mutadatabase
DESCRIPTION
A slide presentation of MutaDATABASE which can be found on http://www.mutadatabase.orgTRANSCRIPT
The MutaDATABASE project
Wim Van Criekinge, BIOBIX, Univ Ghent, Belgium
Sherri Bale, GENEDX, Gaithersburg, USA
Frederik Decouttere, GENOHM, Ghent, Belgium
Heidi Rehm, PhD, Harvard Medical Schoool, Boston, USA
Bob Nussbaum, Dept Human Genetics, UCSF, USA
Johan Den Dunnen, Leiden University, the Netherlands
Patrick Willems, GENDIA, Antwerp, Belgium
The Problem
Novel mutations are not being made public through publication or database entry
Many remain unclassified variants which is a challenge for genetic counseling
The problem is being PCR-amplified
Genetic testing is moving towards testing of whole populations
for multifactorial disease (common and rare variants)
Genetic testing is moving towards testing of whole exomes/genomes
on next generation sequencing platforms
Next Generation SequencingNext generation sequencing panels Nr genesCATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA (CPVT) 2
BRUGADA SYNDROME 5
ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY (ARVC) 7
AUTOSOMAL RECESSIVE AND SPORADIC RETINITIS PIGMENTOSA 7
FAMILIAL HYPERCHOLESTEROLEMIA 7
NOONAN, LEOPARD, COSTELLO AND CARDIOFACIOCUTANEOUS SYNDROME 8
LONG QT SYNDROME 10
MUSCULAR DYSTROPHY 12
PARKINSON 14
HYPERTROPHIC CARDIOMIOPATHY (HCM) 17
DEMENTIA 18
USHER SYNDROME AND NON-SYNDROMIC DEAFNESS 19
DILATED CARDIOMIOPATHY (DCM) 23
FAMILIAL ARRHYTHMIA 24
CONGENITAL DISORDERS OF GLYCOSYLATION (CDG) 24
EPILEPSIA 55
FAMILIAL CARDIOMYOPATHY 57
X-LINKED MENTAL RETARDATION 93
RETINAL PATHOLOGY 160
WHOLE EXOME 23.000
Mutation Databases
Database Genes Centralised Standardised Mutations Free
HGVS 600 - ?Few
+
LOVD 895 - + 163.061 +
MutDB < 1000 + + ?
Few
+
UMD < 50 + + ?
Few
+
HGMD 3611 + + 96.631 -
DMuDB 83 + + 12.000 +
TOTAL 3611 < 200.000
Nothing new under the sun ?
Deafness : 50 genes (apart from GJB2)
• In total literature + databases : 230 mutations
• 1 single lab : > (unpublished) 1800 mutations
Input mutations into public domain
Input mutations into public domain
HCM Gene MutaDATABASELab 1 (Harvard)
HGVS DATABASE
ACTC 36 9
MYBPC3 463 180
MYH7 480 236
TNNI3 85 41
TNNT2 108 43
TPM1 68 14
MYL2 44 10
MYL3 21 5
TOTAL 1305 538
BRCA1/2 : +/- 17.000 bp coding sequence
3.500 variations
Total genome : +/- 34.000.000 bp coding sequence
7.000.000 variations
Estimated number of mutations
Estimation is that less than 10 % mutations is in public domain
Research labs : Many mutations in the past
Few mutations over the last years
Diagnostic labs: Europe : moderate number
USA : few mutations
Input mutations into public domain
TOO DIFFICULT
TOO TIME CONSUMING
NO EASY GATEWAY
Why do we not put mutations into the public domain ?
Where do we go fishing for mutations ?
GENEDXLABCORPCORRELAGENATHENA DIAGNOSTICSGENZYMEQUESTARUPMAYOHOUSTONEMORYDUARTECHICAGOGREENWOODBOSTON
MYRIAD ??
