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 (unpublished) 1800 mutations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 : info@mutaDATABASE.org

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