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Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings.

Axel SchmidtMagdalena DanyelKathrin GrundmannTheresa BrunetHannah KlinkhammerTzung-Chien HsiehHartmut EngelsSophia PetersAlexej KnausShahida MoosaLuisa AverdunkFelix BoschannHenrike Lisa SczakielSarina SchwartzmannMartin Atta MensahJean Tori PantelManuel HoltgreweAnnemarie BöschClaudia WeißNatalie WeinholdAude-Annick SuterCorinna StoltenburgJulia NeugebauerTillmann KallinichAngela M KaindlSusanne HolzhauerChristoph BührerPhilip BuflerUwe KornakClaus-Eric OttMarkus SchuelkeHoa Huu Phuc NguyenSabine HoffjanCorinna GrasemannTobias RothoeftFolke BrinkmannNora MatarSugirthan SivalingamClaudia PerneElisabeth MangoldMartina KreissKirsten CremerRegina C BetzMartin MückeLorenz GrigullThomas KlockgetherIsabel SpierAndré HeimbachTim BenderFabian BrandChristiane StieberAlexandra Marzena MorawiecPantelis KarakostasValentin Sebastian SchäferSarah BernsenPatrick WeydtSergio Castro-GomezNasir Ahmad AzizMarcus Grobe-EinslerOkka KimmichXenia KobelevaDemet ÖnderHellen LesmannSheetal KumarPawel TacikMeghna Ahuja BasinPietro IncardonaMin Ae Lee-KirschReinhard BernerCatharina SchuetzJulia KörholzTanita KretschmerNataliya Di DonatoEvelin SchröckAndré HeinenUlrike ReunerAmalia-Mihaela HanßkeFrank J KaiserEva MankaMartin MunteanuAlma KuechlerKiewert CordulaRaphael HirtzElena SchlapakowChristian SchleinJasmin LisfeldChristian KubischTheresia HergetMaja HempelChristina Weiler-NormannKurt UllrichChristoph SchrammCornelia RudolphFranziska RilligMaximilian GroffmannAnia MuntauAlexandra TibeliusEva Maria Christina SchwaiboldChristian P SchaafMichal ZawadaLilian KaufmannKatrin HinderhoferPamela M OkunUrania KotzaeridouGeorg F HoffmannDaniela ChoukairMarkus BettendorfMalte SpielmannAnnekatrin RipkeMartje G PaulyAlexander MünchauKatja LohmannIrina HüningBritta HankerTobias BäumerRebecca HerzogYorck HellenbroichDominik Sebastian WestphalTim StromReka KovacsKorbinian Maria RiedhammerKatharina MayerhanserElisabeth GrafMelanie BruggerJulia HoefeleKonrad OexleNazanin Mirza-SchreiberRiccardo BeruttiUlrich SchatzMartin KrennChristine MakowskiHeike WeigandSebastian SchröderMeino RohlfsKatharina VillFabian H HauckIngo BorggraefeWolfgang Müller-FelberIngo KurthMiriam ElbrachtCordula KnoppMatthias BegemannFlorian KraftJohannes R LemkeJulia HentschelKonrad PlatzerVincent StrehlowRami Abou JamraMartin KehrerGerman DemidovStefanie Beck-WödlHolm GraessnerMarc SturmLena ZeltnerLudger J SchölsJanine MaggAndrea BevotChristiane KehrerNadja KaiserErnest TurroDenise HornAnnette Grüters-KieslichChristoph KleinStefan MundlosMarkus Maria NöthenOlaf H RießThomas MeitingerHeiko KrudePeter M KrawitzTobias B HaackNadja EhmkeMatias Wagner
Published in: Nature genetics (2024)
Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 1:50,000. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams.
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