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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.
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
URL: https://doi.org/10.1038/s10038-020-0803-1
DOI: 10.1038/s10038-020-0803-1
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