Bioinformatics & Genetics Team

Universal Mutation Database

A generic software to create locus-specific databases (LSDBs)

The UMD software includes an optimized structure to assist and secure data entry and to allow the input of a wide range of clinical data. In addition various analyzing tools have been specifically designed to assist clinicians (phenotype-genotype correlations...), geneticists (distribution and frequency of mutations...) and research biologists (structural domains, molecular epidemiology...). Thanks to the flexible structure of the UMD software, it has been successfully adapted to many genes either involved in cancer (APC, BRCA1, BRCA2, TP53, RB1, MEN1, SUR1, VHL, WT1...) or in genetic diseases (FBN1, LDLR, DMD, VLCAD, MCAD, LMNA, EMD, FKRP, SGCG, SGCA, ATP7B...). This tool is freely available. To download the software please visit the download policy webpage.

• Publication: Béroud C, Collod-Béroud G, Boileau C, Soussi T, Junien C. UMD (Universal mutation database): a generic software to build and analyze locus-specific databases. Hum Mutat. 2000;15(1):86-94. doi: 10.1002/(SICI)1098-1004(200001)15:1<86::AID-HUMU16>3.0.CO;2-4

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Human Splicing Finder

The reference system for splicing analysis

With the completion of the Human Genome Project our vision of human genetic diseases has changed. Thousands of mutations are identified in diagnostic and research laboratories yearly. The knowledge of these mutations associated with clinical and biological data is essential for clinicians, geneticists and researchers. In order to better understand intronic and exonic mutations leading to splicing defects, we decided to create the Human Splicing Finder website. This tool is aimed to help studying the pre-mRNA splicing more about splicing background.
To calculate the consensus values of potential splice sites and search for branch points, new algorithms were developed. Furthermore, we have integrated all available matrices to identify exonic and intronic motifs, as well as new matrices to identify hnRNP A1, Tra2-β and 9G8. We hope that this tool will be useful for your research. In order to improve it, please send us comments and new matrices to identify specific sequences involved in splicing.

• Publication: Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 2009 May;37(9):e67. doi: 10.1093/nar/gkp215

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UMD-Predictor

A mutation pathogenicity prediction system

With the development of Next Generation Sequencing technologies, the amount of data generated has reached an unprecedent level. Approximately half of gene lesions responsible for human inherited diseases are due to an amino acid substitution. Distinguishing neutral sequence variations from those responsible for the phenotype is of major interest in human genetics. To further differentiate neutral variants from pathogenic nucleotide substitutions, we developed a new tool, UMD-Predictor. This tool provides a combinatorial approach, to identify potential pathogenic variations, that associates the following data: localization within the protein, conservation, biochemical properties of the mutant and wild-type residues, and the potential impact of the variation on mRNA.

• Publication: Salgado D, Desvignes JP, Rai G, Blanchard A, Miltgen M, Pinard A, Lévy N, Collod-Béroud G, Béroud C. UMD-Predictor: a High Throughput Sequencing Compliant System for Pathogenicity Prediction of any Human cDNA Substitution. Human Mutat. 2016 May;37(5):439-46. doi: 10.1002/humu.22965

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VarAFT

The Variant Annotation and Filtration Tool

The identification of disease-causing mutations in human genetics remains challenging despite the NGS revolution as up to 70% of cases are still unsolved. To tackle this challenge, we developed the VarAFT software to improve annotation and filtration steps.
VarAFT provides experiments’ quality, annotates, and allows the filtration of VCF files. Data from multiple samples may be combined to address different Mendelian Inherited Disorders, Population Genetics or Cancers. It contains unique features including data from OMIM, HPO, Gene Ontology, pathways and predictions from UMD-Predictor and Human Splicing Finder in addition to classical annotations from dbNSFP that can be combined to optimally select candidate pathogenic mutations.
VarAFT is a standalone and multiplatform (Windows, Mac, Unix) system which is easy to install and easy to use. It does not require skills in informatics or a powerful computer.
VarAFT is developed by the Genetics and Bioinformatics team at INSERM UMRS_910 in the Medical School of la Timone Aix-Marseille University in Marseille, France. The VarAFT system is freely available to non-commercial users.

• Publication: Desvignes JP, Bartoli M, Delague V, Krahn M, Miltgen M, Béroud C, Salgado D. VarAFT: a variant annotation and filtration system for human next generation sequencing data. Nucleic Acids Res. 2018 Jul 2;46(W1):W545-W553. doi: 10.1093/nar/gky471

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BANCCO

The French database of constitutionnal CNVs

The Freanch database of constitutionnal CNVs is developed to collect CNV from diagnostic area. This database collects phenotypic and genotypic data for each patient to aim to facilitate the interpretation of CNV data.

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RDVD

The French Rare Disease Variants Database

The Freanch Rare Disease Variants Database is developed to collect SNV/Indels from NGS. This database collects phenotypic and genotypic data for each patient to aim to facilitate the interpretation of SNP and Indels data. RDVD is linked with BANCCO.

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Skip-E

Exon skipping builder system

Skip-E, is a bioinformatics system built to assist researchers in selecting the best region of interest to design Antisense Oligonucleotide (AON) to induce exon skipping. It can be used to restore a functional protein or silence a gene. AON & ASO have been used as research tools in the post-genome era, as well as new types of therapeutic agents.
For better sharing of the experimented and published efficient or inifficient AON, literature reports are regularly screened, collected and stored. Till now, approximately 350 AON & ASO targeting 90 mRNAs/gene/exon are contained in the AonDBase. Users can check whether their AON & ASO have already been reported. To add an AON/ASO, please send us information to enrich the database.

