The clinical-phenotype continuum in DYNC1H1-related disorders—genomic profiling and proposal for a novel classification

  1. Becker, Lena-Luise ORCID logo
  2. Dafsari, Hormos Salimi
  3. Schallner, Jens
  4. Abdin, Dalia
  5. Seifert, Michael
  6. petit, florence ORCID logo
  7. Smol, Thomas ORCID logo
  8. Bok, Levinus
  9. Rodan, Lance
  10. Krapels, Ingrid
  11. Spranger, Stephanie
  12. Weschke, Bernhard ORCID logo
  13. Johnson, Katherine
  14. Straub, Volker ORCID logo
  15. Kaindl, Angela M.
  16. Di Donato, Nataliya ORCID logo
  17. von der Hagen, Maja
  18. Cirak, Sebahattin

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1000 Titel
  • The clinical-phenotype continuum in DYNC1H1-related disorders—genomic profiling and proposal for a novel classification
1000 Autor/in
  1. Becker, Lena-Luise |
  2. Dafsari, Hormos Salimi |
  3. Schallner, Jens |
  4. Abdin, Dalia |
  5. Seifert, Michael |
  6. petit, florence |
  7. Smol, Thomas |
  8. Bok, Levinus |
  9. Rodan, Lance |
  10. Krapels, Ingrid |
  11. Spranger, Stephanie |
  12. Weschke, Bernhard |
  13. Johnson, Katherine |
  14. Straub, Volker |
  15. Kaindl, Angela M. |
  16. Di Donato, Nataliya |
  17. von der Hagen, Maja |
  18. Cirak, Sebahattin |
1000 Erscheinungsjahr 2020
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2020-08-12
1000 Erschienen in
1000 Quellenangabe
  • 65(11):1003-1017
1000 Copyrightjahr
  • 2020
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1038/s10038-020-0803-1 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719554/ |
1000 Publikationsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • 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.
1000 Sacherschließung
lokal Female [MeSH]
lokal Lower Extremity Deformities, Congenital/genetics [MeSH]
lokal Brain/pathology [MeSH]
lokal Brain/diagnostic imaging [MeSH]
lokal Lower Extremity Deformities, Congenital/pathology [MeSH]
lokal Mutation, Missense/genetics [MeSH]
lokal Brain/abnormalities [MeSH]
lokal Humans [MeSH]
lokal Cytoplasmic Dyneins/genetics [MeSH]
lokal Muscular Atrophy, Spinal/pathology [MeSH]
lokal Disease genetics
lokal DNA Mutational Analysis [MeSH]
lokal Lower Extremity/diagnostic imaging [MeSH]
lokal Muscular Atrophy, Spinal/classification [MeSH]
lokal Article
lokal Muscular Atrophy, Spinal/genetics [MeSH]
lokal Genomics [MeSH]
lokal Infant [MeSH]
lokal Male [MeSH]
lokal Lower Extremity Deformities, Congenital/diagnostic imaging [MeSH]
lokal Phenotype [MeSH]
lokal Lower Extremity/pathology [MeSH]
lokal Muscular Atrophy, Spinal/diagnostic imaging [MeSH]
lokal Epilepsy
1000 Liste der Beteiligten
  1. https://orcid.org/0000-0003-4622-8695|https://frl.publisso.de/adhoc/uri/RGFmc2FyaSwgSG9ybW9zIFNhbGltaQ==|https://frl.publisso.de/adhoc/uri/U2NoYWxsbmVyLCBKZW5z|https://frl.publisso.de/adhoc/uri/QWJkaW4sIERhbGlh|https://frl.publisso.de/adhoc/uri/U2VpZmVydCwgTWljaGFlbA==|https://orcid.org/0000-0002-1368-1023|https://orcid.org/0000-0002-0119-5896|https://frl.publisso.de/adhoc/uri/Qm9rLCBMZXZpbnVz|https://frl.publisso.de/adhoc/uri/Um9kYW4sIExhbmNl|https://frl.publisso.de/adhoc/uri/S3JhcGVscywgSW5ncmlk|https://frl.publisso.de/adhoc/uri/U3ByYW5nZXIsIFN0ZXBoYW5pZQ==|https://orcid.org/0000-0003-4533-0743|https://frl.publisso.de/adhoc/uri/Sm9obnNvbiwgS2F0aGVyaW5l|https://orcid.org/0000-0001-9046-3540|https://frl.publisso.de/adhoc/uri/S2FpbmRsLCBBbmdlbGEgTS4=|https://orcid.org/0000-0001-9439-4677|https://frl.publisso.de/adhoc/uri/dm9uIGRlciBIYWdlbiwgTWFqYQ==|https://frl.publisso.de/adhoc/uri/Q2lyYWssIFNlYmFoYXR0aW4=
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1000 Erstellt am 2023-11-18T18:54:33.805+0100
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