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Phenotypes and genotypes of ten pediatric patients with pathogenic <jats:italic>DYNC1H1<\/jats:italic> 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 <jats:italic>DYNC1H1<\/jats:italic>. We identified ten patients with nine novel mutations in the <jats:italic>DYNC1H1<\/jats:italic> 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 <jats:italic>DYNC1H1<\/jats:italic>, specifically on toleration towards missense variants in the linker domain. A retrospective analysis of all published mutations revealed domain-specific genotype\u2013phenotype correlations, i.e., mutations in the dimerization domain with reductions in lower limb strength in <jats:italic>DYNC1H1<\/jats:italic>\u2013NMD and motor domain with cerebral malformations in <jats:italic>DYNC1H1<\/jats:italic>\u2013NDD. 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 <jats:italic>DYNC1H1<\/jats:italic>-related disorders. We propose a novel clinical classification for <jats:italic>DYNC1H1<\/jats:italic>-related disorders encompassing a spectrum from <jats:italic>DYNC1H1\u2013<\/jats:italic>NMD with an exclusive PNS phenotype to <jats:italic>DYNC1H1<\/jats:italic>\u2013NDD with concomitant CNS involvement.<\/jats:p>","DOI":"10.1038\/s10038-020-0803-1","type":"journal-article","created":{"date-parts":[[2020,8,12]],"date-time":"2020-08-12T09:04:02Z","timestamp":1597223042000},"page":"1003-1017","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["The clinical-phenotype continuum in DYNC1H1-related disorders\u2014genomic profiling and proposal for a novel classification"],"prefix":"10.1038","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4622-8695","authenticated-orcid":false,"given":"Lena-Luise","family":"Becker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hormos Salimi","family":"Dafsari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Schallner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalia","family":"Abdin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Seifert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1368-1023","authenticated-orcid":false,"given":"Florence","family":"Petit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0119-5896","authenticated-orcid":false,"given":"Thomas","family":"Smol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Levinus","family":"Bok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lance","family":"Rodan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Krapels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Spranger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4533-0743","authenticated-orcid":false,"given":"Bernhard","family":"Weschke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9046-3540","authenticated-orcid":false,"given":"Volker","family":"Straub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela M.","family":"Kaindl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9439-4677","authenticated-orcid":false,"given":"Nataliya","family":"Di Donato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"von der Hagen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebahattin","family":"Cirak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,8,12]]},"reference":[{"key":"803_CR1","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1212\/WNL.0b013e3181ec800c","volume":"75","author":"MB Harms","year":"2010","unstructured":"Harms MB, Allred P, Gardner R Jr, Fernandes Filho JA, Florence J, Pestronk A, et al. 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