Genetic variant pathogenicity prediction trained using disease-specific clinical sequencing data sets METHOD

Recent advances in DNA sequencing have expanded our understanding of the molecular basis of genetic disorders and increased the utilization of clinical genomic tests. Given the paucity of evidence to accurately classify each variant and the difficulty of experimentally evaluating its clinical significance, a large number of variants generated by clinical tests are reported as variants of unknown clinical significance. Population-scale variant databases can improve clinical interpretation. Specifically, pathogenicity prediction for novel missense variants can use features describing regional variant constraint. Constrained genomic regions are those that have an unusually low variant count in the general population. Computational methods have been introduced to capture these regions and incorporate them into pathogenicity classifiers, but these methods have yet to be compared on an independent clinical variant data set. Here, we introduce one variant data set derived from clinical sequencing panels and use it to compare the ability of different genomic constraint metrics to determine missense variant pathogenicity. This data set is compiled from 17,071 patients surveyed with clinical genomic sequencing for cardiomyopathy, epilepsy, or RASopathies. We further use this data set to demonstrate the necessity of disease-specific classifiers and to train PathoPredictor, a disease-specific ensemble classifier of pathogenicity based on regional constraint and variant-level features. Pa...
Source: Genome Research - Category: Genetics & Stem Cells Authors: Tags: METHOD Source Type: research

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Literature remains constrained to case reports with respect to epilepsy-associated takotsubo cardiomyopathy (TC) or stress-induced cardiomyopathy and its impact on in-hospital outcomes remains largely obscure.
Source: International Journal of Cardiology - Category: Cardiology Authors: Tags: Short communication Source Type: research
Recent advances in DNA sequencing have expanded our understanding of the molecular basis of genetic disorders and increased the utilization of clinical genomic tests. Given the paucity of evidence to accurately classify each variant and the difficulty of experimentally evaluating its clinical significance, a large number of variants generated by clinical tests are reported as variants of unknown clinical significance. Population-scale variant databases can improve clinical interpretation. Specifically, pathogenicity prediction for novel missense variants can use features describing regional variant constraint. Constrained ...
Source: Genome Research - Category: Genetics & Stem Cells Authors: Tags: METHOD Source Type: research
Takotsubo Cardiomyopathy (TC) is an acute stress-induced cardiomyopathy with characteristic transient wall motion abnormalities that may occur in the contet of acute illness or emotional stress. A database search of Pubmed, Embase and Medline of stress, broken heart or takotsubo cardiomyopathy with epilepsy, seizure and status epilepticus revealed 48 TC cases reported related to seizure activity, and our review revealed 16 articles which included 14 case reports and 2 articles related to status epilepticus in adults.
Source: Heart, Lung and Circulation - Category: Cardiology Authors: Tags: 128 Source Type: research
In conclusion, this case shows the efficacy of VRCZ combined with L-AMB for refractory pulmonary cryptococcosis.
Source: CEN Case Reports - Category: Urology & Nephrology Source Type: research
ABSTRACT D ésiré-Magloire Bourneville ought to be thought of as the father of Pediatric Neurology for his significant contributions to the field. He worked as a physician, politician, writer, and editor. He was the first to describe the autosomal dominant genetic condition known as “ tuberous sclerosis complex ” , after conducting an autopsy on a young female patient, where the main finding in the central nervous system was multiple dense tubers. The patient had refractory epilepsy and intellectual disability. His work was based on the study of epilepsy and idiocy, and he was also an advocate of p...
Source: Arquivos de Neuro-Psiquiatria - Category: Neurology Source Type: research
Conclusion The m.10191T>C mutation in the mtDNA of the complex I (CI) subunit of MTND3 results in the substitution of a highly conserved amino acid (p.Ser45Pro) within the ND3 protein, leading to CI dysfunction through impaired enzyme catalysis rather than impaired stability or assembly, causing a broad clinical spectrum of disorders (26). Patients with the m.10191T>C mutation are rare. In the present study, we report on a family of patients with the extremely rare adult-onset Leigh-like syndrome with the m.10191T>C mutation. Including the two patients from our reported family, the m.10191T>C mutation has bee...
Source: Frontiers in Neurology - Category: Neurology Source Type: research
by Mark T. Handley, Kaalak Reddy, Jimi Wills, Elisabeth Rosser, Archith Kamath, Mihail Halachev, Gavin Falkous, Denise Williams, Phillip Cox, Alison Meynert, Eleanor S. Raymond, Harris Morrison, Stephen Brown, Emma Allan, Irene Aligianis, Andrew P. Jackson, Bernard H. Ramsahoye, Alex von Kriegsheim, Robert W. Taylor, Andrew J. Finch, David R. FitzPatrick Typical Martsolf syndrome is characterized by congenital cataracts, postnatal microcephaly, developmental delay, hypotonia, short stature and biallelic hypomorphic mutations in eitherRAB3GAP1 orRAB3GAP2. Genetic analysis of 85 unrelated “mutation negative” pro...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research
Publication date: Available online 9 March 2019Source: Neurochemistry InternationalAuthor(s): C.J. CarterAbstractPrenatal and early childhood infections have been implicated in autism. Many autism susceptibility genes (206 Autworks genes) are localised in the immune system and are related to immune/infection pathways. They are enriched in the host/pathogen interactomes of 18 separate microbes (bacteria/viruses and fungi) and to the genes regulated by bacterial toxins, mycotoxins and Toll-like receptor ligands. This enrichment was also observed for misregulated genes from a microarray study of leukocytes from autistic toddl...
Source: Neurochemistry International - Category: Neuroscience Source Type: research
Authors: Sakhi R, Theuns DAMJ, Szili-Torok T, Yap SC Abstract INTRODUCTION: Recurrent unexplained syncope is a well-established indication for an insertable cardiac monitor (ICM). Recently, the indications for an ICM has been expanded. Areas covered: This review article discusses the current indications for ICMs and gives an overview of the latest generation of commercially available ICMs. Expert commentary: The 2018 ESC Syncope guidelines have expanded the indications for an ICM to patients with inherited cardiomyopathy, inherited channelopathy, suspected unproven epilepsy, and unexplained falls. ICMs are also inc...
Source: Expert Review of Medical Devices - Category: Medical Devices Tags: Expert Rev Med Devices Source Type: research
We report on a new phenotype of COQ4 deficiency: a childhood onset spinocerebellar ataxia with stroke-like episodes.
Source: Molecular Genetics and Metabolism Reports - Category: Genetics & Stem Cells Source Type: research
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