Fig. 4

Overview of overlapping clinical disease manifestation of DYNC1H1-associated disorders and domain-specific presentation of genotype–phenotype correlation based on literature review. a On the left, Venn diagram of the recorded symptoms in patients with each of the three known entities associated with DYNC1H1 mutations and the overlap of phenotypes in DYNC1H1-associated disorders: Charcot-Marie-Tooth disease Type 20 (CMT20), lower extremity-predominant spinal muscular atrophy (SMALED), and cortical malformations. The symptoms were taken from an extensive PubMed literature search (“dync1h1”, with each “motor neuropathy”, “CMT20”, “charcot-marie-tooth”, “SMALED”, “spinal muscular atrophy”, “malformation”, “MRD13”, “mental retardation”). Specifically, neuromuscular symptoms as in CMT20 and SMALED were mostly observed in patients with mutations in the dimerization domain and cortical malformation was mostly observed in motor domain mutations. On the right, a simplified overview of the protein model from Fig. 1b. b Balloon plot for symptoms “reduction of upper limb strength” and “reduction of lower limb strength” recorded in the literature search with mutations in the beginning tail, dimerization, linker, and motor domains. The size of patient groups denoted with the size of circles on the right (smallest circle 20, biggest circle 80). The calculated normalization quotient (from green to blue to red, on the right) from Pearson’s chi-square test as described in methods revealed clustering of reductions of lower limb strength with preserved upper limb strength in the dimerization domain. c Balloon plot for symptoms “seizures”, “intellectual disability”, “behavioral abnormalities”, “MRI abnormalities” in general, “pachygyria”, “enlarged ventricles”, “hypoplasia corpus callosum”, “hypoplasia cerebellum”, “hypoplasia brain stem”, and “gray matter heterotopia” recorded in the literature search with mutations in the beginning tail, dimerization, linker, and motor domains. The size of patient groups denoted with the size of circles on the right (smallest circle 10, biggest circle 50). The calculated normalization quotient from Pearson’s chi-square test as described in methods revealed clustering of intellectual disability and behavioral abnormalities in patients with mutations in the beginning tail, linker, and motor domains. Seizures and all MRI abnormalities specifically clustered in patients with mutations in the motor domain. Patients with mutations in the dimerization domain were largely spared of these symptoms, thus underlining the hypothesis that DYNC1H1–NMD and –NDD can be traced to specific domain mutations