Mind the gap - Exomes and CNVs testing in primary immunodeficiencies. A. Stray-Pedersen1,2, H. S. Sorte2, P. S. Samarakoon2, L. Forbes3,4, T. Gambin1, O. K. Rødningen2, I. C. Hanson3, L. M. Noroski3, C. Davis3, F. Seeborg3, S. K. Nicholas3, J. W. Caldwell5, C. R. Beck1, T. J. Vece6, W. Wiszniewski, SJ Penney1, S. N. Jhangiani1, L. Mæhle1, A. Patel7, H. C. Erichsen, TE Abrahamsen8,9, G. E. Tjonnfjord9,10, B. E. Kristiansen, M. Kulset2, L. T. Osnes11, W. T. Shearer3, B. Fevang12, K. R. Heimdal2, D. E. Undlien2,9, R. A. Gibbs1,13, R. Lyle2, J. S. Orange3,4, J. R. Lupski1,7,13,14, The Centers for Mendelian Genomics 1) Baylor-Hopkins Center for Mendelian Genomics at Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; 2) Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; 3) Immunology, Allergy and Rheumatology, Texas Childrens Hospital, Houston, TX; 4) Center for Human Immunobiology, Texas Childrens Hospital and Department of Pediatrics, Baylor College of Medicine, Houston, TX; 5) Section Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest Baptist Medical Center, Winston-Salem, NC; 6) Department of Pulmonology, Texas Childrens Hospital, Houston, TX; 7) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; 8) Department of Pediatrics, Oslo University Hospital, Oslo, Norway; 9) University of Oslo, Norway; 10) Department of Hematology, Oslo University Hospital, Oslo, Norway; 11) Department of Immunology, Oslo University Hospital, Oslo, Norway; 12) Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Oslo, Norway; 13) Human Genome Sequencing Center HGSC, Houston, TX; 14) Pediatrics, Baylor College of Medicine and Texas Childrens Hospital, Houston, TX.

   Primary immunodeficiencies (PIDDs) constitute a heterogenous group of genetic diseases affecting the immune system. Dependent on the genetic etiology, symptoms range from mild to severe and life threatening. Knowledge of the molecular genetic cause and disease mechanism is important and can direct targeted and curative therapy. However, categorization of the subtypes is challenging as patients with different immunodeficiencies may have overlapping immunological and clinical phenotypes. In addition, more than 200 causal genes have been reported, and few are offered for clinical diagnostic genetic testing. We examined the utility of combining exome sequencing (exomeSeq) and array comparative genomic hybridizaton (aCGH) in the diagnostic workup and research of PIDDs. As of June 2013, 120 patients with extensive immunological and genetic testing from 90 families have been recruited from Oslo University Hospital (Norway) and Texas Childrens Hospital (Houston, USA). Initial analyses were individually tailored based on clinical data and immunophenotyping and family history. ExomeSeq data was systematically screened for variants in all reported PIDD genes. Generally, exomeSeq data does not directly detect copy number variants (CNVs), but a computational CNV prediction pipeline was applied to predict potential PIDD-causing CNVs from the exomeSeq data. Predicted PIDD-causing variants were validated using custom high-resolution aCGH containing exon-wise probes. After analysing the exomeSeq data alone in the first 60 families (78 patients), five novel genes were identified. PIDD relevant variants were detected in 60 percent (41 families), 21 of these attaining a definitive molecular PIDD diagnosis. The remaining (20) patients had either a heterozygous potential disease-causing variant in a putative recessive condition or a previously reported PIDD-causing variant, but an unexpected or extended phenotype, or potential causative variants were detected in OMIM genes not previously reported in PIDD. No potential causative variants identified in 19 families. In 6 out of 60 families more than one PIDD-causing gene variant was involved, i.e. one family with 3 affected males with X-linked FANCB mutation combined with X-linked SH2D1A mutation. This study shows that exomeSeq is an efficient method to detect disease-causing variants in a large set of candidate genes. Combining data from exomeSeq and aCGH has proven useful and important to identify PIDD causing variants.

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