Biology subjects

Traeger-Synodinos, J.

Publications and source records attributed to Traeger-Synodinos, J..

3 recordsLinked to original sources

bioRxiv2022

Evaluation of in silico predictors on short nucleotide variants in HBA1, HBA2 and HBB associated with haemoglobinopathies

IntroductionHaemoglobinopathies are the commonest monogenic diseases worldwide and are caused by variants in the globin gene clusters. With over 2400 variants detected to date, their interpretation using the ACMG/AMP guidelines is challenging, with computational evidence able to provide valuable input about their functional annotation. While many in silico predictors have already been developed, their performance varies for different genes and diseases. Materials and MethodsWe evaluate 31 in silico predictors using a dataset of 1627 variants in HBA1, HBA2, and HBB. Through varying the decision threshold for each tool, we analyse their performance (a) as binary classifiers of pathogenicity, and (b) using different nonoverlapping pathogenic and benign thresholds for their optimal use in the ACMG/AMP framework. ResultsCADD, Eigen-PC, and REVEL are the overall top performers, with the former reaching moderate strength level for pathogenic prediction. Eigen-PC and REVEL achieve the highest accuracies for missense variants, while CADD is also a reliable predictor of nonmissense variants. Moreover, SpliceAl is the top performing splicing predictor, reaching strong level of evidence, while GERP++ and phyloP are the most accurate conservation tools. DiscussionThis study provides evidence about the optimal use of computational evidence in globin gene clusters under the ACMG/AMP framework.

bioinformatics↗

bioRxiv2019

ATR16 Syndrome: Mechanisms Linking Monosomy to Phenotype

BackgroundSporadic deletions removing 100s-1000s kb of DNA, and variable numbers of poorly characterised genes, are often found in patients with a wide range of developmental abnormalities. In such cases, understanding the contribution of the deletion to an individuals clinical phenotype is challenging.\n\nMethodsHere, as an example of this common phenomenon, we analysed 34 patients with simple deletions of [~]177 to [~]2000 kb affecting one allele of the well characterised, gene dense, distal region of chromosome 16 (16p13.3), referred to as ATR-16 syndrome. We characterised precise deletion extent and screened for genetic background effects, telomere position effect and compensatory up regulation of hemizygous genes.\n\nResultsWe find the risk of developmental and neurological abnormalities arises from much smaller terminal chromosome 16 deletions ([~]400 kb) than previously reported. Beyond this, the severity of ATR-16 syndrome increases with deletion size, but there is no evidence that critical regions determine the developmental abnormalities associated with this disorder. Surprisingly, we find no evidence of telomere position effect or compensatory upregulation of hemizygous genes, however, genetic background effects substantially modify phenotypic abnormalities.\n\nConclusionsUsing ATR-16 as a general model of disorders caused by sporadic copy number variations, we show the degree to which individuals with contiguous gene syndromes are affected is not simply related to the number of genes deleted but also depends on their genetic background. We also show there is no critical region defining the degree of phenotypic abnormalities in ATR-16 syndrome and this has important implications for genetic counselling.

genetics↗

bioRxiv2017

ITHANET: Information and database community portal for haemoglobinopathies

Haemoglobinopathies are the commonest monogenic diseases, with millions of carriers and patients worldwide. Online resources for haemoglobinopathies are largely divided into specialised sites catering for patients, researchers and clinicians separately. However, the severity, ubiquity and surprising genetic complexity of the haemoglobinopathies call for an integrated website to serve as a free and comprehensive repository and tool for patients, scientists and health professionals alike. This paper presents the ITHANET community portal, an expanding resource for clinicians and researchers dealing with haemoglobinopathies. It integrates information on news, events, publications, clinical trials and haemoglobinopathy-related organisations and experts and, most importantly, databases of variations, epidemiology and diagnostic and clinical data. Specifically, ITHANET provides annotation for 2690 haemoglobinopathy-related variations, epidemiological data for more than 180 countries and information for more than 600 HPLC diagnostic reports. The ITHANET portal accepts and incorporates contributions to its content by local experts from any country in the world and is freely available for the public at http://www.ithanet.eu.

bioinformatics↗