This project represents a continuation of series of collaborative studies performed to better characterize and understand immune deficiency. Mutations involving the genes for the common gamma chain (X-SCID) and Fas (ALPS) were being evaluated using Sanger sequencing techniques of genomic DNA with fluorescent probes. These studies have continued to identify a number of new mutations in both diseases and these data have been entered into the NIH NHGRI web site supporting each of these two disorders. This was followed by the inclusion of mutation analysis of patients with hyper IgM syndrome directed at the genes encoding CD40L and NEMO followed by sequencing for immune deficiency associated mutations focused on host defense defects with recurrent infections involving opportunistic intracellular organisms including genes encoding the interferon gamma receptor 1 and 2, the IL-12P40 and IL-12 receptor beta 1 genes. Finally, new additional genes have been added to the repertoire including genes encoding: AIRE, ARTEMIS, BTK, FOXP3, ICOS, IL-7R alpha, JAK3, mu heavy chain,SAP, WASp. That initial work is now complemented by NextGen sequencing studies evaluating panels of genes or whole exome sequencing (WES) using the Ion Torrent platform, and more recently the Illumina platform. This approach allowed us to screen patients referred to the NIH and on clinical research protocols with suspected primary immunodeficiency disorders. To date this approach allowed us to contributed to the identification and further identification of patients with novel and previously known primary immunodeficiency defects that were further confirmed by Sanger sequencing and functional testing. Our experience to date suggests that this is a cost effective approach for screening referred patients with clear evidence of defects in host defense and that resequencing using the standard Sanger method under defined circumstances may not be necessary in the future.

Agency
National Institute of Health (NIH)
Institute
Clinical Center (CLC)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIACL010304-20
Application #
9785969
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Clinical Center
Department
Type
DUNS #
City
State
Country
Zip Code
Bogaert, Delfien J; Kuehn, Hye Sun; Bonroy, Carolien et al. (2018) A novel IKAROS haploinsufficiency kindred with unexpectedly late and variable B-cell maturation defects. J Allergy Clin Immunol 141:432-435.e7
Giannelou, Angeliki; Wang, Hongying; Zhou, Qing et al. (2018) Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors. Ann Rheum Dis 77:612-619
Heimall, Jennifer R; Hagin, David; Hajjar, Joud et al. (2018) Use of Genetic Testing for Primary Immunodeficiency Patients. J Clin Immunol 38:320-329
Heimall, Jennifer R; Hagin, David; Hajjar, Joud et al. (2018) Correction to: Use of Genetic Testing for Primary Immunodeficiency Patients. J Clin Immunol 38:540-541
Boutboul, David; Kuehn, Hye Sun; Van de Wyngaert, Zoé et al. (2018) Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency. J Clin Invest 128:3071-3087
Vargas-Hernández, Alexander; Mace, Emily M; Zimmerman, Ofer et al. (2018) Ruxolitinib partially reverses functional natural killer cell deficiency in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations. J Allergy Clin Immunol 141:2142-2155.e5
Ma, Chi A; Stinson, Jeffrey R; Zhang, Yuan et al. (2017) Corrigendum: Germline hypomorphic CARD11 mutations in severe atopic disease. Nat Genet 49:1661
Ma, Chi A; Xi, Liqiang; Cauff, Brian et al. (2017) Somatic STAT5b gain-of-function mutations in early onset nonclonal eosinophilia, urticaria, dermatitis, and diarrhea. Blood 129:650-653
Marciano, Beatriz E; Zerbe, Christa S; Falcone, E Liana et al. (2017) X-linked carriers of chronic granulomatous disease: Illness, lyonization, and stability. J Allergy Clin Immunol :
Delmonte, Ottavia M; Biggs, Catherine M; Hayward, Anthony et al. (2017) First Case of X-Linked Moesin Deficiency Identified After Newborn Screening for SCID. J Clin Immunol 37:336-338

Showing the most recent 10 out of 50 publications