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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

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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, Jahrgang 56, Nr. 8, 08.2024, S. 1644-1653.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Schmidt, A, Danyel, M, Grundmann, K, Brunet, T, Klinkhammer, H, Hsieh, T-C, Engels, H, Peters, S, Knaus, A, Moosa, S, Averdunk, L, Boschann, F, Sczakiel, HL, Schwartzmann, S, Mensah, MA, Pantel, JT, Holtgrewe, M, Bösch, A, Weiß, C, Weinhold, N, Suter, A-A, Stoltenburg, C, Neugebauer, J, Kallinich, T, Kaindl, AM, Holzhauer, S, Bührer, C, Bufler, P, Kornak, U, Ott, C-E, Schülke, M, Nguyen, HHP, Hoffjan, S, Grasemann, C, Rothoeft, T, Brinkmann, F, Matar, N, Sivalingam, S, Perne, C, Mangold, E, Kreiss, M, Cremer, K, Betz, RC, Mücke, M, Grigull, L, Klockgether, T, Spier, I, Heimbach, A, Bender, T, Brand, F, Stieber, C, Morawiec, AM, Karakostas, P, Schäfer, VS, Bernsen, S, Weydt, P, Castro-Gomez, S, Aziz, A, Grobe-Einsler, M, Kimmich, O, Kobeleva, X, Önder, D, Lesmann, H, Kumar, S, Tacik, P, Basin, MA, Incardona, P, Lee-Kirsch, MA, Berner, R, Schuetz, C, Körholz, J, Kretschmer, T, Di Donato, N, Schröck, E, Heinen, A, Reuner, U, Hanßke, A-M, Kaiser, FJ, Manka, E, Munteanu, M, Kuechler, A, Cordula, K, Hirtz, R, Schlapakow, E, Schlein, C, Lisfeld, J, Kubisch, C, Herget, T, Hempel, M, Weiler-Normann, C, Ullrich, K, Schramm, C, Rudolph, C, Rillig, F, Groffmann, M, Muntau, A, Tibelius, A, Schwaibold, EMC, Schaaf, CP, Zawada, M, Kaufmann, L, Hinderhofer, K, Okun, PM, Kotzaeridou, U, Hoffmann, GF, Choukair, D, Bettendorf, M, Spielmann, M, Ripke, A, Pauly, M, Münchau, A, Lohmann, K, Hüning, I, Hanker, B, Bäumer, T, Herzog, R, Hellenbroich, Y, Westphal, DS, Strom, T, Kovacs, R, Riedhammer, KM, Mayerhanser, K, Graf, E, Brugger, M, Hoefele, J, Oexle, K, Mirza-Schreiber, N, Berutti, R, Schatz, U, Krenn, M, Makowski, C, Weigand, H, Schröder, S, Rohlfs, M, Vill, K, Hauck, F, Borggraefe, I, Müller-Felber, W, Kurth, I, Elbracht, M, Knopp, C, Begemann, M, Kraft, F, Lemke, JR, Hentschel, J, Platzer, K, Strehlow, V, Abou Jamra, R, Kehrer, M, Demidov, G, Beck-Wödl, S, Graessner, H, Sturm, M, Zeltner, L, Schöls, LJ, Magg, J, Bevot, A, Kehrer, C, Kaiser, N, Turro, E, Horn, D, Grüters-Kieslich, A, Klein, C, Mundlos, S, Nöthen, M, Riess, O, Meitinger, T, Krude, H, Krawitz, PM, Haack, T, Ehmke, N & Wagner, M 2024, 'Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings', NAT GENET, Jg. 56, Nr. 8, S. 1644-1653. https://doi.org/10.1038/s41588-024-01836-1

APA

Schmidt, A., Danyel, M., Grundmann, K., Brunet, T., Klinkhammer, H., Hsieh, T-C., Engels, H., Peters, S., Knaus, A., Moosa, S., Averdunk, L., Boschann, F., Sczakiel, H. L., Schwartzmann, S., Mensah, M. A., Pantel, J. T., Holtgrewe, M., Bösch, A., Weiß, C., ... Wagner, M. (2024). Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings. NAT GENET, 56(8), 1644-1653. https://doi.org/10.1038/s41588-024-01836-1

Vancouver

Schmidt A, Danyel M, Grundmann K, Brunet T, Klinkhammer H, Hsieh T-C et al. Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings. NAT GENET. 2024 Aug;56(8):1644-1653. https://doi.org/10.1038/s41588-024-01836-1

