extreme neuropathic pain phenotypes. The majority of these variants were found in ion channels. Combining genetic analysis with functional validation can lead to a better understanding as to how rare variants in ion channels lead to sensory neuron hyper-excitability, and how cold, as an environmental trigger, interacts with the gain-of-function NaV1.7 p.Arg185His variant. Our findings highlight the role of ion channel variants in the pathogenesis of extreme neuropathic pain disorders, likely mediated through changes in sensory neuron excitability and interaction with environmental triggers