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Crawfish

Exon trans-splicing builder system.

One sees that in all these cases, intervention by genetic engineering to modify a given transcript in the target cell population could be beneficial. This is what proposes the technology of spliceosome‐mediated RNA trans‐splicing by diverting the spliceosome machinery to modify part of the exons of an endogenous transcript, using an artificial RNA brought by gene transfer into the cells to be corrected. Since finding effective target sites within RNA is a hard work for binding domains design, various experimental methods and computational approaches have been proposed.
CRAWFISH, is a bioinformatics system built to assist researchers in selecting the best region of interest to design sequences to induce the exon trans‐splicing. It can be used to restore functional proteine or silence a gene/transcript.

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Registries

French National Registry for patients with FSHD

The French FSHD Registry aims to gather information on as many patients living in France as possible with the same disease. It consists in collecting data from these patients, without changing their usual care, and without imposing additional examinations.
These data are genetic (accurate description of the variations of the gene responsible for the disease) and clinical (description of the disease and its consequences on muscles, heart, lungs...). They come from self-reports and/or clinical evaluation questionnaires filled in with the physician during consultations.

• Publication: Guien C, Blandin G, Lahaut P, Sanson B, Nehal K, Rabarimeriarijaona S, Bernard R, Lévy N, Sacconi S, Béroud C. The French National Registry of patients with Facioscapulohumeral muscular dystrophy. Orphanet J Rare Dis. 2018 Dec 4;13(1):218. doi: 10.1186/s13023-018-0960-x
• Publication: Sanson B, Stalens C, Guien C, Villa L, Eng C, Rabarimeriarijaona S, Bernard R, Cintas P, Solé G, Tiffreau V, Echaniz-Laguna A, Magot A, Juntas Morales R, Boyer FC, Nadaj-Pakleza A, Jacquin-Piques A, Béroud C, Sacconi S; French FSHD registry collaboration group. Convergence of patient- and physician-reported outcomes in the French National Registry of Facioscapulohumeral Dystrophy. Orphanet J Rare Dis. 2022 Mar 2;17(1):96. doi: 10.1186/s13023-021-01793-6

Network on Marfan syndrome and non syndromic overlapping diseases

The aim of our project is to link functional genomics to pathophysiology of aneurysms and dissections of the human thoracic ascending aorta (TAAD) whatever their aetiology, genetic and non-genetic, through final common pathways involving common risk factors of dissection, epigenetic model of SMC expression regulation, SMC disappearance and involvement of tissue proteolysis. As compared to current studies, mainly focused on monogenic forms (13) and on a possible direct relationship between gene mutations and TAAD phenotype, the originality and novelty of our project is its translational genomic approach from highly morbid pathologies to molecular effectors, possible targets for potential new diagnostic and therapeutic tools.

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SoVaD

Somatic Variant Database

This is a database of somatic variants of unknown significance (VUS) identified by targeted NGS. Its purpose is to share annotations made at the local level nationwide and thus contribute to improving their classification.

• Publication: Koeppel F, Muller E, Harlé A, Guien C, Sujobert P, Trabelsi Grati O, Kosmider O, Miguet L, Mauvieux L, Cayre A, Salgado D, Preudhomme C, Karayan-Tapon L, Tachon G, Coulet F, Lespagnol A, Béroud C, Leroy K, Rouleau E, Soubeyran I. Standardisation of pathogenicity classification for somatic alterations in solid tumours and haematologic malignancies. Eur J Cancer. 2021 Dec;159:1-15. doi: 10.1016/j.ejca.2021.08.047

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Dolphin

DOmain Logo Protein for Human INformation

One of the most challenging ACMG-AMP guidelines evidence is the PM1, used in about 10% of cases, while the most widely used is the PM2/BS1 reported in 50% of cases. To revisit the PM1 and enrich the BS1 criteria to allow a better classification of human missense variations through protein domains’ information, we built the DOLPHIN system. Using ClinVar data, we showed that DOLPHIN accurately identifies key domain residues without relying on neighboring benign variations, thus revisiting the PM1 evidence. Concomitantly, we demonstrated that DOLPHIN provides a frequency for 32.6% of mutations located in protein domains vs. 7.8% by gnomAD, thus strongly enriching BS1 evidence as illustrated by the 570,498 mutations having a DOLPHIN frequency >1% and not reported in gnomAD. These elements allow an easier classification of amino acid substitutions localized in protein domains that account for almost 40.2% of proteins and where most pathogenic mutations are located.

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BioKnExt

Biological Knowledge Extractor

Following-up the scientific literature is a time-consuming task accentuated by the considerable increase of available data. Currently, Locus Specific Databases (LSDB) are mainly manually curated and play a crucial role in the interpretation of variants. However, the transition to Next Generation Sequencing requires the creation of thousands of them, which is difficult to do manually. Thus, text mining and automation of information extraction became a key element of the biocuration process. We developed BioKnExt, a Biological Knowledge Extractor. It combines different approaches to identify and automatically extract genes and associated variations from the literature. With a Marfan use case of 550 articles, we demonstrated that it has an excellent efficiency with an average F1 score of 0.934 to retrieve the 3,645 variations from the FBN1, MYH11, ACTA2, MYLK and SMAD3 genes. We believe that the BioKnExt system can efficiently assist humans in most parts of the biocuration process to update reference databases and extract variations from the literature.

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