Fig. 1

Overview of DYNC1H1 variants identified in this study. Calculated MTR and CADD-Phred score values for the variants from the healthy population and our patient collective show that pathogenic DYNC1H1 mutations cluster in regions of less genetic heterogeneity, specifically in highly conserved domains. a Ten variants in the DYNC1H1 gene (NM_001376.5, 78 exons) identified in our patients and concomitant position in b. DYNC1H1 protein structure (Q14204); pictogram with protein domains: coiled coil domain (CC, gray), ATPase associated with various cellular activities domain (AAA, red), ATP-binding region in AAA domain (ATP, dark brown), rest of protein in blue. We noted all regions (beginning tail region gray, linker region dark blue, motor region red, stalk/microtubule-binding domain green, end tail region gray) and specified the dimerization domain in yellow with interaction partners DYNC1I2 and DYNC1LI2 noted below. The mutations on protein level are presented in the above-mentioned color scheme. c Missense tolerant ratio (MTR) gene viewer result for DYNC1H1 (ENST00000360184) with window size 21 (http://biosig.unimelb.edu.au/mtr-viewer/); patients’ variants are marked with blue crosses. Protein regions noted below as in b. d CADD-Phred scores of all gnomAD variants with ClinVar patient variants (marked with red asterisks) and our patient’s variants (marked with blue asterisks), score >20 indicates likely pathogenic computation, score >30 indicates pathogenic [48]. In general, CADD is a gene-level scoring for potential proxy-deleterious variants and has to be treated with caution. The linker mutations in our patient collective show amino acid exchanges with more significant changes in physicochemical properties when compared with variants from a healthy population dataset. The patients’ mutations in the motor region are found in highly conserved AAA domains with higher CADD-Phred score values. However, the pathogenic mutations from patients are in regions where allele frequencies and high CADD-Phred scores are “thinned out”. For the raw data, please see Supplementary Table 2. Protein regions noted below as in b. e Violin plot for CADD-Phred scores for variants recorded in gnomAD database (left in blue, https://gnomad.broadinstitute.org/); likely pathogenic and pathogenic variants according to ClinVar (middle in orange, https://www.ncbi.nlm.nih.gov/clinvar/), and ten patients variants (right in red), please see Supplementary Table 2 for raw data. Variance analysis (ANOVA, SigmaPlot 12.5, SYSTAT, USA) revealed significant differences between the groups “gnomAD variants” and “ClinVar variants” (**p < 0.01) as well as the groups “gnomAD variants” and “patients’ variants” in our ten patients (*p < 0.05). There was no significant difference between the groups “ClinVar variants” and “patients’ variants”