DYNC1H1 gene encodes cytoplasmic dynein heavy chain 1, part of the complex that plays a key role in axonal transport/neuronal migration. SMALED is characterized by muscle weakness and atrophy in the lower extremities, from congenital/early childhood loss of spinal cord motor neurons. CMT2O presents in early childhood with delayed motor milestones and distal-predominant weakness in lower more than upper extremities. Cortical brain malformations arise from defective neuronal proliferation/migration and are often associated with severe ID and epilepsy.

Over 100 pathogenic variants are reported in DYNC1H1 gene, only a handful in the linker domain (aa 1374–1867). While our patient has severe ID, brain imaging is normal, which has been reported previously in patients harboring mutations in this region. His likely pathologic mutation is most likely causing disease on the spectrum of SMALED to CMT2O with ID/ASD. Additionally, his hypermobility and Chiari malformation is likely due Klinefelter syndrome. Thus, we recommend broader genetic testing for children with atypical presentations.