Monogenic variants in dystonia: an exome-wide sequencing study

J 2020

Monogenic variants in dystonia: an exome-wide sequencing study

ZECH, M., R. JECH, S. BOESCH, M. SKORVANEK, S. WEBER et. al.

Basic information

Original name

Monogenic variants in dystonia: an exome-wide sequencing study

Authors

ZECH, M., R. JECH, S. BOESCH, M. SKORVANEK, S. WEBER, M. WAGNER, C. ZHAO, A. JOCHIM, J. NECPAL, Y. DINCER, K. VILL, F. DISTEIMAIER, M. STOKLOSA, M. KRENN, S. GRUNWALD, T. BOCK-BIERBAUM, A. FECIKOVA, P. HAVRANKOVA, J. ROTH, I. PRIHODOVA, M. ADAMOVICOVA, O. ULMANOVA, K. BECHYNE, Pavlína DANHOFER (203 Czech Republic, belonging to the institution), B. VESELY, V. HAN, P. PAVELEKOVA, Z. GDOVINOVA, T. MANTEL, T. MEINDL, A. SITZBERGER, S. SCHRODER, A. BLASCHEK, T. ROSER, M. BONFERT, E. HABERLANDT, B. PLECKO, B. LEINEWEBER, S. BERWECK, T. HERBERHOLD, B. LANGGUTH, J. SVANTNEROVA, M. MINAR, G. A. RAMOS-RIVERA, M. H. WOJCIK, S. PAJUSALU, K. OUNAP, U. A. SCHATZ, L. POLSLER, I. MILENKOVIC, F. LACCONE, V. PILHOFER, R. COLOMBO, S. PATZER, A. IUSO, J. VERA, M. TRONCOSO, F. FANG, H. PROKISCH, F. WILBERT, M. ECKENWEILER, E. GRAF, D. S. WESTPHAL, K. M. RIEDHAMMER, T. BRUNET, B. ALHADDAD, R. BERUTTI, T. M. STROM, M. HECHT, M. BAUMANN, M. WOLF, A. TELEGRAFI, R. E. PERSON, F. M. ZAMORA, L. B. HENDERSON, D. WEISE, T. MUSACCHIO, J. VOLKMANN, A. SZUTO, J. BECKER, K. CREMER, T. SYCHA, F. ZIMPRICH, V. KRAUS, C. MAKOWSKI, P. GONZALEZ-ALEGRE, T. M. BARDAKJIAN, L. J. OZELIUS, A. VETRO, R. GUERRINI, E. MAIER, I. BORGGRAEFE, A. KUSTER, S. B. WORTMANN, A. HACKENBERG, R. STEINFELD, B. ASSMANN, C. STAUFNER, T. OPLADEN, E. RUZICKA, R. D. COHN, D. DYMENT, W. K. CHUNG, H. ENGELS, A. CEBALLOS-BAUMANN, R. PLOSKI, O. DAUMKE, B. HASLINGER, V. MALL, K. OEXLE and J. WINKEHNANN (guarantor)

Edition

Lancet Neurology, London, UK, Elsevier, 2020, 1474-4422

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30103 Neurosciences

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 44.182

RIV identification code

RIV/00216224:14110/20:00117064

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1016/S1474-4422(20)30312-4

UT WoS

000581121200023

Keywords in English

dystonia; monogenic variants

Abstract

V originále

Background Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. Methods For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. Findings We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. Interpretation In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations.

