Gene variant databases

Transcription

1 Gene variant databases demands and possibilities ( LSDBs ) Johan den Dunnen

2 Human & Clinical Genetics ( Leiden University Medical Center ) CMSB Genetic Disease neuromuscular disorders diagnosis treatment / therapy exon skipping DMD Genome Technology try and apply facilitate Leiden Genome Technology Center /

3 Organisations get all variants/consequences found easily accessible standards for databases and variant description EU FP7 project Genotype to Phenotype software for webbased gene databases

4 Subjects value of databases available software gene variant databases > LOVD why share immediately (pre-publication)

5 Soon... Soon we will be able to sequence a complete human genome, but if we can not make sense out of the variants detected, as to whether they are "pathogenic or not", this information is useless, and worse misinterpretation.

6 Genome (exome) sequence 1 exome > 22,500 variants 1 genome > 3,500,000 variants what do all these variants mean??

7 An example FLNA variant c.5217g>a no amino acid change last nucleotide exon affects splicing? > no RNA available Terminal Osseous Dysplasia (TOD)

8 DNA variant identified2 reported before?! database, literature, web,... family structure consequence of change RNA, protein functional test

9 Variant, phenotype & treatment gene variant database found in severable databases focus on DNA variant and detection...phenotype description often limited details available DNA labs does not see the patient...treatment & outcome rarely available limitation? > data not added

10 Paper piles Johan vd Leij

11 ..a great help a computer a tool to help you... does anything you like... finds anything in seconds... entering data only once is sufficient

12 World UCV c.636c>a p.ser212arg c.636c>a p.ser212arg c.636c>a p.ser212arg c.636c>a p.ser212arg? c.636c>a p.ser212arg not reporting findings

13 Why share data? to help patients / their families for diagnosis / treatment based on shared findings you swore an oath to work in best interest patient share findings with your coleagues yourself collaboratives studies publications ( i.e. submit unpublished data )

14 Is there gene DB? Use the url GeneSymbol.LOVD.nl ( e.g. JAK2.lovd.nl ) and you are there! + lists at several sites

15 GeneSymbol.LOVD.nl 2 second acknowledgement

16 EPOR.lovd.nl

17 TP53.lovd.nl

18 GeneSymbol.LOVD.nl no database found...it still happens...but a DB for all disease genes exists...but many have no curator / data e.g. HIF2A

19 DNA variant DBs central databases HGMD inch deep, mile wide lists first published report > no frequencies pathogenic only ( most ) OMIM list firsts report(s) & some interesting cases dbsnp all variants ( originally esp. non pathogenic ) literature all publications internet search gene variant databases all details per gene inch wide, mile deep all variants unpublished data from direct submission

20 Variant databases3 germline variants, not somatic variants HGMD impressive list nearly all phenotype related variants some exceptions, e.g. splicing >+2 / -2 from publications only data partly public HGVS description not used A hit means "pathogenic"...but not complete

21 Somatic variants

22 Variant databases4 gene-centered databases (LSDBs) impressive list of variants not yet curated for all genes all variants from publications AND direct submissions active curator searching, asking,... phenotype data often limited HGVS description used data in many formats, variable quality, standards A hit means data on consequences for function are available

23 General DB <> LSDB2

24 LSDB software platforms LOVD Leiden Open Variation Database free, open source, HGVS standards UMD Universal Mutation Database free, closed source, open standards MutBase open source, open standards bioinf.uta.fi/mutbase MutaDATABASE under development

25 LOVD hosting free software open source, PHP / MySQL internet-based LSDB ~100 installations world-wide >20,000 genes LOVD offer free server & space free installation & help incl. private installation incl. back-ups & software updates free of charge through

26 LOVD structure LOVD installation manager 1 manager 2 gene 1 gene 2 curator 1 curator 2 curator 3 curator 4 gene 3 gene 7 gene 4 gene 6 submitter 6 submitter 1 gene 5 submitter 5 submitter 2 submitter 4 submitter 3

27 LOVD connections.nl contact through central site LSDB list webservice (exome queries)

28 LOVD access visitor levels submitter curator DB manager LOVD 3 - collaborator

29 LOVD access levels website visitor WWW-pages and DB-queries submitters register, login, submit, update collaborator(s) access through submitter login, specific LSDBs, view curator(s) access through manager login, specific LSDBs, curate & edit manager(s) access through system operator login, creates genes, new columns, curators DB management LOVD administrator installs LOVD, overall DB management not all data can be seen by everybody

30 Security as weak as users hacking attempted, it will succeed once LOVD features login / password simple passwords not accepted login locked after 3 failed attempts from specified IP-address only optional SSL encryption ( ) any data entry requires password serious threat? who is interested what data can be obtained? private hospital installation at Leiden server

31 LOVD home Ivo Fokkema

32 LOVD to genome2 CAPN3 compact view UCSC >> all variants per gene

33 Your submissions ( link on your institute's homepage )

34 LOVD mutcheck

35 module Mutalyzer combination of alleles stored

36 LOVD features store all data, incl. negative findings

37 LOVD features one patient > variants in 3 genes

38 LOVD data growthp public ( www ) data are public or not-public per data field (curators decide)

39 LOVD data growtha all data

40 link to files - internet LOVD data growth - local growth curve saves privacy + shows data are available

41 Little clinical data not a database limitation data not available / not shared submission takes too much time consent of patient...

42 Non-public MUTYH

43 Non-public data non-public data are useful, without showing, they can be queried! result = number of records NOT the records themselves e.g. DMD protein data / no DMD stain > 123 / 127 records allows to query for new combinations then contact curators > permission + publish

44 From LOVD to... dbsnp collaboration reward for submitter standard exchange button activated by curator nanopublication new universal publication format incl. full accreditation (name submitter)

45 Variant unknown effect c.636c>t / r.(?) / p.(=) what to do? option 1 What is more effective? "reward?" minimal reporting option 2

46 reporting World new variants already known only... reporting all variants only...

47 Why not share findings advantages?? ( already pre-publication ) I want to publish my findings...will you ever find time? database submission harms publication...hgvs price for first rejection never collected

48 Why share immediately advantages you are the first to publish a colleague/competitor finds your data to publish they have to cite your work ( already pre-publication ) a colleague/competitor finds your data they contact you and you become a co-author a colleague working in another field finds your data they contact you and you become a co-author

49 Why share findings necessary help the patients database essential for best diagnostics help ourselves saves time, stop literature searches help our colleagues they have similar problems free QC through submission check against error-free list publication records curated submission is checked description, consequences all changes are informative frequency, Variant of Unknown Significance (VUS) gives contact to colleague

50 Rewards?! 100% guarantee: no submission = no credits feeling good helped patients and colleagues many thank you's, positive PR, free electronic recording link from institute website to LSDB proof of performance others have to refer to you to your data in publications the web is faster then paper others will help you contact to discuss and solve problem Variants Unknown Significance (VUS)

51 Follow the recommendations when you disagree, start a debate - do not use private rules, this only causes confusion

52 ..this community HIF2A > EPAS1 JAK2V617F NM_ (JAK2):c.1849G>T r.(?) / p.(val617phe)...or c.1848_1849delinsct

53 An opportunity establish database pull all data together contact colleagues world-wide give 2 weeks to share their data add all data to database write paper e.g. for Human Mutation

54 Urgent request back home submit ALL variants ( immediately ) or send us your file as start of new LSDB

55 Become a curator looks great on your CV...be quick! 22,000 genes for 7,000,000,000 people chance only 1 / 300,000 check LSDB list curator vacancy