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Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria.

ABSTRACT: The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3-5). It identified 'mutational hotspots' (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that 'well-established' functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common 'incidental' findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3-COL4A5 genes remains a challenge.

SUBMITTER: Savige J

PROVIDER: S-EPMC8384871 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundReporting guidelines for different study designs are currently available to report studies with accuracy and transparency. There is a need to develop supplementary guideline items that are specific to areas within Pediatric Dentistry. This study aims to develop Reporting stAndards for research in PedIatric Dentistry (RAPID) guidelines using a pre-defined expert consensus-based Delphi process.MethodsThe development of the RAPID guidelines was based on the Guidance for Developers of Health Research Reporting Guidelines. Following a comprehensive search of the literature, the Executive Group identified ten themes in Pediatric Dentistry and compiled a draft checklist of items under each theme. The themes were categorized as: General, Oral Medicine, Pathology and Radiology, Children with Special Health Care Needs, Sedation and Hospital Dentistry, Behavior Guidance, Dental Caries, Preventive and Restorative Dentistry, Pulp Therapy, Traumatology, and Interceptive Orthodontics. A RAPID Delphi Group (RDG) was formed comprising of 69 members from 15 countries across six continents. Items were scored using a 9-point rating Likert scale. Items achieving a score of seven and above, marked by at least 70% of RDG members were accepted into the RAPID checklist items. Weighted mean scores were calculated for each item. Statistical significance was set at p < 0.05 and one-way ANOVA was used to calculate the difference in the weighted mean scores between the themes.ResultsThe final RAPID checklist comprised of 128 items that were finalized and approved by the RDG members in the online consensus meeting. The percentage for high scores (scores 7 to 9) ranged from 69.57 to 100% for individual items. The overall weighted mean score of the final items ranged from 7.51 to 8.28 (out of 9) and the difference was statistically significant between the themes (p < 0.05).ConclusionsThe RAPID statement provides guidance to researchers, authors, reviewers and editors, to ensure that all elements relevant to particular studies are adequately reported.

Project description:IntroductionLoss of skeletal muscle mass and function (sarcopenia) is common in individuals with obesity due to metabolic changes associated with a sedentary lifestyle, adipose tissue derangements, comorbidities (acute and chronic diseases) and during the ageing process. Co-existence of excess adiposity and low muscle mass/function is referred to as sarcopenic obesity (SO), a condition increasingly recognized for its clinical and functional features that negatively influence important patient-centred outcomes. Effective prevention and treatment strategies for SO are urgently needed, but efforts are hampered by the lack of a universally established SO definition and diagnostic criteria. Resulting inconsistencies in the literature also negatively affect the ability to define prevalence as well as clinical relevance of SO for negative health outcomes.Aims and methodsThe European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) launched an initiative to reach expert consensus on a definition and diagnostic criteria for SO. The jointly appointed international expert panel proposes that SO is defined as the co-existence of excess adiposity and low muscle mass/function. The diagnosis of SO should be considered in at-risk individuals who screen positive for a co-occurring elevated body mass index or waist circumference, and markers of low skeletal muscle mass and function (risk factors, clinical symptoms, or validated questionnaires). Diagnostic procedures should initially include assessment of skeletal muscle function, followed by assessment of body composition where presence of excess adiposity and low skeletal muscle mass or related body compartments confirm the diagnosis of SO. Individuals with SO should be further stratified into stage I in the absence of clinical complications or stage II if cases are associated with complications linked to altered body composition or skeletal muscle dysfunction.ConclusionsESPEN and EASO, as well as the expert international panel, advocate that the proposed SO definition and diagnostic criteria be implemented into routine clinical practice. The panel also encourages prospective studies in addition to secondary analysis of existing data sets, to study the predictive value, treatment efficacy and clinical impact of this SO definition.

Project description:Randomized trials support carotid endarterectomy (CEA) in asymptomatic patients with ?60% internal carotid artery (ICA) stenosis. The widely referenced Society for Radiologists in Ultrasound Consensus Statement on carotid duplex ultrasound (CDUS) imaging indicates that an ICA peak systolic velocity (PSV) ?230 cm/s corresponds to a ?70% ICA stenosis, leading to the potential conclusion that asymptomatic patients with an ICA PSV ?230 cm/s would benefit from CEA. Our goal was to determine the natural history stroke risk of asymptomatic patients who might have undergone CEA based on consensus statement PSV of ?230 cm/s but instead were treated medically based on more conservative CDUS imaging criteria.All patients who underwent CDUS imaging at our institution during 2009 were retrospectively reviewed. The year 2009 was chosen to ensure extended follow-up. Asymptomatic patients were included if their ICA PSV was ?230 cm/s but less than what our laboratory considers a ?80% stenosis by CDUS imaging (PSV ?430 cm/s, end-diastolic velocity ?151 cm/s, or ICA/common carotid artery PSV ratio ?7.5). Study end points included freedom from transient ischemic attack (TIA), freedom from any stroke, freedom from carotid-etiology stroke, and freedom from revascularization.Criteria for review were met by 327 patients. Mean follow-up was 4.3 years, with 85% of patients having >3-year follow-up. Four unheralded strokes occurred during follow-up at <1, 17, 25, and 30 months that were potentially attributable to the index carotid artery. Ipsilateral TIA occurred in 17 patients. An additional 12 strokes occurred that appeared unrelated to ipsilateral carotid disease, including hemorrhagic events, contralateral, and cerebellar strokes. Revascularization was undertaken in 59 patients, 1 for stroke, 12 for TIA, and 46 for asymptomatic disease. Actuarial freedom from carotid-etiology stroke was 99.7%, 98.4%, and 98.4% at 1, 3, and 5 years, respectively. Freedom from TIA was 98%, 96%, and 95%, freedom from any stroke was 99%, 96%, and 93%, and freedom from revascularization was 95%, 86%, and 81% at 1, 3, and 5 years, respectively.Patients with intermediate asymptomatic carotid stenosis (ICA PSV 230-429 cm/s) do well with medical therapy when carefully monitored and intervened upon using conservative CDUS criteria. Furthermore, a substantial number of patients would undergo unnecessary CEA if consensus statement CDUS thresholds are used to recommend surgery. Current velocity threshold recommendations should be re-evaluated, with potentially important implications for upcoming clinical trials.

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Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria.

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