Abstract
Objective: Patients with primary immunodeficiencies (PID) verified by clinical disease and standard immunological diagnostics but without a genetic diagnosis remain a challenge. Genetic diagnosis is important in order to plan follow-up and treatment possibilities including bone marrow transplantation and genetic counselling. Methods: We used array comparative genomic hybridization (aCGH) analysis to investigate a cohort of pediatric patients with PID of unknown genetic origin in order to investigate the diagnostic yield of applying this technique to such patients and in an attempt to identify new possible genetic explanations for immunodeficiencies. Results: Chromosomal imbalances were found in four of 14 investigated patients. In two cases a genetic diagnosis was established involving the SH2 domain-containing protein 1A gene (SH2D1A) and the Coronin-1a gene (CORO1A) causing atypical SLAM (signaling lymphocyte activation molecule)-associated protein (SAP) deficiency and Coronin-1a deficiency, respectively. Identification of the heterozygote deletion including the CORO1A gene by aCGH analysis led to sequencing of the other allele and identification of a novel point mutation. The clinical relevance of the deletions in the remaining two patients is not yet clarified but involves genes (the dedicator of cytokinesis 4 gene (DOCK4) and the protease, serine, 16 (thymus) gene (PRSS16) with suspected immunological functions. Conclusion: Applying aCGH analysis in case of rare severe symptoms of immunodeficiency may be of great importance in order to establish a diagnosis and treat the patients appropriately. We identified a case of atypical SAP deficiency with no comparable cases in the literature, and a case of Coronin-1a deficiency of which only two families have previously been described.
Highlights
The use of novel genomic techniques, coupled with an increased knowledge of molecular mechanisms of the immune system, have resulted in the identification of several novel primary immunodeficiencies (PIDs), but still many clinical entities remain without a genetic diagnosis [1,2]
We used array comparative genomic hybridization analysis to investigate a cohort of pediatric patients with PID of unknown genetic origin in order to investigate the diagnostic yield of applying this technique to such patients and in an attempt to identify new possible genetic explanations for immunodeficiencies
Identification of the heterozygote deletion including the CORO1A gene by array comparative genomic hybridization (aCGH) analysis led to sequencing of the other allele and identification of a novel point mutation
Summary
The use of novel genomic techniques, coupled with an increased knowledge of molecular mechanisms of the immune system, have resulted in the identification of several novel primary immunodeficiencies (PIDs), but still many clinical entities remain without a genetic diagnosis [1,2]. Patients with PID determined by molecular defects and clinical symptoms but without a genetic diagnosis remain a challenge in the clinical setting. We used array comparative genomic hybridization (aCGH) analysis to investigate a cohort of pediatric patients with PID of unknown genetic origin in order to ascertain the diagnostic yield of applying the technique to this group of patients and to identify new possible genetic explanations for immunodeficiencies. The clinical relevance of the deletions in the remaining patients has yet to be fully elucidated but involves the dedicator of cytokinesis 4 gene (DOCK4) and the protease, serine, 16 (thymus) gene (PRSS16), both with suspected immunological functions
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