Targeted next-generation sequencing: A novel diagnostic tool for primary immunodeficiencies

被引:113
作者
Nijman, Isaac J. [1 ]
van Montfrans, Joris M. [2 ]
Hoogstraat, Marlous [3 ]
Boes, Marianne L. [2 ]
van de Corput, Lisette [4 ]
Renner, Ellen D. [5 ]
van Zon, Patrick [1 ]
van Lieshout, Stef [1 ]
Elferink, Martin G. [1 ]
van der Burg, Mirjam [6 ]
Vermont, Clementien L. [7 ]
van der Zwaag, Bert [1 ]
Janson, Esther [1 ]
Cuppen, Edwin [1 ]
van Amstel, Johannes K. Ploos [1 ]
van Gijn, Marielle E. [1 ]
机构
[1] Univ Med Ctr Utrecht, Dept Med Genet, NL-3508 AB Utrecht, Netherlands
[2] Univ Med Ctr Utrecht, Dept Pediat Immunol & Infect Dis, NL-3508 AB Utrecht, Netherlands
[3] Univ Med Ctr Utrecht, Dept Med Oncol, NL-3508 AB Utrecht, Netherlands
[4] Univ Med Ctr Utrecht, Dept Immunol, NL-3508 AB Utrecht, Netherlands
[5] Univ Munich, Univ Childrens Hosp, Dept Immunol, Munich, Germany
[6] Univ Med Ctr Rotterdam, Dept Immunol, Erasmus MC, Rotterdam, Netherlands
[7] Leiden Univ, Dept Pediat Infect Dis Immunol & Stem Cell Transp, Med Ctr, NL-2300 RA Leiden, Netherlands
关键词
Primary immunodeficiency; diagnosis; genetics; next-generation sequencing; GENOMIC ENRICHMENT; WHOLE-EXOME; IDENTIFICATION; MUTATIONS;
D O I
10.1016/j.jaci.2013.08.032
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
Background: Primary immunodeficiency (PID) disorders are a heterogeneous group of inherited disorders caused by a variety of monogenetic immune defects. Thus far, mutations in more than 170 different genes causing PIDs have been described. A clear genotype-phenotype correlation is often not available, which makes a genetic diagnosis in patients with PIDs complex and laborious. Objective: We sought to develop a robust, time-effective, and cost-effective diagnostic method to facilitate a genetic diagnosis in any of 170 known PID-related genes by using next-generation sequencing (NGS). Methods: We used both targeted array-based and in-solution enrichment combined with a SOLiD sequencing platform and a bioinformatic pipeline developed in house to analyze genetic changes in the DNA of 41 patients with PIDs with known mutations and 26 patients with undiagnosed PIDs. Results: This novel NGS-based method accurately detected point mutations (sensitivity and specificity >99% in covered regions) and exonic deletions (100% sensitivity and specificity). For the 170 genes of interest, the DNA coverage was greater than 203 in 90% to 95%. Nine PID-related genes proved not eligible for evaluation by using this NGS-based method because of inadequate coverage. The NGS method allowed us to make a genetic diagnosis in 4 of 26 patients who lacked a genetic diagnosis despite routine functional and genetic testing. Three of these patients proved to have an atypical presentation of previously described PIDs. Conclusion: This novel NGS tool facilitates accurate simultaneous detection of mutations in 161 of 170 known PID-related genes. In addition, these analyses will generate more insight into genotype-phenotype correlations for the different PID disorders.
引用
收藏
页码:529 / +
页数:7
相关论文
共 24 条
[1]   Relevance of laboratory testing for the diagnosis of primary immunodeficiencies: A review of case-based examples of selected immunodeficiencies [J].
Abraham R.S. .
Clinical and Molecular Allergy, 9 (1)
[2]   Primary immunodefciency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Priary Immunodeficiency [J].
Al-Herz, Waleed ;
Bousfiha, Aziz ;
Casanova, Jean-Laurent ;
Chapel, Helen ;
Conley, Mary Ellen ;
Cunningham-Rundles, Charlotte ;
Etzioni, Amos ;
Fischer, Alain ;
Luis Franco, Jose ;
Geha, Raif S. ;
Hammarstrom, Lennart ;
Nonoyama, Shigeaki ;
Notarangelo, Luigi Daniele ;
Ochs, Hans Dieter ;
Puck, Jennifer M. ;
Roifman, Chaim M. ;
Seger, Reinhard ;
Tang, Mimi L. K. .
