Scientists have found genetic mutations that can result in children having little to no immune defense against infections. In a recent study, researchers have linked mutations in the NudC domain–containing 3(NUDCD3) gene to severe combined immunodeficiency (SCID) and Omenn syndrome. These are rare, life-threatening immunodeficiency disorders that impede the development of diverse immune cells needed to fight various pathogens.
The findings, published in Science Immunology, have the potential to facilitate early diagnosis and intervention for severe immunodeficiencies. Severe combined immunodeficiency (SCID) and Omenn syndrome significantly increase the susceptibility of pediatric patients to life-threatening infections. Without prompt treatment, such as stem cell transplantation to replace the defective immune system, many affected children may not survive beyond their first year. While newborn screening can detect T cell deficiencies, pinpointing the precise genetic cause enhances diagnostic accuracy and informs therapeutic decisions. At present, this specific genetic identification remains unattainable for at least 10% of affected families.
The researchers examined 11 children from four families, two of whom had SCID and nine had Omenn syndrome. All inherited mutations that disrupted the NUDCD3 protein were previously unlinked to the immune system. Through detailed analyses of patient-derived cells and mouse models, the team showed that NUDCD3 mutations impair V(D)J recombination, a crucial process for generating diverse T cell receptors and antibodies necessary to combat pathogens. While mice with the same NUDCD3 mutations exhibited milder immune issues, human patients faced severe, life-threatening outcomes. However, two patients survived after receiving stem cell transplants, underscoring the importance of early diagnosis and treatment.
The researchers underscored that early detection is critical for neonates with high-risk immunodeficiencies. These conditions render newborns highly susceptible to infections that are typically non-threatening to the general population. The identification of this novel disease gene will enable clinicians to rapidly diagnose affected patients, thereby facilitating the timely administration of life-saving treatments. The current research aims to enable molecular diagnoses for families while advancing knowledge of the immune system in health and disease.
Reference
Chen R, Lukianova E, van der Loeff IS, Spegarova JS, Willet JDP, James KD, et al. NUDCD3 deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome. Science Immunology. 2024 May 24;9(95):eade5705.