Mutation analysis in primary immunodeficiency diseases: case studies.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Laboratory of Clinical Infectious Disease, NIAID, National Institutes of Health, Bethesda, Maryland, USA.
Amy P
AP
Hsu
Thomas A
TA
Fleisher
Julie E
JE
Niemela
D056735:Autoimmune Lymphoproliferative Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D001424:Bacterial Infections / Q000276:immunology; D023201:CD40 Ligand / Q000235:genetics; D002648:Child; D004252:DNA Mutational Analysis; D003951:Diagnostic Errors; D053358:Ectodermal Dysplasia 1, Anhidrotic / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D005260:Female; D006801:Humans; D053307:Hyper-IgM Immunodeficiency Syndrome, Type 1 / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D051550:I-kappa B Kinase / Q000235:genetics; D007223:Infant; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics; D008206:Lymphatic Diseases; D008297:Male; D009154:Mutation; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D016511:Severe Combined Immunodeficiency / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology
C491731:IKBKG protein, human; D053631:Interleukin Receptor Common gamma Subunit; D023201:CD40 Ligand; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D051550:I-kappa B Kinase