Links

ROZV/28/LF6/2020, interní kód MU

Name: Etiopatogeneze poruch autistického spektra (PAS): genetické a neuroimunologické aspekty

Investor: Ministry of Education, Youth and Sports of the CR, Internal development projects

Citovat

ZECH, M., R. JECH, S. BOESCH, M. SKORVANEK, S. WEBER, M. WAGNER, C. ZHAO, A. JOCHIM, J. NECPAL, Y. DINCER, K. VILL, F. DISTEIMAIER, M. STOKLOSA, M. KRENN, S. GRUNWALD, T. BOCK-BIERBAUM, A. FECIKOVA, P. HAVRANKOVA, J. ROTH, I. PRIHODOVA, M. ADAMOVICOVA, O. ULMANOVA, K. BECHYNE, Pavlína DANHOFER, B. VESELY, V. HAN, P. PAVELEKOVA, Z. GDOVINOVA, T. MANTEL, T. MEINDL, A. SITZBERGER, S. SCHRODER, A. BLASCHEK, T. ROSER, M. BONFERT, E. HABERLANDT, B. PLECKO, B. LEINEWEBER, S. BERWECK, T. HERBERHOLD, B. LANGGUTH, J. SVANTNEROVA, M. MINAR, G. A. RAMOS-RIVERA, M. H. WOJCIK, S. PAJUSALU, K. OUNAP, U. A. SCHATZ, L. POLSLER, I. MILENKOVIC, F. LACCONE, V. PILHOFER, R. COLOMBO, S. PATZER, A. IUSO, J. VERA, M. TRONCOSO, F. FANG, H. PROKISCH, F. WILBERT, M. ECKENWEILER, E. GRAF, D. S. WESTPHAL, K. M. RIEDHAMMER, T. BRUNET, B. ALHADDAD, R. BERUTTI, T. M. STROM, M. HECHT, M. BAUMANN, M. WOLF, A. TELEGRAFI, R. E. PERSON, F. M. ZAMORA, L. B. HENDERSON, D. WEISE, T. MUSACCHIO, J. VOLKMANN, A. SZUTO, J. BECKER, K. CREMER, T. SYCHA, F. ZIMPRICH, V. KRAUS, C. MAKOWSKI, P. GONZALEZ-ALEGRE, T. M. BARDAKJIAN, L. J. OZELIUS, A. VETRO, R. GUERRINI, E. MAIER, I. BORGGRAEFE, A. KUSTER, S. B. WORTMANN, A. HACKENBERG, R. STEINFELD, B. ASSMANN, C. STAUFNER, T. OPLADEN, E. RUZICKA, R. D. COHN, D. DYMENT, W. K. CHUNG, H. ENGELS, A. CEBALLOS-BAUMANN, R. PLOSKI, O. DAUMKE, B. HASLINGER, V. MALL, K. OEXLE and J. WINKEHNANN. Monogenic variants in dystonia: an exome-wide sequencing study. Lancet Neurology. London, UK: Elsevier, 2020, vol. 19, No 11, p. 908-918. ISSN 1474-4422. Available from: https://dx.doi.org/10.1016/S1474-4422(20)30312-4.

