Hyuk Jee1, Zhengping Huang2, Samantha Baxter3, Yuelong Huang4, Maria L Taylor1, Lauren A Henderson1, Sofia Rosenzweig5, Aman Sharma6, Eugene P Chambers7, Michael S Hershfield8, Qing Zhou9, Fatma Dedeoglu1, Ivona Aksentijevich5, Peter A Nigrovic10, Anne O'Donnell-Luria11, Pui Y Lee12. 1. Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass. 2. Department of Rheumatology and Immunology, Guangdong Second Provincial General Hospital, Guangzhou, China; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. 3. Center for Mendelian Genomics, The Broad Institute of MIT and Harvard, Cambridge, Mass. 4. Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. 5. Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Md. 6. Clinical Immunology and Rheumatology Services, Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India. 7. Department of Surgery, Vanderbilt University Medical Center, Nashville, Tenn; DADA2 Foundation, Nashville, Tenn. 8. Department of Medicine and Biochemistry, Duke University School of Medicine, Durham, NC. 9. Life Sciences Institute, Zhejiang University, Zhejiang, China. 10. Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. 11. Center for Mendelian Genomics, The Broad Institute of MIT and Harvard, Cambridge, Mass; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Mass. 12. Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. Electronic address: pui.lee@childrens.harvard.edu.
Abstract
BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by deleterious ADA2 variants. The frequency of these variants in the general population, and hence the expected disease prevalence, remain unknown. OBJECTIVE: We aimed to characterize the functional impact and carrier frequency of ADA2 variants. METHODS: We performed functional studies and in silico analysis on 163 ADA2 variants, including DADA2-associated variants and population variants identified in the Genome Aggregation Database. We estimated the carrier rate using the aggregate frequency of deleterious variants. RESULTS: Functional studies of ADA2 variants revealed that 77 (91%) of 85 of DADA2-associated variants reduced ADA2 enzymatic function by >75%. Analysis of 100 ADA2 variants in the database showed a full spectrum of impact on ADA2 function, rather than a dichotomy of benign versus deleterious variants. We found several in silico algorithms that effectively predicted the impact of ADA2 variants with high sensitivity and specificity, and confirmed a correlation between the residual function of ADA2 variants in vitro and the plasma ADA2 activity of individuals carrying these variants (n = 45; r = 0.649; P < .0001). Using <25% residual enzymatic activity as the cutoff to define potential pathogenicity, integration of our results with the database population data revealed an estimated carrier frequency of at least 1 in 236 individuals, corresponding to an expected DADA2 disease prevalence of ~1 in 222,000 individuals. CONCLUSIONS: Functional annotation guides the interpretation of ADA2 variants to create a framework that enables estimation of DADA2 carrier frequency and disease prevalence.
BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by deleterious ADA2 variants. The frequency of these variants in the general population, and hence the expected disease prevalence, remain unknown. OBJECTIVE: We aimed to characterize the functional impact and carrier frequency of ADA2 variants. METHODS: We performed functional studies and in silico analysis on 163 ADA2 variants, including DADA2-associated variants and population variants identified in the Genome Aggregation Database. We estimated the carrier rate using the aggregate frequency of deleterious variants. RESULTS: Functional studies of ADA2 variants revealed that 77 (91%) of 85 of DADA2-associated variants reduced ADA2 enzymatic function by >75%. Analysis of 100 ADA2 variants in the database showed a full spectrum of impact on ADA2 function, rather than a dichotomy of benign versus deleterious variants. We found several in silico algorithms that effectively predicted the impact of ADA2 variants with high sensitivity and specificity, and confirmed a correlation between the residual function of ADA2 variants in vitro and the plasma ADA2 activity of individuals carrying these variants (n = 45; r = 0.649; P < .0001). Using <25% residual enzymatic activity as the cutoff to define potential pathogenicity, integration of our results with the database population data revealed an estimated carrier frequency of at least 1 in 236 individuals, corresponding to an expected DADA2 disease prevalence of ~1 in 222,000 individuals. CONCLUSIONS: Functional annotation guides the interpretation of ADA2 variants to create a framework that enables estimation of DADA2 carrier frequency and disease prevalence.
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Authors: Karyl S Barron; Ivona Aksentijevich; Natalie T Deuitch; Deborah L Stone; Patrycja Hoffmann; Ryan Videgar-Laird; Ariane Soldatos; Jenna Bergerson; Camilo Toro; Cornelia Cudrici; Michele Nehrebecky; Tina Romeo; Anne Jones; Manfred Boehm; Jennifer A Kanakry; Dimana Dimitrova; Katherine R Calvo; Hawwa Alao; Devika Kapuria; Gil Ben-Yakov; Dominique C Pichard; Londa Hathaway; Alessandra Brofferio; Elisa McRae; Natalia Sampaio Moura; Oskar Schnappauf; Sofia Rosenzweig; Theo Heller; Edward W Cowen; Daniel L Kastner; Amanda K Ombrello Journal: Front Immunol Date: 2022-01-10 Impact factor: 7.561