Page1of3

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

Page2of3

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.

Page3of3

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