Input mutations into public domain
by US labs
MutaDATABASE
An international project to get standardized gene
mutation databases on a central database platform
(MutaDATABASE)
– by converting existing gene databases to a standardized format
– by addition of new gene databases
Website MutaDATABASE
Gene curators MutaCURATORS
Mutation collectors MutaADMINISTRATORS
Clinical info MutaCLINICIANS
Software MutaREPORTER
Lab circles MutaCIRCLES
Journal MutaREVIEWS
Entities
MutaREVIEWS
MutaCURATORS
PUBLIC
MutaCIRCLES
MutaDATABASE
MutaCLINICIANS
MutaADMINISTRATORS
MutaDATABASE
collects all human gene variations related to monogenetic disease
into a database which is :
• centralized (server University Ghent)
• standardized • freely available• open access• freely exportable to other databases
MutaDATABASE
1. Provides general information on human disease genes
2. Provides overviews of all mutations in these genes
3. Provides overviews of diseases associated with these genes
3. Provides tables of :• cDNA sequence • Amino acid sequence • Exon-intron sequences• Disease mutations
4. Provides figures of :• Cytogenetic localization• Physical map • Genomic structure• Mutations listed as observations in single patients together with clinical info
5. Allows easy submission of molecular and clinical info
MutaDATABASE - LOVD
MutaDATABASE and LOVD
are collaborating
through Johan Den Dunnen
MutaCURATORS
• Control gene databases in MutaDATABASE
• Review all info submitted to MutaDATABASE
• Supervise MutaCIRCLES
• Write gene reviews for MutaREVIEWS
MutaADMINISTRATORS
• Travel to large test labs to put info into MutaDATABASE
• Contact small test labs to put info into MutaDATABASE
• Teach labs how to put information into MutaDATABASE
MutaCIRCLES
• Labs that work on the same gene form a gene circle
• The exchanged info is available on the website
• Questions automatically go to all members of the circle
• The lab circles joinedly write the gene reviews for the Journal
• The lab circles joinedly write the gene reviews for the Website
Lab 1 Lab 2
Lab 3 Lab 4
MutaCIRCLES
MutaCIRCLES
MutaCIRCLES
DISEASE HCM Long QT Arrhyth Noonan Aorta MODY MR Usher Colon Deaf
GENES 7 10 10 9 6 6 10 9 6 10
GeneDx X X X X -- x x x - --
Partners X X X X x -- X -- x
Correlagen X x X X x x -- -- -- --
Athena -- -- -- X -- x -- -- -- x
Arup -- -- -- x x -- -- -- x x
Emory -- -- -- x -- -- x -- x x
Duarte -- -- -- -- x -- x -- x --
INSIGHT -- --- -- -- -- -- -- -- X --
MutaREVIEWS
• Online journal, no hard copy
• Free access
• Only gene reviews, 300 genes per year
• Within 5 years most important genes (1500) are covered
• All papers have the same lay out
• MutaCURATORS coordinate
• Every year all reviews are updated
MutaREPORTER
MutaREPORTER
• Is software interface between lab sequencers and website
• Imports patient’s gene sequence into database
• Picks up gene variations
• Generates the correct nomenclature for the variation
• Qualifies variations into known or novel
• Uses software prediction programs to estimate pathogenicity of novel mutations
• Generates a report for the variation with known or predicted functional significance, gene figure with mutation location, surrounding
sequence, references
• Submits novel variations to gene master that evaluates before entering variation into database
MutaREPORTER
MutaREPORTER
•Access to all info in MutaDATABASE
•A genome browser with track-based sequence views
•A variation checker for HGVS nomenclature
•Facilitated access to prediction tools (Splice site, SIFT, POLYPHEN)
•Possibility to automatically import variants from in-house databases
•Possibility to submit variants into MutaDATABASE
•Possibility to communicate with other genetic labs (MutaCIRCLES)
MutaREPORTER key principles
Facilitates data input of variants with a few keystrokes
Visualizes all variant related information in 1
comprehensive, dynamic view
Includes gene analyses & qualification tools
Operates seamless across MutaDATABASE projects and participants
MutaREPORTER
• Assembly aware storage, reference database independent
(Ensembl / Genbank)
meaning variants will be named according to user preference
• Submits novel variations to MutaCURATORS
who evaluates before accepting variation into MutaDATABASE
• Generates the correct nomenclature for the variation
(HGVS, BIG, …)
Offered as a “Software as a Service” or SaaS Centrally managed on mutareporter servers, configured
on a high-availability linux cluster Fine-grained security model: public – curator – circle – lab Client requirement: every web browser with flash support built with java and flex (adobe) technologies Supports simultaneous login & real-time variant updates
within 1 lab and/or MutaCIRCLE: easy collaboration amongst your colleagues
Open data access (nightly database exports) Import/export functions for other popular databases like
LOVD, …
MutaREPORTER Technical background
