The clinical-phenotype continuum in ...
Document type :
Article dans une revue scientifique: Article original
PMID :
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Title :
The clinical-phenotype continuum in dync1h1-related disorders-genomic profiling and proposal for a novel classification
Author(s) :
Becker, Lena-Luise [Auteur]
Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
Dafsari, Hormos Salimi [Auteur]
University Hospital of Cologne [Cologne]
Schallner, Jens [Auteur]
Technische Universität Dresden = Dresden University of Technology [TU Dresden]
Abdin, Dalia [Auteur]
Technische Universität Dresden = Dresden University of Technology [TU Dresden]
Seifert, Michael [Auteur]
Technische Universität Dresden = Dresden University of Technology [TU Dresden]
Petit, Florence [Auteur]
Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Smol, Thomas [Auteur]
Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Bok, Levinus A. [Auteur]
ASML [VELDHOVEN] [ASML]
Rodan, Lance H. [Auteur]
Department of Neurology, Children's Hospital [Boston]
Krapels, Ingrid [Auteur]
Maastricht University [Maastricht]
Spranger, Stephanie [Auteur]
University of Bremen
Weschke, Bernhard [Auteur]
Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
Johnson, Katherine [Auteur]
Newcastle University [Newcastle]
Straub, Volker [Auteur]
Newcastle University [Newcastle]
Kaindl, Angela M. [Auteur]
Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
Di Donato, Nataliya [Auteur]
Technische Universität Dresden = Dresden University of Technology [TU Dresden]
Von Der Hagen, Maja [Auteur]
Technische Universität Dresden = Dresden University of Technology [TU Dresden]
Cirak, Sebahattin [Auteur]
Center for Molecular Medicine [Cologne] [CMMC]
Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
Dafsari, Hormos Salimi [Auteur]
University Hospital of Cologne [Cologne]
Schallner, Jens [Auteur]
Technische Universität Dresden = Dresden University of Technology [TU Dresden]
Abdin, Dalia [Auteur]
Technische Universität Dresden = Dresden University of Technology [TU Dresden]
Seifert, Michael [Auteur]
Technische Universität Dresden = Dresden University of Technology [TU Dresden]
Petit, Florence [Auteur]
Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Smol, Thomas [Auteur]
Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Bok, Levinus A. [Auteur]
ASML [VELDHOVEN] [ASML]
Rodan, Lance H. [Auteur]
Department of Neurology, Children's Hospital [Boston]
Krapels, Ingrid [Auteur]
Maastricht University [Maastricht]
Spranger, Stephanie [Auteur]
University of Bremen
Weschke, Bernhard [Auteur]
Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
Johnson, Katherine [Auteur]
Newcastle University [Newcastle]
Straub, Volker [Auteur]
Newcastle University [Newcastle]
Kaindl, Angela M. [Auteur]
Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
Di Donato, Nataliya [Auteur]
Technische Universität Dresden = Dresden University of Technology [TU Dresden]
Von Der Hagen, Maja [Auteur]
Technische Universität Dresden = Dresden University of Technology [TU Dresden]
Cirak, Sebahattin [Auteur]
Center for Molecular Medicine [Cologne] [CMMC]
Journal title :
Journal of human genetics
Abbreviated title :
J. Hum. Genet.
Volume number :
65
Pages :
1003-1017
Publication date :
2020-08-12
ISSN :
1435-232X
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
Mutations in the cytoplasmic dynein 1 heavy chain gene (DYNC1H1) have been identified in rare neuromuscular (NMD) and neurodevelopmental (NDD) disorders such as spinal muscular atrophy with lower extremity dominance (SMALED) ...
Show more >Mutations in the cytoplasmic dynein 1 heavy chain gene (DYNC1H1) have been identified in rare neuromuscular (NMD) and neurodevelopmental (NDD) disorders such as spinal muscular atrophy with lower extremity dominance (SMALED) and autosomal dominant mental retardation syndrome 13 (MRD13). Phenotypes and genotypes of ten pediatric patients with pathogenic DYNC1H1 variants were analyzed in a multi-center study. Data mining of large-scale genomic variant databases was used to investigate domain-specific vulnerability and conservation of DYNC1H1. We identified ten patients with nine novel mutations in the DYNC1H1 gene. These patients exhibit a broad spectrum of clinical findings, suggesting an overlapping disease manifestation with intermixed phenotypes ranging from neuropathy (peripheral nervous system, PNS) to severe intellectual disability (central nervous system, CNS). Genomic profiling of healthy and patient variant datasets underlines the domain-specific effects of genetic variation in DYNC1H1, specifically on toleration towards missense variants in the linker domain. A retrospective analysis of all published mutations revealed domain-specific genotype-phenotype correlations, i.e., mutations in the dimerization domain with reductions in lower limb strength in DYNC1H1-NMD and motor domain with cerebral malformations in DYNC1H1-NDD. We highlight that the current classification into distinct disease entities does not sufficiently reflect the clinical disease manifestation that clinicians face in the diagnostic work-up of DYNC1H1-related disorders. We propose a novel clinical classification for DYNC1H1-related disorders encompassing a spectrum from DYNC1H1-NMD with an exclusive PNS phenotype to DYNC1H1-NDD with concomitant CNS involvement.Show less >
Show more >Mutations in the cytoplasmic dynein 1 heavy chain gene (DYNC1H1) have been identified in rare neuromuscular (NMD) and neurodevelopmental (NDD) disorders such as spinal muscular atrophy with lower extremity dominance (SMALED) and autosomal dominant mental retardation syndrome 13 (MRD13). Phenotypes and genotypes of ten pediatric patients with pathogenic DYNC1H1 variants were analyzed in a multi-center study. Data mining of large-scale genomic variant databases was used to investigate domain-specific vulnerability and conservation of DYNC1H1. We identified ten patients with nine novel mutations in the DYNC1H1 gene. These patients exhibit a broad spectrum of clinical findings, suggesting an overlapping disease manifestation with intermixed phenotypes ranging from neuropathy (peripheral nervous system, PNS) to severe intellectual disability (central nervous system, CNS). Genomic profiling of healthy and patient variant datasets underlines the domain-specific effects of genetic variation in DYNC1H1, specifically on toleration towards missense variants in the linker domain. A retrospective analysis of all published mutations revealed domain-specific genotype-phenotype correlations, i.e., mutations in the dimerization domain with reductions in lower limb strength in DYNC1H1-NMD and motor domain with cerebral malformations in DYNC1H1-NDD. We highlight that the current classification into distinct disease entities does not sufficiently reflect the clinical disease manifestation that clinicians face in the diagnostic work-up of DYNC1H1-related disorders. We propose a novel clinical classification for DYNC1H1-related disorders encompassing a spectrum from DYNC1H1-NMD with an exclusive PNS phenotype to DYNC1H1-NDD with concomitant CNS involvement.Show less >
Language :
Anglais
Audience :
Internationale
Popular science :
Non
Administrative institution(s) :
Université de Lille
Collections :
Submission date :
2021-09-02T07:01:39Z
2021-10-27T08:39:09Z
2021-10-27T08:39:09Z