Abstract

Introduction: Chile is divided into 15 regions, and most clinical immunologists are based in the capital city of Santiago. The health system is covered 75% by public and 25% by private insurance. Within the public system, primary care facilities refer patients to larger hospitals, and in turn those centers refer more complex patients to Santiago. Immunologists in Chile are scarce but have increased over the last 5 years. Primary immune deficiency (PID) awareness has improved during the last five years contributing to an increase in PID referrals. However, no genetic testing is available locally, and in most cases diagnosis is based on clinical presentation and functional flow cytometry studies, which are only available only in Santiago and Temuco. Therefore, genetic causes for most of PID patients in Chile remain unknown. We hypothesized that due to the unique geographical characteristics and cultural admixture of Chile, novel PID causing genes would be identified using an unbiased sequencing approach.. Objectives: We report a cohort of Chilean patients with unknown PIDs in which whole exome sequencing (WES) was performed. Results: More than 30 family trios (proband and parents) with undiagnosed PIDs and strong heterogeneous proband phenotypes were referred to the Center for Human Immunobiology at Texas Children’s Hospital in collaboration with the Center for Mendelian Genomics for genomic analysis. Nine patients in this cohort fulfilled criteria for hemophagocytic lymphohistiocytosis (HLH). Other common phenotypes included were hyper-IgE syndrome (n=4) and combined immunodeficiency (n=3). Analysis has been completed for 19 trios. A known genetic cause of PID was found in 6 patients; 5 of which correspond to either an expanded or a blended phenotype. A strong novel candidate gene was identified in at least 3 families (5 patients), one of which has been functionally confirmed. Conclusion: The epidemiology of PIDs in Chile is currently unknown, and genetic diagnostic testing is not currently available. Our results showing diagnosis, phenotypic expansion and potential new genetic causes of PID suggest WES is a useful tool for both diagnosis and identification of new PID genes in Chile. Further analysis of this cohort may contribute to understanding the underlying pathways of known and novel PIDs.