MutaREPORTER Final goal
• Recording variants directly from sequencer
• Interpretation variants using algorithm
• Ranking variants in order of importance
• Issuying result report
• Input info into MutaDATABASE
Early Adopter program (EAP)
• Early Adopter program (EAP) for MutaREPORTER
• Proof-of-principle for MutaREPORTER, MutaCIRCLES and MutaDATABASE
• This will also facilitate grant applications to NIH and EU/EBI
• The EAP program could be presented to +/- 10 labs for +/- 10 heterogenic diseases for +/- 50 genes
• The choice of labs and genes-diseases is based upon the amount of variants expected (Large US labs, labs doing next generation sequencing)
MutaCURATORS
Patients
MutaDATABASE
CliniciansLabs
MutaREPORTER
Input Mutation information
MutaADMINISTRATORS
Charter The MutaDATABASE Charter on Intellectual Property
Pertaining to DNA Variants and the Information Embedded Therein
We, the undersigned participants in and supporters of the MutaDATABASE, take the position that variants in human DNA are the ultimate open-source resource: they should be freely available for scientists to study, clinicians to test, and patients (and everyone) to derive health and/or other benefits from. Our view is that human DNA and human DNA information are res publicae [1]. As such, there can be no abiding claims on these data, not by clinical testing laboratories, research laboratories, universities, commercial sequencing and/or genomic interpretation enterprises, gene curators, informaticians, insurers, the state, multinational governance organizations, database proprietors, or persons from whom these data are derived. Maximization of benefits from genomic variant data will require successful interactions among all of these entities with as few barriers in place as possible. Accordingly, MutaDATABASE will be completely "Open Access." There will be no restrictions and no usage fees. Each participating laboratory and investigator agrees to these terms and agrees to place no strings whatsoever on any data they deposit into MutaDATABASE. Variants in MutaDATABASE are governed by a Creative Commons CC0 license [2]. Specifically, MutaDATABASE depositors waive all copyrights, intellectual property rights, and related or neighboring rights, such as their moral rights (to the extent waivable), their publicity or privacy rights, rights they have protecting against unfair competition, and database rights and rights protecting the extraction, dissemination and reuse of any and all data deposited into MutaDATABASE.
1. Ossorio, P.N., The human genome as common heritage: Common sense or legal nonsense? J Law Med Ethics, 2007. 35 (3): 425-439.2. http://creativecommons.org/choose/zero/
Charter
DNA variants are public property
TOO DIFFICULT
TOO TIME CONSUMING
NO EASY GATEWAY
Why do we not put clinical info into the public domain ?
PHENEXPLORER
Patients
MutaDATABASE
Clinicians Labs
Input Clinical information
Real - time genotype - phenotype correlation
Mutation X in L1CAM
Observation Lab Dr Patient Features using Phenexplorer
Hydrocephalus Macrocephaly Paraparesis
1 A X 098765 + - +
2 B Y 012387 - - +
3 C X 945628 + + -
4 A Z 126784 + + +
5 C T 453986 + - -
TOTAL 80 % 40 % 60 %
MutaCLINICIANS
• Review all clinical info submitted
• Contact clinicians
• Contact patient groups
• Make phenotype-genotype correlations
MutaCLINICIANS
• Group of supervising dysmorphologists :
Raoul Hennekam, Les Biesecker, Peter Robinson, Ada Hamosh, Patrick Willems
• Phenotype ontology (Clinical coding features) is integrating:
– Elements of Morphology (http://research.nhgri.nih.gov/morphology/index.cgi)
– London Dysmorphology database (LDDB)
– HPO - Human Phenotype Ontology (Phenexplorer)
• MutaDATABASE uses Phenexplorer for input of clinical info
Input clinical info
Listing mutations as “OBSERVATIONS” will allow to :
– Determine the frequency of mutations
– Add clinical features from each individual patient
– Refer the diagnosing lab and clinician
– Automatically extract frequency of features for each mutation
MutaDATABASE
Clinical info
Input information
Molecular info
PHENEXPLORER
MutaREPORTER
Labs through MutaDATABASEMutaREPORTER
MutaCURATORS through MutaREPORTER
MutaADMINISTRATORS through MutaREPORTER
MutaCLINICIANS through MutaREPORTER
Clinicians through MutaDATABASE
Patients through MutaDATABASE
Input mutations
MutaREVIEWS
MutaCURATORS
PUBLIC
MutaCIRCLES
MutaDATABASE
MutaCLINICIANS
MutaADMINISTRATORS
Principal Investigators
1. Wim Van Criekinge, PhD University of Ghent, Belgium
2. Sherri Bale, PhD GENEDX, Gaithersburg, USA
3. Frederik Decouttere, PhD GENOHM, Ghent, Belgium
4. Heidi Rehm, PhD Harvard Medical Schoool, Boston, USA
5. Bob Nussbaum, MD UCSF, USA
6. Johan Den Dunnen, PhD Leiden University, The Netherlands
7. Patrick Willems, MD, PhD GENDIA, Antwerp, Belgium
Funding
Short term : GHENT University
GENEDX
GENDIA
Long term : NIH ?
