A team of researchers has discovered the genetic cause of certain severe immunodeficiency disorders in newborns. These findings could lead to the development of screening methods and new treatments. The study, which involved 11 individuals with the condition, was conducted by scientists from Newcastle University, the Wellcome Sanger Institute, the Great North Children’s Hospital, and their partners. They identified mutations in the NUDCD3 gene as being linked to Severe Combined Immunodeficiency and Omenn syndrome.1 – uncommon and dangerous immunodeficiency disorders. These genetic changes hindered the normal growth of various immune cells necessary to fight off various pathogens2.
The results, released today (24 May) in Science Immunology, create opportunities for early detection and intervention for this condition.
Severe Combined Immunodeficiency (SCID) and Omenn syndrome are both uncommon genetic disorders that leave children without a functional immune system and at risk of life-threatening infections. Without immediate treatment, such as stem cell transplants to replace the faulty immune system.
Many individuals affected by severe combined immunodeficiency (SCID) will not survive their first year due to the lack of a functioning immune system.
Newborn screening methods can detect T cell deficiency, but identifying the specific genetic cause is crucial for an accurate diagnosis of SCID and to determine the most effective treatment. Unfortunately, this knowledge is not accessible to at least 10% of affected families.
In a recent study, researchers from Newcastle University, the Wellcome Sanger Institute, and their partners examined 11 children from four families. Two children had SCID, while the other nine had Omenn syndrome. All of them had inherited mutations that impaired the NUDCD3 protein’s function, a previously unknown genetic cause.The immune system has previously been associated with autism. Detailed studies of patient-derived cells and mouse models have shown that mutations in NUDCD3 impair an important gene-rearranging process known as V(D)J recombination. This process is crucial for generating diverse T cell receptors and antibodies that are necessary to identify and combat various pathogens. While mice with the same NUDCD3 mutations had less severe immune problems, human patients experienced severe, life-threatening consequences. Two patients did survive after receiving a stem cell transplant, highlighting the importance of this procedure.Importance of early diagnosis and intervention is crucial for babies born with high-risk immunodeficiencies, according to Dr. Gosia Trynka, the author of the study at the Wellcome Sanger Institute and science director at Open Targets. She emphasized that early detection can make the difference between life and death for these newborns, who are defenseless against pathogens that most people can easily fight off. Identifying a new disease gene will enable clinicians to promptly diagnose affected patients at a molecular level, allowing them to receive life-saving treatments more quickly. Professor Sophie Hambleton, the senior author of the study at Newcastle, also emphasized the significance of early diagnosis and intervention in these cases.University and practicing paediatric immunologist at the Great North Children’s Hospital, stated that severe combined immunodeficiency (SCID) and Omenn syndrome are extremely serious conditions that require intricate and prompt treatments. The more knowledge we gain about the root causes of these disorders, the better equipped we will be to care for affected infants. Our research is focused on filling in the missing pieces so that families can receive a molecular diagnosis while we continue to expand our understanding of how the immune system functions in both health and disease. We are profoundly thankful to the families whose invaluable participation in this study will benefit future generations.”
Notes
1. Children with severeThe combined immunodeficiency disorder causes a complete lack of T cells, which are necessary to fight infections. On the other hand, people with Omenn syndrome have abnormal T cells that not only fail to combat infections but also attack the body’s own tissues. This requires immediate management and treatment of infections.
2. More specifically, the mutant NUDCD3 was unable to regulate RAG1, an important enzyme needed for V(D)J recombination. As a result, RAG1 became trapped within cell nucleoli instead of facilitating the gene rearrangements that create immune diversity.
