Identification and characterization of noncoding mutations causing autoinflammatory diseases
General Genetics and Functional Genome Biology
Final Report Abstract
In summary, during my time at the NHGRI, I used a variety of genomic datasets to identify non-coding variants causative for the pathogenesis of autoinflammatory and autoimmune diseases. The combined application of bioinformatic and wet-lab experiments over the course of the projects presented above was fruitful in different aspects. First, a definite diagnosis could be made for several patients seen in the NHGRI Inflammatory Disease Section and consequently helped to guide therapy for these patients. Most of them had been on a diagnostic odyssey for many years and the identification of the disease-causing variant or variants often affected the immediate treatment strategy and helped to improve their quality of life. In most of the described cases, the pathogenic variant was not located within a novel regulatory element, but rather in already established non-coding regions, such as gene promoters or splice regulatory regions. Nevertheless, these variants were missed by standard genetic analyses, including exome sequencing, and more comprehensive testing methods and subsequent functional analyses were needed to establish the pathogenicity of these variants. Second, a GWAS on an African American cohort of patients with systemic sclerosis (SSc) led to the identification of several susceptibility loci including one variant located within a potential regulatory region for the TGFB3 gene. These findings help to explain the higher prevalence and more severe phenotype of SSc in the African American population and pinpointed the TGFB3 signaling pathway as a potential target for novel therapies. Additional studies including the generation of an animal model are still ongoing but will hopefully help to further support the significance of the identified regulatory region. Third, a targeted gene approach in patients with Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) was used to identify a noncoding variant upstream of IL-12 which is significantly associated with disease. In vitro experiments using patient cells showed that this variant significantly increased IL-12p70 production from monocytes upon stimulation, indicating that individuals carrying the risk allele exhibit elevated Th1 cell activation. This finding supports the potential efficacy of ustekinumab, a monoclonal antibody targeting the p40 subunit of IL-12 as therapy for severe cases of PFAPA. Lastly, I screened for pathogenic variants in ADA2 in patients with idiopathic PAN, granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA) and found that a subset of patients with idiopathic PAN meet genetic criteria for deficiency of ADA2. Given that TNF-inhibitors are highly efficacious in DADA2 but are not the standard therapy for PAN, these results suggest that ADA2 testing should be strongly considered in patients with idiopathic PAN with onset of symptoms earlier than age 25 years.
Publications
- Mendelian diseases of dysregulated canonical NF-𝜿B signaling: From immunodeficiency to inflammation. J Leukoc Biol
Schnappauf O., Aksentijevich I
(See online at https://doi.org/10.1002/jlb.2mr0520-166r) - Disrupted N-linked glycosylation as a disease mechanism in deficiency of ADA2. J Allergy Clin Immunol. 2018;142(4):1363-1365.e8.
Lee PY, Huang Y, Zhou Q, Schnappauf O., et al.
(See online at https://doi.org/10.1016/j.jaci.2018.05.038) - Thirty Years of Followup in 3 Patients with Familial Polyarteritis Nodosa due to Adenosine Deaminase 2 Deficiency. J Rheumatol. 2018;46(8):1059-1060
Liebowitz J, Hellmann DB, Schnappauf O
(See online at https://doi.org/10.3899/jrheum.180820) - Current and future advances in genetic testing in systemic autoinflammatory diseases. Rheumatology (Oxford). 2019;58(Suppl 6):vi44-vi55
Schnappauf O, Aksentijevich I
(See online at https://doi.org/10.1093/rheumatology/kez294) - The Pyrin Inflammasome in Health and Disease. Front Immunol. 2019;10:1745
Schnappauf O, Chae JJ, Kastner DL, Aksentijevich I
(See online at https://doi.org/10.3389/fimmu.2019.01745) - Deficiency of adenosine deaminase 2: Is it an elephant after all?. J Allergy Clin Immunol. 2020;145(6):1560-1561
Schnappauf O, Ombrello AK, Kastner DL
(See online at https://doi.org/10.1016/j.jaci.2020.04.023)