Contact
Address : MutaDATABASE BIOBIX Dept of Molecular Biotechnology
University of Ghent Coupure Links 653 9000 Ghent, Belgium
Phone : + 32 495250382
Email : [email protected]
Website : www.mutaDATABASE.index.php
www.mutaDATABASE.org (june)
Advisory Board• Abbaszadegan Iran (Mashhad)
• Algazali Lihadh UAE (Al Ain city)
• Angrist Misha USA (Durham)
• Auerbach Marleen USA (New York)
• Antonarakis Stylianos Switzerland (Geneve)
• Bale Sherri USA (Gaithersburg)
• Batish Sat Dev USA (Worcester)
• Baumgart Karl Australia (Sidney)
• Beales Philip UK (London)
• Beaudet Art USA (Houston)
• Biesecker Leslie USA (NIH)
• Brais Bernard Canada (Montreal)
• Braverman Nancy Canada (Montreal)
• Brice Alexis France (Paris)
• Brody Lawrence USA (Bethesda)
• Burn John UK (Newcastle)
• Byers Peter USA (Seattle)
• Carson Nancy Canada (Ottawa)
• Chakravarti Aravinda USA (Baltimore)
• Chelly Jamel France (Paris)
• Church George USA (Boston)
• Corey Braastad USA (Worcester)
• Cutting Garry USA (Baltimore)
• Dallapicolla Bruno Italy (Rome)
• Das Soma USA (Chicago)
• De La Chapelle Albert USA (Columbus)
• Decouttere Frederik Belgium (Ghent)
• Eng Charis USA (Cleveland)
• Fiorentino Francesco Italy (Rome)
• Friez Michael USA (Greenwood)
• Garcia-Planells Javier Spain (Valencia)
• Gecz Jozef Australia (Adelaide)
• Grosfeld Frank The Netherlands (Rotterdam)
• Hahn Sihoun USA (Seattle)
• Hamosh Ada USA (OMIM)
• Hegde Mathuri USA (Atlanta)
• Hennekam Raoul The Netherlands (Amsterdam)
• Heinz Gabriel Germany (Osnabrueck)
• Holinski Elke Germany (Munchen)
• Kaluzewski Bogdan (Poland) Lodz
• Kimberling Bill USA (Iowa City)
• Klinger Katherine USA (Cambridge)
• Kohlhase Juergen Germany ( Freiburg)
• Lane Birgit Singapore
• Lennon Greg USA (Potomac)
• Levett Lisa UK (London)
• Lyon Elaine USA (Salt Lake City)
• Matsubara Yoichi Japan (Sendai)
• Melegh Bela Hungary (Pecz)• Milunski Jeff USA (Boston)
• Ming Qi China (Bejing)
• Mortier Geert Belgium (Antwerp)
• Morton Cynthia USA (Boston)
• Mukerji Mitali India (Delhi)
• Mundlos Stefan Germany (Berlin)
• Nelson Tanya Canada (Vancouver)
• Nussbaum Bob USA (San Francisco)
• Ostrer Harry USA (New York)
• Pena Sergio Brasil (Belo Horizonte)
• Petersen Michael Greece (Athens)
• Pratt Vicky USA (Chantilly)
• Preising Marcus Germany (Giessen)
• Rehm Heidi USA (Cambridge)
• Restrepo Carlos Colombia (Bogota)
• Richards Sue USA (Portland)
• Rogaev Evgeny Russia (Moscow)
• Rouleau Guy Canada (Quebec)
• Saldivar Sebastian USA (Duarte)
• Scott Patrick Canada (Edmonton)
• Shaffer Lisa USA (Spokane)
• Sunyaev Shamil USA (Boston)
• Tadmouri Ghazi UAE (Dubai)
• Tavares Purita Portugal (Porto)
• Tsuji Lap-Chee China (Hongkong)
• Van Criekinge Wim Belgium (Ghent)
• Van de Spek Peter Netherlands (Rotterdam)
• Warren Steve USA (Atlanta)
• Waterham Hans (The Netherlands (Amsterdam)
• Willems Patrick Belgium (Antwerp)
DO NOT LITTER