The clinical utility of molecular diagnostic testing for primary immune deficiency disorders: a case based review

Primary immune deficiency disorders (PIDs) were first identified in 1952, with the description of agammaglobulinemia by Bruton [1]. In the last few years, the genetic basis of many PID disorders has been identified [2,3]. Most are inherited as single gene defects. Several are X-linked, which accounts for the preponderance of PIDs amongst males. While rare, most are amenable to specific treatment. For example, successful haematopoeitic stem cell transplantation may be curative in patients with severe combined immune deficiency syndrome (SCID). In other PIDs, delayed diagnosis may be associated with disabling complications such as bronchiectasis [4].Clinical history and physical examination can be helpful in identifying PIDs and the need for further investigation. Once these patients are referred to an immunologist, other tests including vaccine responses can be undertaken [5,6]. Further advanced tests including the enumeration of subsets of lymphocytes using flow cytometry can be useful in evaluating patients [7,8]. For instance, NKT cells may be absent in patients with some forms of X-linked lymphoproliferative disease (XLP), which is caused by mutations in the SH2D1A or XIAP genes [9]. Elevated double-negative CD4-CD8- TCR alpha/beta+ T (DNT) cells are useful markers for autoimmune lymphoproliferative syndrome due to mutations in the fas gene [10]. Ultimately, however, identification of the molecular basis of the disorder will secure the diagnosis. We believe molecular diagnostic testing is a critical part of modern patient management and should be regarded as the standard of care.We have described the development of a customised molecular testing service for PIDs at Auckland City Hospital [11]. We offer full length (Sanger) sequencing with results within a week if the test is established, or two to three weeks for a customised test [11]. In patients with a typical phenotype but normal genomic sequence we offer cDNA sequencing to exclude the possibility of a comple