FRONTIERS IN IMMUNOLOGY, 2011, 2
[3]  
[Anonymous], 1993, DETECT HANDLE OUTLIE
[4]   Multiple pathogenic and benign genomic rearrangements occur at a 35 kb duplication involving the NEMO and LAGE2 genes [J].
Aradhya, S ;
Bardaro, T ;
Galgóczy, P ;
Yamagata, T ;
Esposito, T ;
Patlan, H ;
Ciccodicola, A ;
Munnich, A ;
Kenwrick, S ;
Platzer, M ;
D'Urso, M ;
Nelson, DL .
HUMAN MOLECULAR GENETICS, 2001, 10 (22) :2557-2567
[5]   Exome sequencing reveals a pallidin mutation in a Hermansky-Pudlak-like primary immunodeficiency syndrome [J].
Badolato, Raffaele ;
Prandini, Alberto ;
Caracciolo, Sonia ;
Colombo, Francesca ;
Tabellini, Giovanna ;
Giacomelli, Mauro ;
Cantarini, Maria E. ;
Pession, Andrea ;
Bell, Callum J. ;
Dinwiddie, Darrell L. ;
Miller, Neil A. ;
Hateley, Shannon L. ;
Saunders, Carol J. ;
Zhang, Lu ;
Schroth, Gary P. ;
Plebani, Alessandro ;
Parolini, Silvia ;
Kingsmore, Stephen F. .
BLOOD, 2012, 119 (13) :3185-3187
[6]   Neonatal diagnosis of severe combined immunodeficiency leads to significantly improved survival outcome: the case for newborn screening [J].
Brown, Lucinda ;
Xu-Bayford, Jinhua ;
Allwood, Zoe ;
Slatter, Mary ;
Cant, Andrew ;
Davies, E. Graham ;
Veys, Paul ;
Gennery, Andrew R. ;
Gaspar, H. Bobby .
BLOOD, 2011, 117 (11) :3243-3246
[7]   Use of whole exome and genome sequencing in the identification of genetic causes of primary immunodeficiencies [J].
Chou, Janet ;
Ohsumi, Toshiro K. ;
Geha, Raif S. .
CURRENT OPINION IN ALLERGY AND CLINICAL IMMUNOLOGY, 2012, 12 (06) :623-628
[8]   Mutations in Z8T824 Are Associated with Immunodeficiency, Centromeric Instability, and Facial Anomalies Syndrome Type 2 [J].
de Greef, Jessica C. ;
Wang, Jun ;
Balog, Judit ;
den Dunnen, Johan T. ;
Frants, Rune R. ;
Straasheijm, Kirsten R. ;
Aytekin, Caner ;
van der Burg, Mirjam ;
Duprez, Laurence ;
Ferster, Alina ;
Gennery, Andrew R. ;
Gimelli, Giorgio ;
Reisli, Ismail ;
Schuetz, Catharina ;
Schulz, Ansgar ;
Smeets, Dominique F. C. M. ;
Sznajer, Yves ;
Wijmenga, Cisca ;
van Eggermond, Maria C. ;
van Ostaijen-ten Dam, Monique M. ;
Lankester, Arjan C. ;
van Tol, Maarten J. D. ;
van den Elsen, Peter J. ;
Weemaes, Corry M. ;
van der Maarel, Silvere M. .
AMERICAN JOURNAL OF HUMAN GENETICS, 2011, 88 (06) :796-804
[9]   Array-Based Sequence Capture and Next-Generation Sequencing for the Identification of Primary Immunodeficiencies [J].
Ghosh, S. ;
Krux, F. ;
Binder, V. ;
Gombert, M. ;
Niehues, T. ;
Feyen, O. ;
Laws, H. -J. ;
Borkhardt, A. .
SCANDINAVIAN JOURNAL OF IMMUNOLOGY, 2012, 75 (03) :350-354
[10]   Multiplexed array-based and in-solution genomic enrichment for flexible and cost-effective targeted next-generation sequencing [J].
Harakalova, Magdalena ;
Mokry, Michal ;
Hrdlickova, Barbara ;
Renkens, Ivo ;
Duran, Karen ;
van Roekel, Henk ;
Lansu, Nico ;
van Roosmalen, Mark ;
de Bruijn, Ewart ;
Nijman, Isaac J. ;
Kloosterman, Wigard P. ;
Cuppen, Edwin .
NATURE PROTOCOLS, 2011, 6 (12) :1870-1886