Discovering a genetic cause behind rare immune disorders in childhood

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Scientists have identified genetic changes that cause rare childhood immune disorders that leave children with reduced immune defense against infection.

In the new study of 11 patients, researchers from the University of Newcastle, the Wellcome Sanger Institute, Great North Children's Hospital and their collaborators were able to link mutations in the NUDCD3 gene to severe combined immunodeficiency and Umen syndrome, a rare and life-threatening immunodeficiency disorder.

These mutations prevented the normal development of various immune cells needed to combat various pathogens.

The results, published in the journal Science Immunology, open opportunities for early diagnosis and intervention for this condition.

Severe combined immunodeficiency (SCID) and Omen syndrome are rare genetic disorders that leave children without a functioning immune system and at risk of life-threatening infections.

Without urgent treatment, such as a stem cell transplant to replace the defective immune system, many affected people will not live their first year.

While newborn screening methods can indicate T-cell deficiency, knowledge of the specific genetic cause increases confidence in the diagnosis of severe combined immunodeficiency and determines the choice of treatment.

Currently, this remains out of reach for at least one in 10 affected families.

In this new study, researchers from the University of Newcastle, the Wellcome Sanger Institute and their collaborators studied 11 children from four families, two of whom had severe combined immunodeficiency and the other nine had Omen syndrome.

They all inherited mutations that disrupted the function of the NUDCD3 protein, which was not previously associated with the immune system.

Using detailed studies of patient-derived cells and mouse models, the team demonstrated that NUDCD3 mutations impair a crucial gene rearrangement called V(D)J recombination, which is essential for generating the diverse T-cell receptors and antibodies needed to recognize and fight various pathogens.

While mice with the same NUDCD3 mutations had milder immune problems, human patients faced severe, life-threatening consequences. However, two patients survived after receiving a stem cell transplant, reinforcing the importance of early diagnosis and intervention.

“For babies born with high-risk immunodeficiency, early detection can mean the difference between life and death,” said Dr. Josia Trinca, study author at the Wellcome Sanger Institute and scientific director at Open Targets. “These diseases leave newborns essentially defenseless.” "Against pathogens that most of us can easily fend off. Identifying this new disease gene will help doctors make a rapid molecular diagnosis of affected patients, meaning they can receive life-saving treatments more quickly."