Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
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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. / Schmidt, Axel; Danyel, Magdalena; Grundmann, Kathrin; Brunet, Theresa; Klinkhammer, Hannah; Hsieh, Tzung-Chien; Engels, Hartmut; Peters, Sophia; Knaus, Alexej; Moosa, Shahida; Averdunk, Luisa; Boschann, Felix; Sczakiel, Henrike Lisa; Schwartzmann, Sarina; Mensah, Martin Atta; Pantel, Jean Tori; Holtgrewe, Manuel; Bösch, Annemarie; Weiß, Claudia; Weinhold, Natalie; Suter, Aude-Annick; Stoltenburg, Corinna; Neugebauer, Julia; Kallinich, Tillmann; Kaindl, Angela M; Holzhauer, Susanne; Bührer, Christoph; Bufler, Philip; Kornak, Uwe; Ott, Claus-Eric; Schülke, Markus; Nguyen, Hoa Huu Phuc; Hoffjan, Sabine; Grasemann, Corinna; Rothoeft, Tobias; Brinkmann, Folke; Matar, Nora; Sivalingam, Sugirthan; Perne, Claudia; Mangold, Elisabeth; Kreiss, Martina; Cremer, Kirsten; Betz, Regina C; Mücke, Martin; Grigull, Lorenz; Klockgether, Thomas; Spier, Isabel; Heimbach, André; Bender, Tim; Brand, Fabian; Stieber, Christiane; Morawiec, Alexandra Marzena; Karakostas, Pantelis; Schäfer, Valentin S; Bernsen, Sarah; Weydt, Patrick; Castro-Gomez, Sergio; Aziz, Ahmad; Grobe-Einsler, Marcus; Kimmich, Okka; Kobeleva, Xenia; Önder, Demet; Lesmann, Hellen; Kumar, Sheetal; Tacik, Pawel; Basin, Meghna Ahuja; Incardona, Pietro; Lee-Kirsch, Min Ae; Berner, Reinhard; Schuetz, Catharina; Körholz, Julia; Kretschmer, Tanita; Di Donato, Nataliya; Schröck, Evelin; Heinen, André; Reuner, Ulrike; Hanßke, Amalia-Mihaela; Kaiser, Frank J; Manka, Eva; Munteanu, Martin; Kuechler, Alma; Cordula, Kiewert; Hirtz, Raphael; Schlapakow, Elena; Schlein, Christian; Lisfeld, Jasmin; Kubisch, Christian; Herget, Theresia; Hempel, Maja; Weiler-Normann, Christina; Ullrich, Kurt; Schramm, Christoph; Rudolph, Cornelia; Rillig, Franziska ; Groffmann, Maximilian; Muntau, Ania; Tibelius, Alexandra; Schwaibold, Eva M C; Schaaf, Christian P; Zawada, Michal; Kaufmann, Lilian; Hinderhofer, Katrin; Okun, Pamela M; Kotzaeridou, Urania; Hoffmann, Georg F; Choukair, Daniela; Bettendorf, Markus; Spielmann, Malte; Ripke, Annekatrin; Pauly, Martje; Münchau, Alexander; Lohmann, Katja; Hüning, Irina; Hanker, Britta; Bäumer, Tobias; Herzog, Rebecca; Hellenbroich, Yorck; Westphal, Dominik S; Strom, Tim; Kovacs, Reka; Riedhammer, Korbinian M; Mayerhanser, Katharina; Graf, Elisabeth; Brugger, Melanie; Hoefele, Julia; Oexle, Konrad; Mirza-Schreiber, Nazanin; Berutti, Riccardo; Schatz, Ulrich; Krenn, Martin; Makowski, Christine; Weigand, Heike; Schröder, Sebastian; Rohlfs, Meino; Vill, Katharina; Hauck, Fabian; Borggraefe, Ingo; Müller-Felber, Wolfgang; Kurth, Ingo; Elbracht, Miriam; Knopp, Cordula; Begemann, Matthias; Kraft, Florian; Lemke, Johannes R; Hentschel, Julia; Platzer, Konrad; Strehlow, Vincent; Abou Jamra, Rami; Kehrer, Martin; Demidov, German; Beck-Wödl, Stefanie; Graessner, Holm; Sturm, Marc; Zeltner, Lena; Schöls, Ludger J; Magg, Janine; Bevot, Andrea; Kehrer, Christiane; Kaiser, Nadja; Turro, Ernest; Horn, Denise; Grüters-Kieslich, Annette; Klein, Christoph; Mundlos, Stefan; Nöthen, Markus; Riess, Olaf; Meitinger, Thomas; Krude, Heiko; Krawitz, Peter M; Haack, Tobias; Ehmke, Nadja; Wagner, Matias.
