scholarly journals Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 106
Author(s):  
Estefanía Martínez-Barrios ◽  
Sergi Cesar ◽  
José Cruzalegui ◽  
Clara Hernandez ◽  
Elena Arbelo ◽  
...  

Sudden death is a rare event in the pediatric population but with a social shock due to its presentation as the first symptom in previously healthy children. Comprehensive autopsy in pediatric cases identify an inconclusive cause in 40–50% of cases. In such cases, a diagnosis of sudden arrhythmic death syndrome is suggested as the main potential cause of death. Molecular autopsy identifies nearly 30% of cases under 16 years of age carrying a pathogenic/potentially pathogenic alteration in genes associated with any inherited arrhythmogenic disease. In the last few years, despite the increasing rate of post-mortem genetic diagnosis, many families still remain without a conclusive genetic cause of the unexpected death. Current challenges in genetic diagnosis are the establishment of a correct genotype–phenotype association between genes and inherited arrhythmogenic disease, as well as the classification of variants of uncertain significance. In this review, we provide an update on the state of the art in the genetic diagnosis of inherited arrhythmogenic disease in the pediatric population. We focus on emerging publications on gene curation for genotype–phenotype associations, cases of genetic overlap and advances in the classification of variants of uncertain significance. Our goal is to facilitate the translation of genetic diagnosis to the clinical area, helping risk stratification, treatment and the genetic counselling of families.

Author(s):  
Daniel Mahecha ◽  
Haydemar Nuñez ◽  
Maria Lattig ◽  
Jorge Duitama

The growing use of new generation sequencing technologies on genetic diagnosis has produced an exponential increase in the number of Variants of Uncertain Significance (VUS). In this manuscript we compare three machine learning methods to classify VUS as Pathogenic or No pathogenic, implementing a Random Forest (RF), a Support Vector Machine (SVM), and a Multilayer Perceptron (MLP). To train the models, we extracted 82,463 high quality variants from ClinVar, using 9 conservation scores, the loss of function tool and allele frequencies. For the RF and SVM models, hyperparameters were tuned using cross validation with a grid search. The three models were tested on a set of 5,537 variants that had been classified as VUS any time along the last three years but had been reclassified in august 2020. The three models yielded superior accuracy on this set compared to the benchmarked tools. The RF based model yielded the best performance across different variant types and was used to create VusPrize, an open source software tool for prioritization of variants of uncertain significance. We believe that our model can improve the process of genetic diagnosis on research and clinical settings.


2021 ◽  
Author(s):  
Karen I Lange ◽  
Sunayna Best ◽  
Sofia Tsiropoulou ◽  
Ian Berry ◽  
Colin A Johnson ◽  
...  

Purpose: A molecular genetic diagnosis is essential for accurate counselling and management of patients with ciliopathies. Uncharacterized missense alleles are often classified as variants of uncertain significance (VUS) and are not clinically useful. In this study, we explore the use of a tractable animal model (C. elegans) for in vivo interpretation of missense VUS alleles of TMEM67, a gene frequently mutated as a cause of ciliopathies. Methods: CRISPR/Cas9 gene editing was used to generate homozygous worm strains carrying TMEM67 patient variants. Quantitative phenotypic assays (dye filling, roaming, chemotaxis) assessed cilia structure and function. Results were validated by genetic complementation assays in a human TMEM67 knock-out hTERT-RPE1 cell line. Results: Quantitative assays in C. elegans distinguished between known benign (Asp359Glu, Thr360Ala) and pathogenic (Glu361Ter, Gln376Pro) variants. Analysis of seven missense VUS alleles predicted two benign (Cys173Arg, Thr176Ile) and four pathogenic variants (Cys170Tyr, His782Arg, Gly786Glu, His790Arg). Results from one VUS (Gly979Arg) were inconclusive in worms, but additional in vitro validation suggested it was likely benign. Conclusion: Efficient genome editing and quantitative functional assays in C. elegans make it a tractable in vivo animal model that allows stratification and rapid, cost-effective interpretation of ciliopathy-associated missense VUS alleles.


