RESUMO
BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a rare neuroimmunology disorder predominantly affecting the East Asia population, the reason for this preference remains unknown. Genetic factors such as polymorphisms in human leukocyte antigen (HLA) and interleukins (IL) genes have been reported. Although the familial occurrence of NMOSD is rare, it supports that genetic factors may play a role. METHODS: Whole exome sequencing (WES) study was performed on the affected mother and daughter, as well as the unaffected father in a Taiwanese family with NMOSD. A cohort of 19 sporadic patients with aquaporin 4 antibody (AQP4-Ab) positive NMOSD was also recruited; all fulfilled the 2015 International NMOSD Diagnosis Criteria. Sanger sequencing was performed on exon 4 of the CD33 gene on the sporadic NMOSD cohort. RESULTS: WES study revealed a 19 base pair deletion in exon 4 of the CD33 gene, resulting in frameshift premature truncating protein, which segregated with the affected status. CD33 was the most likely candidate gene due to its known function in immune regulation. A total of 19 sporadic NMOSD patients were tested using Sanger sequencing, including 3 patients with other concomitant autoimmune disorders. Two additional NMOSD patients were found to have the same CD33 frameshift variant, which accounts for 19.04% of all NMOSD patients, and 15% following correction for the familial cases; compared to 2% in Taiwanese population controls. CONCLUSION: In this study, we identified a 19 base pair deletion in the CD33 gene may be a potential risk locus for NMOSD, which is predicted to cause loss of function of CD33. The loss of CD33 inhibitory function may affect the regulation of the immune system in NMOSD patients. This finding requires further larger cohorts of NMOSD patients and functional study to corroborate.