In: NAT GENET, Vol. 56, No. 8, 08.2024, p. 1644-1653.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
AU - Schmidt, Axel
AU - Danyel, Magdalena
AU - Grundmann, Kathrin
AU - Brunet, Theresa
AU - Klinkhammer, Hannah
AU - Hsieh, Tzung-Chien
AU - Engels, Hartmut
AU - Peters, Sophia
AU - Knaus, Alexej
AU - Moosa, Shahida
AU - Averdunk, Luisa
AU - Boschann, Felix
AU - Sczakiel, Henrike Lisa
AU - Schwartzmann, Sarina
AU - Mensah, Martin Atta
AU - Pantel, Jean Tori
AU - Holtgrewe, Manuel
AU - Bösch, Annemarie
AU - Weiß, Claudia
AU - Weinhold, Natalie
AU - Suter, Aude-Annick
AU - Stoltenburg, Corinna
AU - Neugebauer, Julia
AU - Kallinich, Tillmann
AU - Kaindl, Angela M
AU - Holzhauer, Susanne
AU - Bührer, Christoph
AU - Bufler, Philip
AU - Kornak, Uwe
AU - Ott, Claus-Eric
AU - Schülke, Markus
AU - Nguyen, Hoa Huu Phuc
AU - Hoffjan, Sabine
AU - Grasemann, Corinna
AU - Rothoeft, Tobias
AU - Brinkmann, Folke
AU - Matar, Nora
AU - Sivalingam, Sugirthan
AU - Perne, Claudia
AU - Mangold, Elisabeth
AU - Kreiss, Martina
AU - Cremer, Kirsten
AU - Betz, Regina C
AU - Mücke, Martin
AU - Grigull, Lorenz
AU - Klockgether, Thomas
AU - Spier, Isabel
AU - Heimbach, André
AU - Bender, Tim
AU - Brand, Fabian
AU - Stieber, Christiane
AU - Morawiec, Alexandra Marzena
AU - Karakostas, Pantelis
AU - Schäfer, Valentin S
AU - Bernsen, Sarah
AU - Weydt, Patrick
AU - Castro-Gomez, Sergio
AU - Aziz, Ahmad
AU - Grobe-Einsler, Marcus
AU - Kimmich, Okka
AU - Kobeleva, Xenia
AU - Önder, Demet
AU - Lesmann, Hellen
AU - Kumar, Sheetal
AU - Tacik, Pawel
AU - Basin, Meghna Ahuja
AU - Incardona, Pietro
AU - Lee-Kirsch, Min Ae
AU - Berner, Reinhard
AU - Schuetz, Catharina
AU - Körholz, Julia
AU - Kretschmer, Tanita
AU - Di Donato, Nataliya
AU - Schröck, Evelin
AU - Heinen, André
AU - Reuner, Ulrike
AU - Hanßke, Amalia-Mihaela
AU - Kaiser, Frank J
AU - Manka, Eva
AU - Munteanu, Martin
AU - Kuechler, Alma
AU - Cordula, Kiewert
AU - Hirtz, Raphael
AU - Schlapakow, Elena
AU - Schlein, Christian
AU - Lisfeld, Jasmin
AU - Kubisch, Christian
AU - Herget, Theresia
AU - Hempel, Maja
AU - Weiler-Normann, Christina
AU - Ullrich, Kurt
AU - Schramm, Christoph
AU - Rudolph, Cornelia
AU - Rillig, Franziska
AU - Groffmann, Maximilian
AU - Muntau, Ania
AU - Tibelius, Alexandra
AU - Schwaibold, Eva M C
AU - Schaaf, Christian P
AU - Zawada, Michal
AU - Kaufmann, Lilian
AU - Hinderhofer, Katrin
AU - Okun, Pamela M
AU - Kotzaeridou, Urania
AU - Hoffmann, Georg F
AU - Choukair, Daniela
AU - Bettendorf, Markus
AU - Spielmann, Malte
AU - Ripke, Annekatrin
AU - Pauly, Martje
AU - Münchau, Alexander
AU - Lohmann, Katja
AU - Hüning, Irina
AU - Hanker, Britta
AU - Bäumer, Tobias
AU - Herzog, Rebecca
AU - Hellenbroich, Yorck
AU - Westphal, Dominik S
AU - Strom, Tim
AU - Kovacs, Reka
AU - Riedhammer, Korbinian M
AU - Mayerhanser, Katharina
AU - Graf, Elisabeth
AU - Brugger, Melanie
AU - Hoefele, Julia
AU - Oexle, Konrad
AU - Mirza-Schreiber, Nazanin
AU - Berutti, Riccardo
AU - Schatz, Ulrich
AU - Krenn, Martin
AU - Makowski, Christine
AU - Weigand, Heike
AU - Schröder, Sebastian
AU - Rohlfs, Meino
AU - Vill, Katharina
AU - Hauck, Fabian
AU - Borggraefe, Ingo
AU - Müller-Felber, Wolfgang
AU - Kurth, Ingo
AU - Elbracht, Miriam
AU - Knopp, Cordula
AU - Begemann, Matthias
AU - Kraft, Florian
AU - Lemke, Johannes R
AU - Hentschel, Julia
AU - Platzer, Konrad
AU - Strehlow, Vincent
AU - Abou Jamra, Rami
AU - Kehrer, Martin
AU - Demidov, German
AU - Beck-Wödl, Stefanie
AU - Graessner, Holm
AU - Sturm, Marc
AU - Zeltner, Lena
AU - Schöls, Ludger J
AU - Magg, Janine
AU - Bevot, Andrea
AU - Kehrer, Christiane
AU - Kaiser, Nadja
AU - Turro, Ernest
AU - Horn, Denise
AU - Grüters-Kieslich, Annette
AU - Klein, Christoph
AU - Mundlos, Stefan
AU - Nöthen, Markus
AU - Riess, Olaf
AU - Meitinger, Thomas
AU - Krude, Heiko
AU - Krawitz, Peter M
AU - Haack, Tobias
AU - Ehmke, Nadja
AU - Wagner, Matias
N1 - © 2024. The Author(s).
PY - 2024/8
Y1 - 2024/8
N2 - 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.
AB - 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.
U2 - 10.1038/s41588-024-01836-1
DO - 10.1038/s41588-024-01836-1
M3 - SCORING: Journal article
C2 - 39039281
VL - 56
SP - 1644
EP - 1653
JO - NAT GENET
JF - NAT GENET
SN - 1061-4036
IS - 8
ER -