Bibtex

@article{63dbfafb743c41268017abbe7cbd6726,
title = "Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings",
abstract = "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.",
author = "Axel Schmidt and Magdalena Danyel and Kathrin Grundmann and Theresa Brunet and Hannah Klinkhammer and Tzung-Chien Hsieh and Hartmut Engels and Sophia Peters and Alexej Knaus and Shahida Moosa and Luisa Averdunk and Felix Boschann and Sczakiel, {Henrike Lisa} and Sarina Schwartzmann and Mensah, {Martin Atta} and Pantel, {Jean Tori} and Manuel Holtgrewe and Annemarie B{\"o}sch and Claudia Wei{\ss} and Natalie Weinhold and Aude-Annick Suter and Corinna Stoltenburg and Julia Neugebauer and Tillmann Kallinich and Kaindl, {Angela M} and Susanne Holzhauer and Christoph B{\"u}hrer and Philip Bufler and Uwe Kornak and Claus-Eric Ott and Markus Sch{\"u}lke and Nguyen, {Hoa Huu Phuc} and Sabine Hoffjan and Corinna Grasemann and Tobias Rothoeft and Folke Brinkmann and Nora Matar and Sugirthan Sivalingam and Claudia Perne and Elisabeth Mangold and Martina Kreiss and Kirsten Cremer and Betz, {Regina C} and Martin M{\"u}cke and Lorenz Grigull and Thomas Klockgether and Isabel Spier and Andr{\'e} Heimbach and Tim Bender and Fabian Brand and Christiane Stieber and Morawiec, {Alexandra Marzena} and Pantelis Karakostas and Sch{\"a}fer, {Valentin S} and Sarah Bernsen and Patrick Weydt and Sergio Castro-Gomez and Ahmad Aziz and Marcus Grobe-Einsler and Okka Kimmich and Xenia Kobeleva and Demet {\"O}nder and Hellen Lesmann and Sheetal Kumar and Pawel Tacik and Basin, {Meghna Ahuja} and Pietro Incardona and Lee-Kirsch, {Min Ae} and Reinhard Berner and Catharina Schuetz and Julia K{\"o}rholz and Tanita Kretschmer and {Di Donato}, Nataliya and Evelin Schr{\"o}ck and Andr{\'e} Heinen and Ulrike Reuner and Amalia-Mihaela Han{\ss}ke and Kaiser, {Frank J} and Eva Manka and Martin Munteanu and Alma Kuechler and Kiewert Cordula and Raphael Hirtz and Elena Schlapakow and Christian Schlein and Jasmin Lisfeld and Christian Kubisch and Theresia Herget and Maja Hempel and Christina Weiler-Normann and Kurt Ullrich and Christoph Schramm and Cornelia Rudolph and Franziska Rillig and Maximilian Groffmann and Ania Muntau and Alexandra Tibelius and Schwaibold, {Eva M C} and Schaaf, {Christian P} and Michal Zawada and Lilian Kaufmann and Katrin Hinderhofer and Okun, {Pamela M} and Urania Kotzaeridou and Hoffmann, {Georg F} and Daniela Choukair and Markus Bettendorf and Malte Spielmann and Annekatrin Ripke and Martje Pauly and Alexander M{\"u}nchau and Katja Lohmann and Irina H{\"u}ning and Britta Hanker and Tobias B{\"a}umer and Rebecca Herzog and Yorck Hellenbroich and Westphal, {Dominik S} and Tim Strom and Reka Kovacs and Riedhammer, {Korbinian M} and Katharina Mayerhanser and Elisabeth Graf and Melanie Brugger and Julia Hoefele and Konrad Oexle and Nazanin Mirza-Schreiber and Riccardo Berutti and Ulrich Schatz and Martin Krenn and Christine Makowski and Heike Weigand and Sebastian Schr{\"o}der and Meino Rohlfs and Katharina Vill and Fabian Hauck and Ingo Borggraefe and Wolfgang M{\"u}ller-Felber and Ingo Kurth and Miriam Elbracht and Cordula Knopp and Matthias Begemann and Florian Kraft and Lemke, {Johannes R} and Julia Hentschel and Konrad Platzer and Vincent Strehlow and {Abou Jamra}, Rami and Martin Kehrer and German Demidov and Stefanie Beck-W{\"o}dl and Holm Graessner and Marc Sturm and Lena Zeltner and Sch{\"o}ls, {Ludger J} and Janine Magg and Andrea Bevot and Christiane Kehrer and Nadja Kaiser and Ernest Turro and Denise Horn and Annette Gr{\"u}ters-Kieslich and Christoph Klein and Stefan Mundlos and Markus N{\"o}then and Olaf Riess and Thomas Meitinger and Heiko Krude and Krawitz, {Peter M} and Tobias Haack and Nadja Ehmke and Matias Wagner",
note = "{\textcopyright} 2024. The Author(s).",
year = "2024",
month = aug,
doi = "10.1038/s41588-024-01836-1",
language = "English",
volume = "56",
pages = "1644--1653",
journal = "NAT GENET",
issn = "1061-4036",
publisher = "NATURE PUBLISHING GROUP",
number = "8",

}

RIS

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 -