2021 ◽  
Vol 108 (10) ◽  
pp. 1907-1923
Author(s):  
Sandrine M. Caputo ◽  
Lisa Golmard ◽  
Mélanie Léone ◽  
Francesca Damiola ◽  
Marine Guillaud-Bataille ◽  
...  

2012 ◽  
Vol 33 (5) ◽  
pp. 900-903 ◽  
Author(s):  
Noralane M. Lindor ◽  
Lucia Guidugli ◽  
Xianshu Wang ◽  
Maxime P. Vallée ◽  
Alvaro N. A. Monteiro ◽  
...  

2011 ◽  
Vol 33 (1) ◽  
pp. 8-21 ◽  
Author(s):  
Noralane M. Lindor ◽  
Lucia Guidugli ◽  
Xianshu Wang ◽  
Maxime P. Vallée ◽  
Alvaro N. A. Monteiro ◽  
...  

2008 ◽  
Vol 68 (9) ◽  
pp. 3523-3531 ◽  
Author(s):  
Daniel J. Farrugia ◽  
Mukesh K. Agarwal ◽  
Vernon S. Pankratz ◽  
Amie M. Deffenbaugh ◽  
Dmitry Pruss ◽  
...  

2021 ◽  
Vol 22 (16) ◽  
pp. 8627
Author(s):  
Jane H. Frederiksen ◽  
Sara B. Jensen ◽  
Zeynep Tümer ◽  
Thomas v. O. Hansen

Lynch syndrome (LS) is one of the most common hereditary cancer predisposition syndromes worldwide. Individuals with LS have a high risk of developing colorectal or endometrial cancer, as well as several other cancers. LS is caused by autosomal dominant pathogenic variants in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, PMS2 or MSH6, and typically include truncating variants, such as frameshift, nonsense or splicing variants. However, a significant number of missense, intronic, or silent variants, or small in-frame insertions/deletions, are detected during genetic screening of the MMR genes. The clinical effects of these variants are often more difficult to predict, and a large fraction of these variants are classified as variants of uncertain significance (VUS). It is pivotal for the clinical management of LS patients to have a clear genetic diagnosis, since patients benefit widely from screening, preventive and personal therapeutic measures. Moreover, in families where a pathogenic variant is identified, testing can be offered to family members, where non-carriers can be spared frequent surveillance, while carriers can be included in cancer surveillance programs. It is therefore important to reclassify VUSs, and, in this regard, functional assays can provide insight into the effect of a variant on the protein or mRNA level. Here, we briefly describe the disorders that are related to MMR deficiency, as well as the structure and function of MSH6. Moreover, we review the functional assays that are used to examine VUS identified in MSH6 and discuss the results obtained in relation to the ACMG/AMP PS3/BS3 criterion. We also provide a compiled list of the MSH6 variants examined by these assays. Finally, we provide a future perspective on high-throughput functional analyses with specific emphasis on the MMR genes.


2011 ◽  
Vol 38 (4) ◽  
pp. 469-480 ◽  
Author(s):  
Susan Miller-Samuel ◽  
Deborah J. MacDonald ◽  
Jeffrey N. Weitzel ◽  
Ferdy Santiago ◽  
Martin A. Martino ◽  
...  

2019 ◽  
Vol 42 (2) ◽  
pp. 275-282 ◽  
Author(s):  
Jingyun Dong ◽  
Ekaterina Subbotina ◽  
Nori Williams ◽  
Barbara A. Sampson ◽  
Yingying Tang ◽  
...  

2013 ◽  
Vol 144 (5) ◽  
pp. S-513-S-514
Author(s):  
Raj P. Raval ◽  
Luis Baez-Cabrera ◽  
John-Paul Plazzer ◽  
Andrea Abbott ◽  
Finlay A. Macrae ◽  
...  

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