Expert Panel Curation of 31 Genes in Relation to Limb Girdle Muscular Dystrophy.

Introduction: Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD. Methods: The ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) convened to evaluate the strength of evidence supporting gene-disease relationships (GDR) using the ClinGen gene-disease clinical validity framework to evaluate 31 genes implicated in LGMD. Results: The GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes (CAPN3, COL6A1, COL6A2, COL6A3) were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns, resulting in curation of 35 GDRs. Of these, 30 (86%) were classified as Definitive, 4 (11%) as Moderate and 1 (3%) as Limited. Two genes, POMGNT1 and DAG1, though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD. Conclusions: The expert-reviewed assertions on the clinical validity of genes implicated in LGMDs form an invaluable resource for clinicians and molecular geneticists. We encourage the global neuromuscular community to publish case-level data that help clarify disputed or novel LGMD associations.

Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions.

BACKGROUND: As the availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including secondary findings. METHODS: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. RESULTS: For 36/65 gene-disease pairs, loss of function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using the CardiacG2P dataset as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. CONCLUSIONS: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is a pre-requisite for scalable genomic testing.

Primary Hyperparathyroidism: Outcomes of Repeated Imaging After Initial Negative Radiological Localization.

BACKGROUND: Radiological localization imaging aids in the identification of abnormal parathyroid glands resulting in primary hyperparathyroidism (PHPT), thereby facilitating minimally invasive parathyroid surgery. Sometimes initial imaging may fail to identify the abnormal gland and imaging may therefore be repeated. This study explored patient outcomes of repeated parathyroid localization imaging, after initial negative gland localization, at a United Kingdom institution. METHODOLOGY: Data was retrospectively collected and analyzed for patients with PHPT undergoing repeated imaging during a five-year period (2015-2020). The total number of episodes of scanning, types of scans performed, the time interval between scans and the imaging success of gland localization were recorded. We explored the reasons for repeated imaging and attempted to identify any factors that might predict subsequent positive radiological localization. RESULTS: A total of 45 patients were identified who underwent repeated localizing imaging after first localizing imaging was negative. Of these, 39 did not undergo surgery despite repeat imaging being undertaken; 11 out of these 39 patients (28%) had subsequent positive localization scans. Again, a large proportion of patients were managed conservatively, despite the repeated sets of imaging being done. Patients undergoing three or four sets of repetitive imaging did not have imaging or surgical success. CONCLUSION: A streamlined parathyroid pathway should be followed whereby patients should be triaged for suitability for surgery prior to repeated imaging. A second set of scans should be offered when patients are unsuitable for conservative management and are willing and fit to undergo surgery. There is no merit to repeating imaging more than twice.

Beyond gene-disease validity: capturing structured data on inheritance, allelic-requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions.

Background: As availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including as secondary findings. Methods: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. Results: For 36/65 gene-disease pairs, loss-of-function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using CardiacG2P as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. Conclusions: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is pre-requisite for scalable genomic testing.

Clinical testing panels for ALS: global distribution, consistency, and challenges.

Objective: In 2021, the Clinical Genome Resource (ClinGen) amyotrophic lateral sclerosis (ALS) spectrum disorders Gene Curation Expert Panel (GCEP) was established to evaluate the strength of evidence for genes previously reported to be associated with ALS. Through this endeavor, we will provide standardized guidance to laboratories on which genes should be included in clinical genetic testing panels for ALS. In this manuscript, we aimed to assess the heterogeneity in the current global landscape of clinical genetic testing for ALS. Methods: We reviewed the National Institutes of Health (NIH) Genetic Testing Registry (GTR) and members of the ALS GCEP to source frequently used testing panels and compare the genes included on the tests. Results: 14 clinical panels specific to ALS from 14 laboratories covered 4 to 54 genes. All panels report on ANG, SOD1, TARDBP, and VAPB; 50% included or offered the option of including C9orf72 hexanucleotide repeat expansion (HRE) analysis. Of the 91 genes included in at least one of the panels, 40 (44.0%) were included on only a single panel. We could not find a direct link to ALS in the literature for 14 (15.4%) included genes. Conclusions: The variability across the surveyed clinical genetic panels is concerning due to the possibility of reduced diagnostic yields in clinical practice and risk of a missed diagnoses for patients. Our results highlight the necessity for consensus regarding the appropriateness of gene inclusions in clinical genetic ALS tests to improve its application for patients living with ALS and their families.

Metastatic parathyroid cancer: a rare cause of hypercalcaemia.

A 45-year-old man presenting with abdominal pain was found to have severe hypercalcaemia with elevated parathyroid hormone. Investigations revealed a parathyroid mass and bone metastases consistent with metastatic parathyroid carcinoma. The patient underwent parathyroidectomy, with histology confirming a right inferior parathyroid carcinoma. His postoperative management was complicated by severe hypercalcaemia refractory to medical therapy, owing to the metastases continuing to produce parathyroid hormone. Despite palliative radiotherapy to the metastases, the patient died within 3 months from end-organ failure related to hypercalcaemia.

Hyperacute And Chronic Changes In Cerebral Magnetic Resonance Images After Pvac, nmarq And Epicardial Thoracoscopic Surgical Ablation For Paroxysmal Atrial Fibrillation.

