This report outlines the clinical features of a complex neurological phenotype shared by three siblings from a consanguineous family, characterized by intellectual disabilities, speech developmental delay, gait disturbance, cerebellar syndrome signs, cataracts, and dysmorphic features (square and coarse facial features, thick lips, deep palate, small and spaced teeth, low-set ears, strabismus, eyelid ptosis, and blond hair). Seizures and brain atrophy were later evident. In the cosegregation analysis, five family members and 12 family controls were studied by whole-exome and Sanger sequencing. The structural and functional effects of the protein were explored to define the mutated variant's potential deleterious impairment. Neurological and neuropsychological follow-ups and brain magnetic resonance imaging (MRI) were performed. We identified a single frameshift homozygous nucleotide deletion in the SPAG9/JIP4 gene (NM_001130528.3): c.2742del (p. Tyr914Ter), causing a premature stop codon and truncating the protein and originating a possible loss of function. The variant cosegregated in affected individuals as an autosomal recessive trait. The in silico protein functional analyses indicate a potential loss of 66 phosphorylation and 29 posttranslational modification sites. Additionally, a mutated protein structure model shows a significant modification of the folding that very likely will compromise functional interactions. SPAG9/JIP4 is a dynein-dynactin motor adapter for retrograde axonal transport, regulating the constitutive movement of neurotrophic factor signaling and autophagy-lysosomal products. Under stress conditions, it can potentiate this transport by the p38 mitogen-activated protein kinases (p38MAPK) signaling cascade. Both functions could be associated with the disease mechanism, altering the axon's development and growth, neuronal specification, dendrite formation, synaptogenesis, neuronal pruning, recycling neurotransmitters and finally, neuronal homeostasis—promising common mechanisms to be used with investigational molecules for neurodevelopmental diseases and neurodegeneration.