@article{1698803,
   author = {Zech, M. and Jech, R. and Boesch, S. and Skorvanek, M. and Weber, S. and Wagner, M. and Zhao, C. and Jochim, A. and Necpal, J. and Dincer, Y. and Vill, K. and Disteimaier, F. and Stoklosa, M. and Krenn, M. and Grunwald, S. and BockandBierbaum, T. and Fecikova, A. and Havrankova, P. and Roth, J. and Prihodova, I. and Adamovicova, M. and Ulmanova, O. and Bechyne, K. and Danhofer, Pavlína and Vesely, B. and Han, V. and Pavelekova, P. and Gdovinova, Z. and Mantel, T. and Meindl, T. and Sitzberger, A. and Schroder, S. and Blaschek, A. and Roser, T. and Bonfert, M. and Haberlandt, E. and Plecko, B. and Leineweber, B. and Berweck, S. and Herberhold, T. and Langguth, B. and Svantnerova, J. and Minar, M. and RamosandRivera, G. A. and Wojcik, M. H. and Pajusalu, S. and Ounap, K. and Schatz, U. A. and Polsler, L. and Milenkovic, I. and Laccone, F. and Pilhofer, V. and Colombo, R. and Patzer, S. and Iuso, A. and Vera, J. and Troncoso, M. and Fang, F. and Prokisch, H. and Wilbert, F. and Eckenweiler, M. and Graf, E. and Westphal, D. S. and Riedhammer, K. M. and Brunet, T. and Alhaddad, B. and Berutti, R. and Strom, T. M. and Hecht, M. and Baumann, M. and Wolf, M. and Telegrafi, A. and Person, R. E. and Zamora, F. M. and Henderson, L. B. and Weise, D. and Musacchio, T. and Volkmann, J. and Szuto, A. and Becker, J. and Cremer, K. and Sycha, T. and Zimprich, F. and Kraus, V. and Makowski, C. and GonzalezandAlegre, P. and Bardakjian, T. M. and Ozelius, L. J. and Vetro, A. and Guerrini, R. and Maier, E. and Borggraefe, I. and Kuster, A. and Wortmann, S. B. and Hackenberg, A. and Steinfeld, R. and Assmann, B. and Staufner, C. and Opladen, T. and Ruzicka, E. and Cohn, R. D. and Dyment, D. and Chung, W. K. and Engels, H. and CeballosandBaumann, A. and Ploski, R. and Daumke, O. and Haslinger, B. and Mall, V. and Oexle, K. and Winkehnann, J.},
   article_location = {London, UK},
   article_number = {11},
   doi = {http://dx.doi.org/10.1016/S1474-4422(20)30312-4},
   keywords = {dystonia; monogenic variants},
   language = {eng},
   issn = {1474-4422},
   journal = {Lancet Neurology},
   title = {Monogenic variants in dystonia: an exome-wide sequencing study},
   url = {https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(20)30312-4/fulltext},
   volume = {19},
   year = {2020}
}

TY  - JOUR
ID  - 1698803
AU  - Zech, M. - Jech, R. - Boesch, S. - Skorvanek, M. - Weber, S. - Wagner, M. - Zhao, C. - Jochim, A. - Necpal, J. - Dincer, Y. - Vill, K. - Disteimaier, F. - Stoklosa, M. - Krenn, M. - Grunwald, S. - Bock-Bierbaum, T. - Fecikova, A. - Havrankova, P. - Roth, J. - Prihodova, I. - Adamovicova, M. - Ulmanova, O. - Bechyne, K. - Danhofer, Pavlína - Vesely, B. - Han, V. - Pavelekova, P. - Gdovinova, Z. - Mantel, T. - Meindl, T. - Sitzberger, A. - Schroder, S. - Blaschek, A. - Roser, T. - Bonfert, M. - Haberlandt, E. - Plecko, B. - Leineweber, B. - Berweck, S. - Herberhold, T. - Langguth, B. - Svantnerova, J. - Minar, M. - Ramos-Rivera, G. A. - Wojcik, M. H. - Pajusalu, S. - Ounap, K. - Schatz, U. A. - Polsler, L. - Milenkovic, I. - Laccone, F. - Pilhofer, V. - Colombo, R. - Patzer, S. - Iuso, A. - Vera, J. - Troncoso, M. - Fang, F. - Prokisch, H. - Wilbert, F. - Eckenweiler, M. - Graf, E. - Westphal, D. S. - Riedhammer, K. M. - Brunet, T. - Alhaddad, B. - Berutti, R. - Strom, T. M. - Hecht, M. - Baumann, M. - Wolf, M. - Telegrafi, A. - Person, R. E. - Zamora, F. M. - Henderson, L. B. - Weise, D. - Musacchio, T. - Volkmann, J. - Szuto, A. - Becker, J. - Cremer, K. - Sycha, T. - Zimprich, F. - Kraus, V. - Makowski, C. - Gonzalez-Alegre, P. - Bardakjian, T. M. - Ozelius, L. J. - Vetro, A. - Guerrini, R. - Maier, E. - Borggraefe, I. - Kuster, A. - Wortmann, S. B. - Hackenberg, A. - Steinfeld, R. - Assmann, B. - Staufner, C. - Opladen, T. - Ruzicka, E. - Cohn, R. D. - Dyment, D. - Chung, W. K. - Engels, H. - Ceballos-Baumann, A. - Ploski, R. - Daumke, O. - Haslinger, B. - Mall, V. - Oexle, K. - Winkehnann, J.
PY  - 2020
TI  - Monogenic variants in dystonia: an exome-wide sequencing study
JF  - Lancet Neurology
VL  - 19
IS  - 11
SP  - 908-918
EP  - 908-918
PB  - Elsevier
SN  - 14744422
KW  - dystonia
KW  - monogenic variants
UR  - https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(20)30312-4/fulltext
L2  - https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(20)30312-4/fulltext
N2  - Background Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. Methods For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. Findings We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. Interpretation In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations.
ER  -

