Toggle Main Menu Toggle Search

Open Access padlockePrints

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

Lookup NU author(s): Dr Katherine JohnsonORCiD, Professor Volker StraubORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2020, The Author(s), under exclusive licence to The Japan Society of Human Genetics.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.

Publication metadata

Author(s): Becker L-L, Dafsari HS, Schallner J, Abdin D, Seifert M, Petit F, Smol T, Bok L, Rodan L, Krapels I, Spranger S, Weschke B, Johnson K, Straub V, Kaindl AM, Di Donato N, von der Hagen M, Cirak S

Publication type: Article

Publication status: Published

Journal: Journal of Human Genetics

Year: 2020

Volume: 65

Issue: 11

Pages: 1003–1017

Print publication date: 01/11/2020

Online publication date: 12/08/2020

Acceptance date: 19/06/2020

Date deposited: 15/10/2020

ISSN (print): 1434-5161

ISSN (electronic): 1435-232X

Publisher: Springer Nature


DOI: 10.1038/s10038-020-0803-1


Altmetrics provided by Altmetric


Funder referenceFunder name
... Kurt+Peter Foundation, Muscular Dystrophy UK, and Coalition to Cure Calpain 3.
Charité-Universitätsmedizin Berlin (to AMK)
Cologne Clinician Scientist Program (CCSP) to HSD via DFG FI 773/15-1,
German Research Foundation (DFG; Emmy Noether Grant CI 218/1-1 to SC and FO3004, SFB1315 to AMK)
Gerok Program/Faculty of Medicine/University of Cologne (to HSD)
MYO-SEQ project was funded by Sanofi Genzyme, Ultragenyx, LGMD2I Research Fund, Samantha J Brazzo Foundation, LGMD2D Foundation, ...
Open access funding provided by Projekt DEAL.