Threshold testing of cardiac rhythm devices is essential to monitoring the proper functioning of such devices (1). However, the currently method of applying multiple ECG leads to the patient is burdensome and time consuming (2). We are presenting a completely new way to perform cardiac rhythm device threshold testing using pulse oximetry. Twenty patients, with varying cardiac rhythm devices and pacing modes, were enrolled and had their atrial and ventricular thresholds tested. A comparison was made between simultaneous threshold determinations via the standard EGM based method and the new pulse oximetry based method. 75% of the ventricular threshold tested and 58% of the atrial thresholds tested were the same with the two testing methods. The remainder of the tests (25% of ventricular threshold and 42% of the atrial threshold tests) varied by +0.25 V. This study shows that pulse oximetry based testing is an accurate, reliable, and easy way to perform cardiac rhythm device threshold testing and may complement traditional methods to perform such tests in the future.

Diminished acquired equivalence yet good discrimination performance in older participants.

We asked younger and older human participants to perform computer-based configural discriminations that were designed to detect acquired equivalence. Both groups solved the discriminations but only the younger participants demonstrated acquired equivalence. The discriminations involved learning the preferences ["like" (+) or "dislike" (-)] for sports [e.g., tennis (t) and hockey (h)] of four fictitious people [e.g., Alice (A), Beth (B), Charlotte (C), and Dorothy (D)]. In one experiment, the discrimination had the form: At+, Bt-, Ct+, Dt-, Ah-, Bh+, Ch-, Dh+. Notice that, e.g., Alice and Charlotte are "equivalent" in liking tennis but disliking hockey. Acquired equivalence was assessed in ancillary components of the discrimination (e.g., by looking at the subsequent rate of "whole" versus "partial" reversal learning). Acquired equivalence is anticipated by a network whose hidden units are shared when inputs (e.g., A and C) signal the same outcome (e.g., +) when accompanied by the same input (t). One interpretation of these results is that there are age-related differences in the mechanisms of configural acquired equivalence.

Endogenous GFAP-positive neural stem/progenitor cells in the postnatal mouse cortex are activated following traumatic brain injury.

Interest in promoting regeneration of the injured nervous system has recently turned toward the use of endogenous stem cells. Elucidating cues involved in driving these precursor cells out of quiescence following injury, and the signals that drive them toward neuronal and glial lineages, will help to harness these cells for repair. Using a biomechanically validated in vitro organotypic stretch injury model, cortico-hippocampal slices from postnatal mice were cultured and a stretch injury equivalent to a severe traumatic brain injury (TBI) applied. In uninjured cortex, proliferative potential under in vitro conditions is virtually absent in older slices (equivalent postnatal day 15 compared to 8). However, following a severe stretch injury, this potential is restored in injured outer cortex. Using slices from mice expressing a fluorescent reporter on the human glial fibrillary acidic protein (GFAP) promoter, we show that GFAP+ cells account for the majority of proliferating neurospheres formed, and that these cells are likely to arise from the cortical parenchyma and not from the subventricular zone. Moreover, we provide evidence for a correlation between upregulation of sonic hedgehog signaling, a pathway known to regulate stem cell proliferation, and this restoration of regenerative potential following TBI. Our results indicate that a source of quiescent endogenous stem cells residing in the cortex and subcortical tissue proliferate in vitro following TBI. Moreover, these proliferating cells are multipotent and are derived mostly from GFAP-expressing cells. This raises the possibility of using this endogenous source of stem cells for repair following TBI.

Blending online techniques with traditional face to face teaching methods to deliver final year undergraduate radiology learning content.

AIM: To review the initial experience of blending a variety of online educational techniques with traditional face to face or contact-based teaching methods to deliver final year undergraduate radiology content at a UK Medical School. MATERIALS AND METHODS: The Brighton and Sussex Medical School opened in 2003 and offers a 5-year undergraduate programme, with the final 5 spent in several regional centres. Year 5 involves several core clinical specialities with onsite radiology teaching provided at regional centres in the form of small-group tutorials, imaging seminars and also a one-day course. An online educational module was introduced in 2007 to facilitate equitable delivery of the year 5 curriculum between the regional centres and to support students on placement. This module had a strong radiological emphasis, with a combination of imaging integrated into clinical cases to reflect everyday practice and also dedicated radiology cases. For the second cohort of year 5 students in 2008 two additional online media-rich initiatives were introduced, to complement the online module, comprising imaging tutorials and an online case discussion room. RESULTS: In the first year for the 2007/2008 cohort, 490 cases were written, edited and delivered via the Medical School managed learning environment as part of the online module. 253 cases contained a form of image media, of which 195 cases had a radiological component with a total of 325 radiology images. Important aspects of radiology practice (e.g. consent, patient safety, contrast toxicity, ionising radiation) were also covered. There were 274,000 student hits on cases the first year, with students completing a mean of 169 cases each. High levels of student satisfaction were recorded in relation to the online module and also additional online radiology teaching initiatives. CONCLUSION: Online educational techniques can be effectively blended with other forms of teaching to allow successful undergraduate delivery of radiology. Efficient IT links and good image quality are essential ingredients for successful student/clinician engagement.

The role of plain films in imaging major trauma.

This article reviews the role of imaging in the management of trauma patients. First the trauma series is reviewed, principally the chest, pelvis and cervical spine radiographs along with an approach to their interpretation. The role of computed tomography in trauma imaging is then discussed.