Mutation Analysis Of Selected Lymphoid Immune Disorders

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Abstract

This project represents an extension of a long-standing 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) are being evaluated using direct gene sequencing 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 begane with an extensive evaluation of the gene encoding FAS (TNFRSF6) that confirmed 9 SNPs and identified two new SNPs among the control DNA samples evaluated. This was followed by the inclusion of mutation analysis of patients with hyper IgM syndrome directed at the genes encoding CD40L and NEMO with the latter focusing on a host of clinical phenotypes beyond the hyper IgM syndrome that has provided insight into genotype-phenotype variability. Additional sequencing for immune deficiency associated mutations has been added to deal with current protocols within NIAID focused on host defense defects with recurrent infections involving opportunisitc intracellular organisms including genes encoding the interferon gamma receptor 1 and 2, the IL-12P40 and IL-12 receptor beta 1 genes. A host of new mutations have been identified among all genes that are now being sequenced and over the past fiscal year a number of additional genes have been added to the repertoire including genes encoding: AIRE, ARTEMIS, BTK, FOXP3, ICOS, IL-7Ralpha, JAK3, mu heavy chain,SAP, WASp. The most recent additions to the mutation analysis menu represent a collaborative effort with investigators from the LHD and LCID in NIAID including the acquisition of an additional capillary sequencer supported by funds from the Scientific Director of NIAID. This program has expanded the number of genes evaluated associated with primary immunodeficiencies to 43: AID, CD40L, FAS, FASLG, KRAS, NRAS, IFNGR1, IFNGR2, IL12RB1, IL12B, IL2RG, NEMO, AIRE, BTK, CASP8, CASP9, CASP10, DKC1, ELA2, FOXP3, ICOS, IKBA, IRAK4, ITK, IL2RA, JAK3, LIG4, MYD88, NBN, NHEJ1, PRF1, RAG1, RAG2, STAT1, STAT3, STIM1, STX11, UNC13D, WAS, XIAP, SAP/SH2D1A, TLR3, ORAI1. In addition, we are now working on a NextGen approach to screening for specific immune defects focusing on disorders with common clinical phenotypes - this approach can prove to increase the speed with which a mutation is identified in a new patient as well as decrease the overall cost for this evaluation. Additional genetic defects associated with primary immunodeficiency disorders have been validated and are now included in the evaluation of CC patients with unknown immune disorders. In addition, the Next Gen resequencing platform, Ion Torrent, has been acquired and is in the process of validating a 150 gene chip to screen for primary immunodeficiencies.