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Mutation analysis in primary immunodeficiency diseases: case studies.

ABSTRACT: PURPOSE OF REVIEW:The application of mutation analysis is becoming an integral part of the complete evaluation of patients with primary immunodeficiencies, and as such, clinicians caring for these patients must develop a better understanding of the utility and challenges of this important laboratory technology. RECENT FINDINGS:Genomic DNA sequencing is currently the standard approach used to characterize a possible gene mutation causing a specific primary immunodeficiency. There are clinical situations in which this approach is revealing of a genetic defect and other circumstances in which this generates a false-positive or false-negative result. One case study is presented that reviews a straightforward analysis that clarifies the genetic basis of a primary immunodeficiency, and four cases are presented that required additional studies to clarify the underlying basis of the immunodeficiency. In the latter circumstances, the rationale for additional studies is outlined and the outcome of these is presented. SUMMARY:The identification of a gene mutation as the underlying basis of a primary immunodeficiency begins with the evaluation of the clinical presentation focusing on the infection history so as to develop a differential diagnosis including potential genetic causes. The next step is to obtain specific laboratory studies, including immunologic function evaluation, and, based on these findings, to proceed with DNA sequencing of one or several selected candidate genes. Genomic DNA sequencing has certain limitations, and alternative follow-up approaches may be necessary to establish the molecular basis of the primary immunodeficiency in a given patient.

SUBMITTER: Hsu AP

PROVIDER: S-EPMC2774237 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Mutation analysis in primary immunodeficiency diseases: case studies.

Hsu Amy P AP Fleisher Thomas A TA Niemela Julie E JE

Current opinion in allergy and clinical immunology 20091201 6

<h4>Purpose of review</h4>The application of mutation analysis is becoming an integral part of the complete evaluation of patients with primary immunodeficiencies, and as such, clinicians caring for these patients must develop a better understanding of the utility and challenges of this important laboratory technology.<h4>Recent findings</h4>Genomic DNA sequencing is currently the standard approach used to characterize a possible gene mutation causing a specific primary immunodeficiency. There a ...[more]

PMID: 19841577

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Project description:Primary immunodeficiency (PID) refers to a group of heterogeneous genetic disorders with a weakened immune system. Mendelian susceptibility to mycobacterial disease (MSMD) is a subset of PID in which patients exhibit defects in intrinsic and innate immunity. It is a rare congenital disorder characterized by severe and recurrent infections caused by weakly virulent mycobacteria or other environmental mycobacteria. Any delay in definitive diagnosis poses a major concern due to the confounding nature of infections and immune deficiencies. Here, we report the clinical, immunological, and genetic characteristics of two siblings (infants) with recurrent infections. There was a history of death of two other siblings in the family after BCG vaccination. Whole exome sequencing of the two affected surviving infants along with their consanguineous parents identified a novel, homozygous single nucleotide splice acceptor site variant in intron 2 of the interferon gamma receptor 2 (IFNGR2) gene. Sanger sequencing of DNA obtained from blood and fibroblasts confirmed the variant. The patients underwent bone marrow transplantation from their father as a donor. RT-PCR and Sanger sequencing of the cDNA of patients from blood samples after transplantation showed the expression of both wild type and mutant transcript expression of IFNGR2. To assess partial or complete expression of IFNGR2 mutant transcripts, fibroblasts were cultured from skin biopsies. RT-PCR and Sanger sequencing of cDNA obtained from patient fibroblasts revealed complete expression of mutant allele and acquisition of a cryptic splice acceptor site in exon 3 that resulted in deletion of 9 nucleotides in exon 3. This led to an in-frame deletion of three amino acids p.(Thr70-Ser72) located in a fibronectin type III (FN3) domain in the extracellular region of IFNGR2. This illustrates individualized medicine enabled by next generation sequencing as identification of this mutation helped in the clinical diagnosis of MSMD in the infants as well as in choosing the most appropriate therapeutic option.

Dataset Information

Mutation analysis in primary immunodeficiency diseases: case studies.

Publications

Mutation analysis in primary immunodeficiency diseases: case studies.

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