Monogenic variants in dystonia: an exome-wide sequencing study

Zech, Michael; Jech, Robert; Boesch, Sylvia; Škorvánek, Matej; Weber, Sandrina; Wagner, Matias; Zhao, Chen; Jochim, Angela; Necpál, Ján; Dincer, Yasemin; Vill, Katharina; Distelmaier, Felix; Stoklosa, Malgorzata; Krenn, Martin; Grunwald, Stephan; Bock-Bierbaum, Tobias; Fečíková, Anna; Havránková, Petra; Roth, Jan; Příhodová, Iva; Adamovičová, Miriam; Ulmanová, Olga; Bechyně, Karel; Danhofer, Pavlína; Veselý, Branislav; Haň, Vladimír; Pavelekova, Petra; Gdovinová, Zuzana; Mantel, Tobias; Meindl, Tobias; Sitzberger, Alexandra; Schröder, Sebastian; Blaschek, Astrid; Roser, Timo; Bonfert, Michaela; Haberlandt, Edda; Plecko, Barbara; Leineweber, Birgit; Berweck, Steffen; Herberhold, T.; Langguth, Berthold; Švantnerová, Jana; Minár, Michal; Ramos-Rivera, Gonzalo Alonso; Wojcik, Monica H.; Pajusalu, Sander; Õunap, Katrin; Schatz, Ulrich; Pölsler, Laura; Milenković, Ivan; Laccone, Franco; Pilshofer, Veronika; Colombo, Roberto; Patzer, Steffi; Iuso, Arcangela; Vera, Julia; Troncoso, Mónica; Fang, Fang; Prokisch, Holger; Wilbert, Friederike; Eckenweiler, Matthias; Graf, Elisabeth; Westphal, Dominik S.; Riedhammer, Korbinian; Brunet, Theresa; Alhaddad, Bader; Berutti, Riccardo; Strom, Tim M.; Hecht, Martin; Baumann, Matthias; Wolf, Marc E.; Telegrafi, Aida; Person, Richard; Zamora, Francisca Millan; Henderson, Lindsay B.; Weise, David; Musacchio, Thomas; Volkmann, Jens; Szuto, Anna; Becker, Jéssica; Cremer, Kirsten; Sycha, Thomas; Zimprich, Fritz; Kraus, Verena; Makowski, Christine; Gonzalez‐Alegre, Pedro; Bardakjian, Tanya; Ozelius, Laurie J.; Vetro, Annalisa; Guerrini, Renzo; Maier, Esther M.; Borggraefe, Ingo; Küster, Alice; Wortmann, Saskia B.; Hackenberg, Annette; Steinfeld, Robert; Assmann, Birgit; Staufner, Christian; Opladen, Thomas; Růžička, Evžen; Cohn, Ronald D.; Dyment, David A.; Chung, Wendy K.; Engels, Hartmut; Ceballos-Baumann, Andrés; Płoski, Rafał; Daumke, Oliver; Haslinger, Bernhard; Mall, Volker; Oexle, Konrad; Winkelmann, Juliane

doi:10.1016/s1474-4422(20)30312-4

Cited by 140 publications

(141 citation statements)

References 30 publications

(54 reference statements)

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“…All nominated candidate genes were submitted to GeneMatcher. Six individuals were subsequently published within large collaborations connected through GeneMatcher and one individual was published as case report following two previous case descriptions, all together establishing six novel disease‐associated genes for NDDs, namely CYFIP2, KDM3B, IMPDH2, FITM2, RALGAPA1 , and VARS 28‐33 . Those seven individuals were considered as solved and assigned to the overall yield (Supplemental Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

De novo variants in neurodevelopmental disorders—experiences from a tertiary care center

et al. 2021

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Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent‐offspring trio exome sequencing in 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different—mostly constrained—genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio‐approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases.

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Section: Resultsmentioning

confidence: 99%

De novo variants in neurodevelopmental disorders—experiences from a tertiary care center

et al. 2021

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“…All 17 individuals described herein (P1–P17) were recruited through GeneMatcher (Sobreira et al, 2015) or personal communication, from different institutions in Germany, Israel, the United States, Saudi Arabia, the United Arab Emirates, Great Britain, Pakistan, and Chile. Genotypic data from P3 and P13 were previously reported without a detailed clinical description (P3: reported as CB‐DYS‐125 in Zech et al, 2020; P13: reported as 09DG00835 (Shams Anazi et al, 2017)).…”

Section: Methodsmentioning

confidence: 99%

Clinical, neuroimaging, and molecular spectrum of TECPR2 ‐associated hereditary sensory and autonomic neuropathy with intellectual disability

et al. 2021

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“…All 13 individuals described herein (P1 - P13) were recruited through GeneMatcher 13 or personal communication, from different institutions in Germany, Israel, United States, Saudi Arabia and the United Arab Emirates. Genotypic data from P3 and P13 were previously reported without a detailed clinical description (P3: reported in 14 ; P13: reported as 09DG00835 15 ).…”

Section: Methodsmentioning

confidence: 99%

Clinical, neuroimaging and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability

Neuser

Brechmann

Heimer

et al. 2020

Preprint

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PURPOSE: Bi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we aim to provide a comprehensive clinical description and variant interpretation framework. METHODS: Through an international collaboration, we identified 13 individuals from 12 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data of this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. RESULTS: A cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections and central/nocturnal hypopnea as core manifestations. A review of brain MRI scans demonstrated a thin corpus callosum in 59%. We evaluated 14 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing β-propeller repeats. Despite constituting nearly half of disease associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains difficult. We estimate a pathogenic variant carrier frequency of 1/1,221 in the general and 1/155 in the Jewish Ashkenazi population. CONCLUSION: Based on clinical, neuroimaging and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.

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Monogenic variants in dystonia: an exome-wide sequencing study

Cited by 140 publications

References 30 publications

De novo variants in neurodevelopmental disorders—experiences from a tertiary care center

De novo variants in neurodevelopmental disorders—experiences from a tertiary care center

Clinical, neuroimaging, and molecular spectrum of TECPR2 ‐associated hereditary sensory and autonomic neuropathy with intellectual disability

Clinical, neuroimaging and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability

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