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ProjectDeliverable
Projectacronym:SOUND GAnumber:633974
Projecttitle:StatisticalMulti-OmicsUnderstandingofPatientData
FundingScheme:CollaborativeProject(H2020-PHC-2014-2015/H2020-PHC-2014-two-stage)Health,novelmedicaldevelopments
Projectstartdate:01September2015 Duration:36months
Project'scoordinator:DrWolfgangHuber(EuropeanMolecularBiologyLaboratory,Heidelberg)
D11.2DatabaseofsolvedcasesDuedateofdeliverable:Month18-28.02.2017Actualsubmissiondate:23.02.2017Organizationnameofleadcontractorforthisdeliverable:TechnischeUniversitätMünchen(TUM-MED)Organizationnameofotherinvolvedpartners:TUMPersonnelinvolved:HolgerProkisch,RobertKopajtich,JulienGagneurandChristianMertes
Projectco-fundedbytheEuropeanCommissionwithintheH2020Program(2015-2018)
DisseminationLevel
PU Public
PP Restrictedtootherprogramparticipants(includingtheCommissionServices)
RE Restrictedtoagroupspecifiedbytheconsortium(includingtheCommissionServices)
CO Confidential,onlyformembersoftheconsortium(includingtheCommissionServices) x
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ResearchProgress
We established a database of genome-wide genotypes (from exome sequencing) of solved and
unsolved patients with suspected mitochondrial disorder suitable for automated benchmarking
(figure1).ThedatabaseisestablishedatTUM-MEDandsharedwithTUM.Usingamachine-learning
algorithm to prioritize potential disease-causing mutations according to variant frequency and
functional gene annotation within Task 3.1,MDH2was ranked as themost likely disease-causing
geneinasofarunsolvedpatient.WithinTask7.1,thepathogenicityofallvariantswasvalidatedin
patient cell lines and a yeast model (Ait-El-Mkadem et al., AJHG 2017). Currently, the database
includes678patientswithgenotypes(n=336solved)including100cases,whichhaveadditionalRNA-
seq data attached (n=57 solved). The combined genotype and RNA-seq data of solved cases have
been used for benchmarking of an expression outlier detection approach developed in Task 3.1
(Kremeretal.,2017).
Figure1:MITOMAPagenotypedatabaseformitochondrialdiseases.ItcontainsallbiosampleIDsforapatientwithsomeadditionalbiochemicalinformation.Fordiagnosedpatientstheknowncausalvariantisintegrated.
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References
References1to4weresubmittedasannexofthetechnicalreport7.1(Technicalreportonnewdiseaseentitiesthatwereidentifiedusingnovelstatisticalmethods).
1. Kopajtich R, Murayama K, Janecke AR, Haack TB, Breuer M, Knisely AS, Harting I, Ohashi T,
Okazaki Y, Watanabe D, Tokuzawa Y, Kotzaeridou U, Kölker S, Sauer S, Carl M, Straub S,EntenmannA,GizewskiE,FeichtingerRG,MayrJA,LacknerK,StromTM,MeitingerT,MüllerT,Ohtake A, Hoffmann GF, Prokisch H, Staufner C. Biallelic IARS Mutations Cause GrowthRetardation with Prenatal Onset, Intellectual Disability, Muscular Hypotonia, and InfantileHepatopathy. Am J Hum Genet. 2016 Aug 4;99(2):414-22. doi: 10.1016/j.ajhg.2016.05.027.PubMedPMID:27426735;PubMedCentralPMCID:PMC4974065.
2. FloydBJ,WilkersonEM,VelingMT,MinogueCE,XiaC,BeebeET,WrobelRL,ChoH,KremerLS,
AlstonCL,GromekKA,DolanBK,UlbrichA,StefelyJA,BohlSL,WernerKM,JochemA,WestphallMS, Rensvold JW, Taylor RW,Prokisch H, Kim JJ, Coon JJ, Pagliarini DJ.Mitochondrial ProteinInteraction Mapping Identifies Regulators of Respiratory Chain Function. Mol Cell. 2016 Aug18;63(4):621-32.doi:10.1016/j.molcel.2016.06.033.PubMedPMID:27499296;PubMedCentralPMCID:PMC4992456.
3. VanHauteL,DietmannS,KremerL,HussainS,PearceSF,PowellCA,RorbachJ,LantaffR,BlancoS,SauerS,KotzaeridouU,HoffmannGF,MemariY,Kolb-KokocinskiA,DurbinR,MayrJA,FryeM,ProkischH,MinczukM.Deficientmethylationandformylationofmt-tRNA(Met)wobblecytosinein a patient carrying mutations in NSUN3. Nat Commun. 2016 Jun 30;7:12039. doi:10.1038/ncomms12039.PubMedPMID:27356879;PubMedCentralPMCID:PMC4931328.
4. Ait-El-MkademS,Dayem-QuereM,GusicM,ChaussenotA,BannwarthS,FrançoisB,GeninEC,FragakiK,Volker-TouwCL,VasnierC,SerreV,vanGassenKL,LespinasseF,RichterS,EisenhoferG,RouzierC,Mochel F,De Saint-MartinA,AbiWardeMT,de Sain-vanderVeldeMG, Jans JJ,Amiel J,AvsecZ,MertesC,HaackTB,StromT,MeitingerT,BonnenPE,TaylorRW,Gagneur J,vanHasseltPM,RötigA,DelahoddeA,ProkischH,FuchsSA,Paquis-FlucklingerV.MutationsinMDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy. Am J HumGenet.2017Jan5;100(1):151-159.doi:10.1016/j.ajhg.2016.11.014.PubMedPMID:27989324.
5. LauraSKremer,DanielMBader,ChristianMertes,RobertKopajtich,GarwinPichler,ArcangelaIuso, TobiasBHaack, ElisabethGraf, Thomas Schwarzmayr, Caterina Terrile, EliskaKonafikova,Birgit Repp, Gabi Kastenmüller, Jerzy Adamski, Peter Lichtner, Christoph Leonhardt, BenoitFunalot, Alice Donati, Valeria Tiranti, Anne Lombes, Claude Jardel, Dieter Gläser, Robert WTaylor,DanieleGhezzi,JohannesAMayr,AgnesRötig,PeterFreisinger,FelixDistelmaier,TimMStrom, Thomas Meitinger, Julien Gagneur, Holger Prokisch, Genetic diagnosis of MendeliandisordersviaRNAsequencing,bioRxiv,066738;doi:https://doi.org/10.1101/066738
