NEIL3

Inheritance Pattern: AR

Disease ID:MONDO:0007179

Submitter: ClinGen

NEIL3 encodes Nei endonuclease VIII-like 3, a DNA glycosylase involved in the base excision repair pathway, with proposed roles in the repair of oxidative DNA damage, particularly in proliferating cells, including immune cells. Evidence involving NEIL3 is limited to a single published report describing 3 siblings with combined LRBA deficiency and NEIL3 variants, as well as one individual with isolated NEIL3 deficiency (Massaad et al., 2016). In this study, three siblings with biallelic LRBA deficiency and NEIL3 variants exhibited severe autoimmunity, while a female individual with NEIL3 deficiency alone demonstrated a mild phenotype characterized by the presence of autoantibodies without overt clinical autoimmunity. Functional studies in the report demonstrated that LRBA deficiency was associated with absent protein expression and was sufficient to explain the primary immune dysregulation phenotype, suggesting that NEIL3 functioned as a modifier enzyme, rather than acting as a primary disease-causing gene. This interpretation has been confirmed with Dr. Michel Massaad, first author of the JCI study, who stated that autoimmunity in the reported patients was primarily attributable to LRBA deficiency, with NEIL3 acting as a modifier. Consistent with this role, NEIL3 was not included as a gene implicated in immune dysregulation in the IUIS classification. To date, there are no additional independent reports establishing NEIL3 as a cause of a monogenic immune disorder, and there is no functional evidence demonstrating that NEIL3 deficiency alone results in a fully penetrant immune regulatory phenotype. While NEIL3 variants can modulate autoimmunity, particularly in the presence of other pathogenic variants, the available evidence does not support a definitive or limited gene–disease relationship. Based on the limited published data, NEIL3 is interpreted as a modifier gene that may modulate autoimmunity in the context of other disease-causing variants, rather than as a gene associated with an independent monogenic primary immune regulatory disorder. Therefore, the relationship between NEIL3 and immune dysregulation is classified as Disputed at this time.