ZECH, M., R. JECH, S. BOESCH, M. SKORVANEK, S. WEBER, M. WAGNER, C. ZHAO, A. JOCHIM, J. NECPAL, Y. DINCER, K. VILL, F. DISTEIMAIER, M. STOKLOSA, M. KRENN, S. GRUNWALD, T. BOCK-BIERBAUM, A. FECIKOVA, P. HAVRANKOVA, J. ROTH, I. PRIHODOVA, M. ADAMOVICOVA, O. ULMANOVA, K. BECHYNE, Pavlína DANHOFER, B. VESELY, V. HAN, P. PAVELEKOVA, Z. GDOVINOVA, T. MANTEL, T. MEINDL, A. SITZBERGER, S. SCHRODER, A. BLASCHEK, T. ROSER, M. BONFERT, E. HABERLANDT, B. PLECKO, B. LEINEWEBER, S. BERWECK, T. HERBERHOLD, B. LANGGUTH, J. SVANTNEROVA, M. MINAR, G. A. RAMOS-RIVERA, M. H. WOJCIK, S. PAJUSALU, K. OUNAP, U. A. SCHATZ, L. POLSLER, I. MILENKOVIC, F. LACCONE, V. PILHOFER, R. COLOMBO, S. PATZER, A. IUSO, J. VERA, M. TRONCOSO, F. FANG, H. PROKISCH, F. WILBERT, M. ECKENWEILER, E. GRAF, D. S. WESTPHAL, K. M. RIEDHAMMER, T. BRUNET, B. ALHADDAD, R. BERUTTI, T. M. STROM, M. HECHT, M. BAUMANN, M. WOLF, A. TELEGRAFI, R. E. PERSON, F. M. ZAMORA, L. B. HENDERSON, D. WEISE, T. MUSACCHIO, J. VOLKMANN, A. SZUTO, J. BECKER, K. CREMER, T. SYCHA, F. ZIMPRICH, V. KRAUS, C. MAKOWSKI, P. GONZALEZ-ALEGRE, T. M. BARDAKJIAN, L. J. OZELIUS, A. VETRO, R. GUERRINI, E. MAIER, I. BORGGRAEFE, A. KUSTER, S. B. WORTMANN, A. HACKENBERG, R. STEINFELD, B. ASSMANN, C. STAUFNER, T. OPLADEN, E. RUZICKA, R. D. COHN, D. DYMENT, W. K. CHUNG, H. ENGELS, A. CEBALLOS-BAUMANN, R. PLOSKI, O. DAUMKE, B. HASLINGER, V. MALL, K. OEXLE and J. WINKEHNANN. Monogenic variants in dystonia: an exome-wide sequencing study. \textit{Lancet Neurology}. London, UK: Elsevier, 2020, vol.~19, No~11, p.~908-918. ISSN~1474-4422. Available from: https://dx.doi.org/10.1016/S1474-4422(20)30312-4.

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