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.

已经在罕见的神经肌肉（NMD）和神经发育（NDD）疾病（例如具有下肢优势的脊髓性肌萎缩症（SMALED）和常染色体显性遗传性智力低下综合征13（MRD13））中发现了细胞质动力蛋白1重链基因（DYNC1H1）的突变。在一项多中心研究中分析了十名患病性DYNC1H1变异的小儿患者的表型和基因型。大规模基因组变异数据库的数据挖掘被用来研究DYNC1H1的特定领域脆弱性和保守性。我们确定了DYNC1H1中有9个新突变的10名患者基因。这些患者表现出广泛的临床发现，表明重叠的疾病表现与从神经病（周围神经系统，PNS）到严重智力障碍（中枢神经系统，CNS）不等的混合表型。健康和患者变异数据集的基因组分析强调了DYNC1H1中遗传变异的特定领域效应，特别是对接头域中错义变异的耐受性。对所有已发表突变的回顾性分析揭示了特定域的基因型与表型的相关性，即DYNC1H1 –NMD中二聚体域中的突变与下肢力量的降低以及DYNC1H1中脑畸形的运动域的降低–NDD。我们强调指出，当前对不同疾病实体的分类并不能充分反映出临床医生在DYNC1H1相关疾病的诊断检查中面临的临床疾病表现。我们提出了一种新的DYNC1H1相关疾病的临床分类，包括从具有专属PNS表型的DYNC1H1- NMD到伴随CNS参与的DYNC1H1- NDD。