|Title||Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.|
|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Stray-Pedersen, A, Sorte, HSørmo, Samarakoon, P, Gambin, T, Chinn, IK, Akdemir, ZHCoban, Erichsen, HChristian, Forbes, LR, Gu, S, Yuan, B, Jhangiani, SN, Muzny, DM, Rødningen, OKristin, Sheng, Y, Nicholas, SK, Noroski, LM, Seeborg, FO, Davis, CM, Canter, DL, Mace, EM, Vece, TJ, Allen, CE, Abhyankar, HA, Boone, PM, Beck, CR, Wiszniewski, W, Fevang, B, Aukrust, P, Tjønnfjord, GE, Gedde-Dahl, T, Hjorth-Hansen, H, Dybedal, I, Nordøy, I, Jørgensen, SF, Abrahamsen, TG, Øverland, T, Bechensteen, AGrete, Skogen, V, Osnes, LTN, Kulseth, MAnn, Prescott, TE, Rustad, CF, Heimdal, KR, Belmont, JW, Rider, NL, Chinen, J, Cao, TN, Smith, EA, Caldirola, MSoledad, Bezrodnik, L, Reyes, SOswaldo Lu, Rosales, FJEspinosa, Guerrero-Cursaru, NDenisse, Pedroza, LAlberto, Poli, CM, Franco, JL, Vargas, CMTrujillo, Becerra, JCarlos Ald, Wright, N, Issekutz, TB, Issekutz, AC, Abbott, J, Caldwell, JW, Bayer, DK, Chan, AY, Aiuti, A, Cancrini, C, Holmberg, E, West, C, Burstedt, M, Karaca, E, Yesil, G, Artac, H, Bayram, Y, Atik, MMusa, Eldomery, MK, Ehlayel, MS, Jolles, S, Flatø, B, Bertuch, AA, I Hanson, C, Zhang, VW, Wong, L-J, Hu, J, Walkiewicz, M, Yang, Y, Eng, CM, Boerwinkle, E, Gibbs, RA, Shearer, WT, Lyle, R, Orange, JS, Lupski, JR|
|Journal||J Allergy Clin Immunol|
|Date Published||2017 01|
|Keywords||Adolescent, Adult, Aged, Child, Child, Preschool, DNA Copy Number Variations, Female, Genomics, High-Throughput Nucleotide Sequencing, Humans, Immunologic Deficiency Syndromes, Infant, Male, Middle Aged, Young Adult|
BACKGROUND: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions.
OBJECTIVE: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs.
METHODS: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping.
RESULTS: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays.
CONCLUSION: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.
|Alternate Journal||J Allergy Clin Immunol|
|PubMed Central ID||PMC5222743|
|Grant List||K23 NS078056 / NS / NINDS NIH HHS / United States |
R01 AI120989 / AI / NIAID NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States