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

作者：Lena‐Luise Becker, Hormos Salimi Dafsari, Jens Schallner, Dalia Abdin, Michael Seifert, Florence Petit, Thomas Smol, Levinus A. Bok, Lance H. Rodan, Ingrid P.C. Krapels, Stephanie Spranger, Bernhard Weschke, Katherine Johnson, Volker Straub, Angela M. Kaindl, Nataliya Di Donato, Maja von der Hagen, Sebahattin Çırak · 发表于：Journal of Human Genetics · 年份：2020 · DOI：10.1038/s10038-020-0803-1 · 被引用次数：54 · 研究领域：Microtubule and mitosis dynamics、Genomics and Rare Diseases、RNA modifications and cancer

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 c...