An exploration of inborn errors of immunity in an Australian cohort in the era of genomics

Inborn errors of immunity (IEIs) are monogenic diseases which involve defects of anti-microbial defences and/or immune regulation. There are more than 350 known IEI genes and widespread implementation of genomic technologies has greatly enhanced the identification of genetic variants associated with these diseases. However, reliably inferring the pathogenicity of novel variants in known or novel genes can be difficult. A primary aim of this study was to recruit a cohort of IEI patients for immunogenetic investigations including panel, whole exome and whole genome sequencing, and to interrogate novel clinical and genotypic features of these diseases. An additional primary aim was to identify novel genes underlying IEIs. The overall cohort includes 118 patients, 91 of whom underwent genomic sequencing, mostly through affiliates of the CIRCA consortium. A number of patients were the stimulus for collaborative studies revealing novel genotypic and phenotypic findings relating to UNC13D, SH2D1A, MAGT1, IL2RG, TMEM173, FAS, and DOCK8 genes, while others have contributed to large studies of the molecular effects of rare IEIs. Three studies revealed novel genetic mechanisms for known disease-associated genes: mild IPEX due to isoform-specific FOXP3 deficiency; severe gain-of-function SAMD9L disease associated with truncating mutations; and compound heterozygous TNFAIP3 deficiency. Three other groups were enlisted into international gene discovery studies, which identified: an auto-inflammatory syndrome associated with de novo mutations in OAS1; a hyper IgE syndrome caused by recessive mutations in ZNF341; and the cause of Roifman syndrome as compound heterozygous RNU4ATAC mutations. Finally, a new type of Mendelian disease was discovered, an ‘anticodonopathy’, resulting from translational infidelity secondary to a non-synonymous mutation in the anticodon of a transfer RNA, and manifesting as humoral immunodeficiency. By adopting an opportunistic and collaborative approach, and combining smaller studies of known genes with more impactful studies of novel genes and genetic mechanisms, this thesis represents a broad and important addition to the study of IEIs in Australia and globally. By introducing Australian patients to international gene discovery projects, while establishing similar studies locally, the project has helped to put in place structures that will support IEI research into the future