A total of 1509 patients who had legacy pacemakers or defibrillators underwent 2103 MRIs according to a prespecified safety protocol. No long-term clinically significant adverse events were reported.
Studies have shown that magnetic resonance imaging (MRI) does not have clinically important effects on the device parameters of non-MRI-conditional implantable cardioverter-defibrillators (ICDs). ...However, data on non-MRI-conditional ICD detection and treatment of arrhythmias after MRI are limited.
To examine if non-MRI-conditional ICDs have preserved shock function of arrhythmias after MRI.
Prospective cohort study. (ClinicalTrials.gov: NCT01130896).
1 center in the United States.
629 patients with non-MRI-conditional ICDs enrolled consecutively between February 2003 and January 2015.
813 total MRI examinations at a magnetic field strength of 1.5 Tesla using a prespecified safety protocol.
Implantable cardioverter-defibrillator interrogations were collected after MRI. Clinical outcomes included arrhythmia detection and treatment, generator or lead exchanges, adverse events, and death.
During a median follow-up of 2.2 years from MRI to latest available ICD interrogation before generator or lead exchange in 536 patients, 4177 arrhythmia episodes were detected, and 97 patients received ICD shocks. Sixty-one patients (10% of total) had 130 spontaneous ventricular tachycardia or fibrillation events terminated by ICD shocks. A total of 210 patients (33% of total) are known to have died (median, 1.7 years from MRI to death); 3 had cardiac arrhythmia deaths where shocks were indicated without direct evidence of device dysfunction.
Data were acquired at a single center and may not be generalizable to other clinical settings and MRI facilities. Implantable cardioverter-defibrillator interrogations were not available for a subset of patients; adjudication of cause of death relied solely on death certificate data in a subset.
Non-MRI-conditional ICDs appropriately treated detected tachyarrhythmias after MRI. No serious adverse effects on device function were reported after MRI.
Johns Hopkins University and National Institutes of Health.
Several studies have shown that receiving a variant of uncertain significance (VUS) result from genetic testing can invoke confusion or anxiety. This has been explored by studies in the setting of ...cancer genetics, but not in the setting of genetic testing for inherited cardiomyopathies. This study compared levels of cardiac anxiety, general anxiety, and depression in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) with a pathogenic, negative, or VUS result from genetic testing, as well patients and family members who did not undergo genetic testing. These individuals are enrolled in the ARVC Research Registry at the Johns Hopkins ARVC Program. There was no significant difference in cardiac anxiety between probands with pathogenic, negative and VUS results (p=0.985). Individuals who have not undergone genetic testing had significantly less cardiac anxiety than individuals who have undergone genetic testing, in any result category (p<0.001), but this was likely due to these individuals’ status as clinically unaffected family members without implantable cardioverter defibrillators (ICDs). Time elapsed between when an individual received their genetic testing result and when they completed the questionnaire did not have a significant impact on cardiac anxiety (p=0.702), general anxiety (p=0.393) or depression (p=0.683). Overall, genetic test results did not appear to be a major driver for cardiac anxiety, anxiety or depression in this population of ARVC patients and their family members when controlling for other factors such as having an ICD.
•c.823-10G>T Microtubule associated tau (MAPT) gene variant was reported in one family with frontotemporal dementia.•No pathological data was available confirming the disease.•This is the first ...description of the pathology confirming that the variant is disease causing.•This is the first description of the MND associated with c.823-10G>T MAPT variant.
We report the first clinical-radiological-genetic-molecular-pathological study of a kindred with c.823-10G>T MAPT intronic variant (rs63749974) associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We describe the clinical spectrum within this family and emphasize the association between MAPT gene variants and motor neuron disease. This report of a second family with FTDP-17 associated with c.823-10G>T MAPT variant strongly supports pathogenicity of the variant and confirms it is a 4-repeat (4R) tauopathy. This intronic point mutation, probably strengthens the polypyrimidine tract and alters the splicing of exon 10 (10 nucleotides into intron 9) close to the 3’ splice site.
The RefSeq project at the National Center for Biotechnology Information (NCBI) maintains and curates a publicly available database of annotated genomic, transcript, and protein sequence records ...(http://www.ncbi.nlm.nih.gov/refseq/). The RefSeq project leverages the data submitted to the International Nucleotide Sequence Database Collaboration (INSDC) against a combination of computation, manual curation, and collaboration to produce a standard set of stable, non-redundant reference sequences. The RefSeq project augments these reference sequences with current knowledge including publications, functional features and informative nomenclature. The database currently represents sequences from more than 55,000 organisms (>4800 viruses, >40,000 prokaryotes and >10,000 eukaryotes; RefSeq release 71), ranging from a single record to complete genomes. This paper summarizes the current status of the viral, prokaryotic, and eukaryotic branches of the RefSeq project, reports on improvements to data access and details efforts to further expand the taxonomic representation of the collection. We also highlight diverse functional curation initiatives that support multiple uses of RefSeq data including taxonomic validation, genome annotation, comparative genomics, and clinical testing. We summarize our approach to utilizing available RNA-Seq and other data types in our manual curation process for vertebrate, plant, and other species, and describe a new direction for prokaryotic genomes and protein name management.
