Variability in pathogenicity prediction programs: impact on clinical diagnostics

Abstract Current practice by clinical diagnostic laboratories is to utilize online prediction programs to help determine the significance of novel variants in a given gene sequence. However, these programs vary widely in their methods and ability to correctly predict the pathogenicity of a given sequence change. The performance of 17 publicly available pathogenicity prediction programs was assayed using a dataset consisting of 122 credibly pathogenic and benign variants in genes associated with the RASopathy family of disorders and limb‐girdle muscular dystrophy. Performance metrics were compared between the programs to determine the most accurate program for loss‐of‐function and gain‐of‐function mechanisms. No one program correctly predicted the pathogenicity of all variants analyzed. A major hindrance to the analysis was the lack of output from a significant portion of the programs. The best performer was MutPred, which had a weighted accuracy of 82.6% in the full dataset. Surprisingly, combining the results of the top three programs did not increase the ability to predict pathogenicity over the top performer alone. As the increasing number of sequence changes in larger datasets will require interpretation, the current study demonstrates that extreme caution must be taken when reporting pathogenicity based on statistical online protein prediction programs in the absence of functional studies. The performance of 17 publicly available pathogenicity prediction progr...
Source: Molecular Genetics & Genomic Medicine - Category: Genetics & Stem Cells Authors: Tags: Original Article Source Type: research

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Publication date: Available online 20 August 2019Source: Stem Cell ResearchAuthor(s): Rovina Davide, Castiglioni Elisa, Farini Andrea, Bellichi Marzia, Cristina Gervasini, Stefania Paganini, Marina Di Segni, Santoro Rosaria, Torrente Yvan, Pompilio Giulio, Gowran AoifeAbstractDuchenne's muscular dystrophy (DMD) is a neuromuscular disorder affecting skeletal and cardiac muscle function, caused by mutations in the dystrophin (DMD) gene. Dermal fibroblasts, isolated from a DMD patient with a reported deletion of exons 51 to 53 in the DMD gene, were reprogrammed into induced pluripotent stem cells (iPSCs) by electroporation wi...
Source: Stem Cell Research - Category: Stem Cells Source Type: research
The FDA has nixed approval of golodirsen injection for the treatment of Duchenne muscular dystrophy, citing concerns over risk for infusion port infections and possible renal toxicity.Medscape Medical News
Source: Medscape Neurology and Neurosurgery Headlines - Category: Neurology Tags: Neurology & Neurosurgery News Source Type: news
Duchenne muscular dystrophy (DMD) is a severe X-linked recessive degenerative disorder of the skeletal muscles that affects 1 in 3,500 male births. It is caused by a mutation in the dystrophin gene, resulting in progressive muscle damage and its replacement by fat and connective tissue. No effective treatments are currently available; however, a number of promising genetic strategies have emerged as potential therapies [1, 2], including stop-codon readthrough and exon-skipping with antisense oligonucleotides, with several treatments currently entering clinical trials.
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Sarepta Therapeutics Inc said on Monday the U.S. Food and Drug Administration declined to approve its newest treatment for Duchenne muscular dystrophy (DMD), citing safety concerns including the risk of infection and kidney toxicity.
Source: Reuters: Health - Category: Consumer Health News Tags: healthNews Source Type: news
Clinical care guidelines are typically developed by clinicians and researchers. Including patient and caregiver voices in guideline development may help create guidelines that are more useful for patients and ...
Source: Orphanet Journal of Rare Diseases - Category: Internal Medicine Authors: Tags: Research Source Type: research
The FDA has denied Sarepta Therapeutics ’ application for its second Duchenne muscular dystrophy treatment, despite the company producing twice the amount of data behind its controversial first product approval in 2016. Sarepta (Nasdaq: SRPT) had hoped to launch a treatment called golodirsen that would have doubled its reach among youn g boys with the disease. The drug, like Sarepta’s sole commercial treatment, was developed to skip over the faulty gene that prevents young boys with the disease…
Source: bizjournals.com Health Care:Pharmaceuticals headlines - Category: Pharmaceuticals Authors: Source Type: news
The U.S. Food and Drug Administration declined to approve Sarepta Therapeutics Inc's newest treatment for Duchenne muscular dystrophy (DMD), a rare muscle-wasting disorder that mainly affects boys, the company said on Monday.
Source: Reuters: Health - Category: Consumer Health News Tags: healthNews Source Type: news
Abstract Excessive mitochondrial matrix Ca2+ and oxidative stress leads to the opening of a high-conductance channel of the inner mitochondrial membrane referred to as the mitochondrial permeability transition pore (mtPTP). Because mtPTP opening can lead to cell death under diverse pathophysiological conditions (e.g. ischemia-reperfusion injury and muscular dystrophy), inhibitors of mtPTP are potential therapeutics for various human diseases. High throughput screening efforts led to the identification of a 3-carboxamide-5-phenol-isoxazole compounds as mtPTP inhibitors. While they showed nM potency against mtPTP, t...
Source: ChemMedChem - Category: Chemistry Authors: Tags: ChemMedChem Source Type: research
This report presents a novel technique termed the pharyngeal clearance maneuver, which uses a modified application of the mechanical insufflation-exsufflation device to mobilize “secretion burden” at the portion of the trachea above the tracheostomy cuff during cuff deflation. Utilization of this strategy may reduce the risk of aspiration, infection, and respiratory compromise for patients with high cervical spinal cord injury in the acute rehabilitation setting. It is of particular benefit for those whose cuffs are being deflated for the first time and who may have large secretion volumes above the cuff. It ca...
Source: American Journal of Physical Medicine and Rehabilitation - Category: Rehabilitation Tags: Brief Reports Source Type: research
Authors: Muntoni F, Desguerre I, Guglieri M, Osorio AN, Kirschner J, Tulinius M, Buccella F, Elfring G, Werner C, Schilling T, Trifillis P, Zhang O, Delage A, Santos CL, Mercuri E Abstract Aim: Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, multicenter registry providing real-world evidence regarding ataluren use in patients with nonsense mutation Duchenne muscular dystrophy (DMD) in clinical practice (NCT02369731). Here, we describe the initial demographic characteristics of the registry population. Patients &methods: Patients will be followed up from en...
Source: Journal of Comparative Effectiveness Research - Category: General Medicine Tags: J Comp Eff Res Source Type: research
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