Genotype-phenotype correlations of DYNC1H1 variants
Generally, the DYNC1H1 protein can be divided into the N-terminal region named DHC_N1 (242-832 aa), the C-terminal region named Dynein_C (4333-4633 aa) and the longest DYN1 region (1046-4329 aa) in between. Of all the DYNC1H1 mutations leading to neuromuscular diseases, none was located in Dynein_C. Therefore, we divided these mutations into two groups according to their locations: the DHC_N1 group (p.G192R also included) and the DYN1 group (p.Y970C also included). The comparison of the phenotypes correlated with these two genotypes was listed in Table 2. Atrophy and weakness of lower limbs were both common in the two groups, and both groups had more cases of distal-dominant atrophy and proximal-dominant weakness. However, the severity of these symptoms between the two groups showed some differences, with more severe lower limb symptoms lying in the DYN1 group (5/18, 27.8% v.s. 3/5, 60.0%;P >0.05 and 4/22, 18.2% v.s. 7/12, 58.3%;P <0.05). Delayed motor milestones were more commonly observed in the DYN1 group than the DHC_N1 group (18/23, 78.3% v.s. 36/67, 53.7%, P =0.038). Besides, the DYN1 group also had a higher percentage of upper limb involvement, trunk involvement, deformities and abnormal tendon reflex, as well as a lower percentage of ambulant patients, although the results were not statistically significant. Abnormal NCV results were also significantly more common in the DYN1 group than in the DHC_N1 group (6/12, 50% v.s. 4/45, 8.9%,P =0.004). These results indicated that mutations in the DYN1 region might present a more severe phenotype and more diverse clinical manifestations than the DHC_N1 mutations.
Mutations in the DYN1 region was more related to CNS impairment as well. More epilepsy was observed in the DYN1 group (6/24, 25.0%) than in the DHC_N1 group (5/77, 6.5%; P =0.030). The incidence of cognitive impairment was significantly higher in the DYN1 group (15/19, 78.9% v.s. 16/75, 21.3%, P <0.001) and ADHD was more common in this group, although the difference was not significant (5/19, 26.3% v.s. 8/75, 10.7%; P =0.164). In accordance with this, abnormalities of the brain were more commonly found on MRI of the DYN1 group (12/14, 85.7%) compared to the DHC_N1 group (6/17, 35.3%;P =0.005).