National and international amalgamation of genomic data offers opportunity for research and audit, including analyses enabling improved classification of variants of uncertain significance. Review of ...individual-level data from National Health Service (NHS) testing of cancer susceptibility genes (2002-2023) submitted to the National Disease Registration Service revealed heterogeneity across participating laboratories regarding (1) the structure, quality and completeness of submitted data, and (2) the ease with which that data could be assembled locally for submission.
In May 2023, we undertook a closed online survey of 51 clinical scientists who provided consensus responses representing all 17 of 17 NHS molecular genetic laboratories in England and Wales which undertake NHS diagnostic analyses of cancer susceptibility genes. The survey included 18 questions relating to 'next-generation sequencing workflow' (11), 'variant classification' (3) and 'phenotypical context' (4).
Widely differing processes were reported for transfer of variant data into their local LIMS (Laboratory Information Management System), for the formatting in which the variants are stored in the LIMS and which classes of variants are retained in the local LIMS. Differing local provisions and workflow for variant classifications were also reported, including the resources provided and the mechanisms by which classifications are stored.
The survey responses illustrate heterogeneous laboratory workflow for preparation of genomic variant data from local LIMS for centralised submission. Workflow is often labour-intensive and inefficient, involving multiple manual steps which introduce opportunities for error. These survey findings and adoption of the concomitant recommendations may support improvement in laboratory dataflows, better facilitating submission of data for central amalgamation.
SDHA pathogenic germline variants (PGVs) are identified in up to 10% of patients with paraganglioma and phaeochromocytoma and up to 30% with wild-type gastrointestinal stromal tumours. Most SDHA PGV ...carriers present with an apparently sporadic tumour, but often the pathogenic variant has been inherited from parent who has the variant, but has not developed any clinical features. Studies of SDHA PGV carriers suggest that lifetime penetrance for SDHA-associated tumours is low, particularly when identified outside the context of a family history. Current recommended surveillance for SDHA PGV carriers follows an intensive protocol. With increasing implementation of tumour and germline large panel and whole-genome sequencing, it is likely more SDHA PGV carriers will be identified in patients with tumours not strongly associated with SDHA, or outside the context of a strong family history. This creates a complex situation about what to recommend in clinical practice considering low penetrance for tumour development, surveillance burden and patient anxiety. An expert SDHA working group was formed to discuss and consider this situation. This paper outlines the recommendations from this working group for testing and management of SDHA PGV carriers in clinical practice.
To describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service ...(NDRS) by the NHS regional molecular genetics laboratories.
Laboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years' missing data.
Individual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed.
The NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry.
Genetics is the backbone of medicine, and particularly Neurology, where a number of disorders have a genetic aetiology and some are complex requiring a dedicated Neurogenetics clinic. At least one ...designated consultant post each within clinical genetics and neurology is recommended per 2,000,000 patients. Genetics in the Republic of Ireland is under-resourced, with the lowest number of consultants per million of population in Europe.In November 2014, we established the first and only monthly adult Neuro-Genetics clinic in Ireland, staffed by 2 consultants and 2 registrars from each speciality. We see patients with complex rare neurological conditions of an unknown genetic aetiology. We performed a retrospective cohort analysis, reviewing symptoms and work-up data.Twenty-seven patients attended a pilot clinic over 12 months. Conditions encountered included: Parkin-related PD, leucodystrophy, ataxia, Fronto-temporal lobar degeneration, SCA 6, ataxia-telangiectasia. Identification of pathogenic mutations directed screening, treatment, and facilitated onward genetic counselling (n=10, 33%). A number of novel mutations were identified in MAPT (“missing tau mutation” published in Brain), SLCA1 and Progranulin. Phenotypic features not previously reported were seen; e.g. writer's cramp in SCA6; paroxysmal myoclonus in GLUT1 deficiency. Breast cancer screening for ATM mutations carriers and referral to international experts in 2 undiagnosed patients were arranged. New treatments were considered, e.g. triheptanoin in GLUT1 deficiency.The establishment of a Neuro-genetics clinic has addressed a gap in service and allowed identification of rare and atypical diagnoses. These complex disorders have a unique psychological burden and ideally the clinic should include psychology input.
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