Genetic cause of rare childhood immune disorders discovered

Researchers at Newcastle University have identified mutations in the NUDCD3 gene associated with Severe Combined Immunodeficiency (SCID) and Omenn syndrome, rare and life-threatening immunodeficiency disorders. This discovery, involving experts from Newcastle University, the Great North Children’s Hospital, and the Wellcome Sanger Institute, is published in Science Immunology. These mutations hinder the proper development of diverse immune cells necessary to combat various pathogens, paving the way for early diagnosis and intervention.

The study, led by Professor Sophie Hambleton, a senior author at Newcastle University and practising paediatric immunologist at the Great North Children’s Hospital, aims to enable families to achieve a molecular diagnosis and advance the understanding of the immune system in health and disease. “Our research is aimed at filling in the gaps so that families can achieve a molecular diagnosis while we continue learning more about how the immune system works in health and disease,” Hambleton said.

In this study, researchers examined 11 children from four families, revealing that mutations impairing the NUDCD3 protein’s function are linked to these conditions. This protein had not previously been associated with the immune system. Professor Hambleton noted the importance of understanding these underlying causes to improve treatment for affected babies. “SCID and Omenn syndrome are devastating disorders, requiring complex and timely treatments. The more we can understand about its underlying causes, the better we can look after affected babies. We are deeply grateful to the families whose invaluable participation in this study will help future generations.” she added.

Detailed studies of patient-derived cells and mouse models demonstrated that NUDCD3 mutations disrupt V(D)J recombination, essential for creating diverse T cell receptors and antibodies to fight various pathogens. While mice with these mutations experienced milder issues, human patients faced severe, life-threatening consequences. However, two patients survived after stem cell transplants, underscoring the importance of early diagnosis and intervention.

Dr Gosia Trynka from the Wellcome Sanger Institute emphasised the impact of early detection. “For babies born with high-risk immunodeficiencies, early detection can mean the difference between life and death. These diseases leave newborns essentially defenceless against pathogens that most of us can easily fend off. The identification of this new disease gene will help clinicians to make a prompt molecular diagnosis in affected patients, meaning they can receive life-saving treatments more quickly,” Trynka said.

Reference: R. Chen, E. Lukianova et al. (2024) ‘NUDCD3 deficiency disrupts V(D)J recombination to cause SCID/Omenn syndrome.’ Science Immunology. DOI: 10.1126/sciimmunol.ade5705