Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.
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Stray-Pedersen Asbjørg, Sorte Hanne Sørmo, Samarakoon Pubudu, Gambin Tomasz, Chinn Ivan K, Coban Akdemir Zeynep H, Erichsen Hans Christian, Forbes Lisa R, Gu Shen, Yuan Bo, Jhangiani Shalini N, Muzny Donna M, Rødningen Olaug Kristin, Sheng Ying, Nicholas Sarah K, Noroski Lenora M, Seeborg Filiz O, Davis Carla M, Canter Debra L, Mace Emily M, Vece Timothy J, Allen Carl E, Abhyankar Harshal A, Boone Philip M, Beck Christine R, Wiszniewski Wojciech, Fevang Børre, Aukrust Pål, Tjønnfjord Geir E, Gedde-Dahl Tobias, Hjorth-Hansen Henrik, Dybedal Ingunn, Nordøy Ingvild, Jørgensen Silje F, Abrahamsen Tore G, Øverland Torstein, Bechensteen Anne Grete, Skogen Vegard, Osnes Liv T N, Kulseth Mari Ann, Prescott Trine E, Rustad Cecilie F, Heimdal Ketil R, Belmont John W, Rider Nicholas L, Chinen Javier, Cao Tram N, Smith Eric A, Caldirola Maria Soledad, Bezrodnik Liliana, Lugo Reyes Saul Oswaldo, Espinosa Rosales Francisco J, Guerrero-Cursaru Nina Denisse, Pedroza Luis Alberto, Poli Cecilia M, Franco Jose L, Trujillo Vargas Claudia M, Aldave Becerra Juan Carlos, Wright Nicola, Issekutz Thomas B, Issekutz Andrew C, Abbott Jordan, Caldwell Jason W, Bayer Diana K, Chan Alice Y, Aiuti Alessandro, Cancrini Caterina, Holmberg Eva, West Christina, Burstedt Magnus, Karaca Ender, Yesil Gözde, Artac Hasibe, Bayram Yavuz, Atik Mehmed Musa, Eldomery Mohammad K, Ehlayel Mohammad S, Jolles Stephen, Flatø Berit, Bertuch Alison A, Hanson I Celine, Zhang Victor W, Wong Lee-Jun, Hu Jianhong, Walkiewicz Magdalena, Yang Yaping, Eng Christine M, Boerwinkle Eric, Gibbs Richard A, Shearer William T, Lyle Robert, Orange Jordan S, Lupski James R
Аннотация
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.