Analysis of genetic overlap between inborn errors of immunity and neurodevelopmental disorders

Inborn errors of immunity (IEI), formerly known as primary immune deficiencies (PID), are a group of genetic disorders that affect the immune system, leading to increased susceptibility to infections, autoimmunity, allergy, and cancer. So far, 449 IEI-causing genes have been identified with more likely to be discovered with the rapid adoption of whole genome sequencing in clinical practice. Patients with IEI often present with neurological symptoms such as cognitive impairments, neurodevelopmental delay and even seizures. These clinical features could be indicative of an increased risk of neurodevelopmental disorders (NDDs) in IEI patient population. However, to date, no exhaustive study has been done on the genetic overlap between NDDs and IEIs. Using publicly available NDD and IEI variant databases, gene ontology analysis, machine learning, and protein-network clustering analysis, we found that one-third of IEI-causing genes were also linked to NDDs. These genes were primarily involved in immune development and DNA repair pathways. In contrast, genes causing exclusively IEIs were enriched in immune response functions. Functional connectivity analysis revealed that NDD-risk genes integrated immune-related networks, including those involved in DNA repair, highlighting immune-NDD interactions. Altogether, this work demonstrates a molecular and protein-network level overlap between NDD and IEI-causing genes. Our analysis strongly suggests that NDD phenotypes in IEI patients could be underreported in NDD-related databases.