Deletion of the SPAG9 gene cause autosomal‐recessive intellectual disability

Intellectual disability (ID) is the limitation of intellectual functioning and adaptive behavior before 18 years of age. In a consanguineous family of 149 members, this disease is expressed in 9 individuals. Here, we report one branch of a family tree with three siblings, presenting severe ID, delayed speech development, cataracts, strabismus, gait disturbance, cerebellar syndrome, seizures in one of them, and eyelid ptosis in two. Brain magnetic resonance imaging (MRI) with hippocampal malrotation, brain atrophy and white matter hyperintensities in all cases. Thinning of the corpus callosum in two of them.We conducted whole exome sequencing analysis in nine subjects from one multigenerational family of Colombian origin. The study was carried out at the University of Antioquia,Colombia with the approval of the ethics committee. A medical, neurological, neuropsychological examination and brain MRI were performed in all cases.We identified a single nucleotide deletion in the SPAG9 gene, which codes for the JIP4 protein. The frameshift generates a premature stop codon (p.Tyr914Ter). The deletion is classified as pathogenic, according to the ACMG / AMP guidelines. The variant co-segregated in the respective family as an autosomal recessive trait.JIP 4 has two functions: As scaffold protein that potentiates the p38 MAPK signaling cascade under stress conditions and as dynein-dynactin motor adapter for lysosomal retrograde flow, regulating the constitutive transport of lysosomes. Both functions could be associated in the disease mechanism. The absence of JIP 4 may be responsible for the disease in the family, altering neuronal homeostasis.