Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders - 18/04/17
Doi : 10.1016/j.jaci.2016.05.042
Asbjørg Stray-Pedersen, MD, PhD a, b, c, d, e, ⁎∗ 
, Hanne Sørmo Sorte, MS f, g, ∗, Pubudu Samarakoon, MS f, g, Tomasz Gambin, PhD a, h, Ivan K. Chinn, MD b, c, i, Zeynep H. Coban Akdemir, PhD a, Hans Christian Erichsen, MD, PhD e, Lisa R. Forbes, MD b, c, i, Shen Gu, PhD a, Bo Yuan, PhD a, j, Shalini N. Jhangiani, MS a, j, k, Donna M. Muzny, MS a, j, k, Olaug Kristin Rødningen, PhD f, Ying Sheng, PhD f, Sarah K. Nicholas, MD, PhD b, c, i, Lenora M. Noroski, MD, MPH c, i, Filiz O. Seeborg, MD, MPH c, i, Carla M. Davis, MD c, i, Debra L. Canter, MS c, i, Emily M. Mace, PhD b, c, Timothy J. Vece, MD i, Carl E. Allen, MD, PhD i, l, m, Harshal A. Abhyankar, MS i, l, m, Philip M. Boone, MD, PhD a, j, Christine R. Beck, PhD a, j, Wojciech Wiszniewski, MD, PhD a, j, Børre Fevang, MD, PhD g, n, Pål Aukrust, MD, PhD g, n, Geir E. Tjønnfjord, MD, PhD g, o, Tobias Gedde-Dahl, MD, PhD o, Henrik Hjorth-Hansen, MD, PhD p, q, Ingunn Dybedal, MD, PhD o, Ingvild Nordøy, MD, PhD g, n, Silje F. Jørgensen, MD n, Tore G. Abrahamsen, MD, PhD e, g, Torstein Øverland, MD e, Anne Grete Bechensteen, MD, PhD e, Vegard Skogen, MD, PhD r, Liv T.N. Osnes, MD, PhD s, Mari Ann Kulseth, PhD f, Trine E. Prescott, MD f, Cecilie F. Rustad, MD f, Ketil R. Heimdal, MD, PhD f, John W. Belmont, MD, PhD j, Nicholas L. Rider, DO b, c, i, Javier Chinen, MD, PhD c, i, Tram N. Cao, MS b, c, i, Eric A. Smith, BSc t, Maria Soledad Caldirola, BSc u, Liliana Bezrodnik, MD u, Saul Oswaldo Lugo Reyes, MD v, Francisco J. Espinosa Rosales, MD v, Nina Denisse Guerrero-Cursaru, BSc w, Luis Alberto Pedroza, PhD w, Cecilia M. Poli, MD b, x, Jose L. Franco, MD, PhD y, Claudia M. Trujillo Vargas, PhD y, Juan Carlos Aldave Becerra, MD z, Nicola Wright, MD aa, Thomas B. Issekutz, MD bb, Andrew C. Issekutz, MD bb, Jordan Abbott, MD cc, Jason W. Caldwell, DO dd, Diana K. Bayer, DO ee, Alice Y. Chan, MD, PhD ff, Alessandro Aiuti, MD, PhD gg, Caterina Cancrini, MD, PhD hh, Eva Holmberg, MD ii, Christina West, MD, PhD jj, Magnus Burstedt, MD, PhD ii, Ender Karaca, MD a, Gözde Yesil, MD a, kk, Hasibe Artac, MD ll, Yavuz Bayram, MD a, Mehmed Musa Atik, BSc a, Mohammad K. Eldomery, MD a, Mohammad S. Ehlayel, MD, PhD mm, Stephen Jolles, MD, PhD nn, Berit Flatø, MD, PhD oo, Alison A. Bertuch, MD, PhD i, l, I. Celine Hanson, MD b, c, i, Victor W. Zhang, PhD j, Lee-Jun Wong, PhD j, Jianhong Hu, PhD j, k, Magdalena Walkiewicz, PhD j, Yaping Yang, PhD j, Christine M. Eng, MD j, Eric Boerwinkle, PhD a, k, pp, Richard A. Gibbs, PhD a, j, k, William T. Shearer, MD, PhD c, i, Robert Lyle, PhD f, Jordan S. Orange, MD, PhD b, c, i, ⁎, ‡ , James R. Lupski, MD, PhD, DSc (Hon) a, i, j, k, ⁎, ‡
, Hanne Sørmo Sorte, MS f, g, ∗, Pubudu Samarakoon, MS f, g, Tomasz Gambin, PhD a, h, Ivan K. Chinn, MD b, c, i, Zeynep H. Coban Akdemir, PhD a, Hans Christian Erichsen, MD, PhD e, Lisa R. Forbes, MD b, c, i, Shen Gu, PhD a, Bo Yuan, PhD a, j, Shalini N. Jhangiani, MS a, j, k, Donna M. Muzny, MS a, j, k, Olaug Kristin Rødningen, PhD f, Ying Sheng, PhD f, Sarah K. Nicholas, MD, PhD b, c, i, Lenora M. Noroski, MD, MPH c, i, Filiz O. Seeborg, MD, MPH c, i, Carla M. Davis, MD c, i, Debra L. Canter, MS c, i, Emily M. Mace, PhD b, c, Timothy J. Vece, MD i, Carl E. Allen, MD, PhD i, l, m, Harshal A. Abhyankar, MS i, l, m, Philip M. Boone, MD, PhD a, j, Christine R. Beck, PhD a, j, Wojciech Wiszniewski, MD, PhD a, j, Børre Fevang, MD, PhD g, n, Pål Aukrust, MD, PhD g, n, Geir E. Tjønnfjord, MD, PhD g, o, Tobias Gedde-Dahl, MD, PhD o, Henrik Hjorth-Hansen, MD, PhD p, q, Ingunn Dybedal, MD, PhD o, Ingvild Nordøy, MD, PhD g, n, Silje F. Jørgensen, MD n, Tore G. Abrahamsen, MD, PhD e, g, Torstein Øverland, MD e, Anne Grete Bechensteen, MD, PhD e, Vegard Skogen, MD, PhD r, Liv T.N. Osnes, MD, PhD s, Mari Ann Kulseth, PhD f, Trine E. Prescott, MD f, Cecilie F. Rustad, MD f, Ketil R. Heimdal, MD, PhD f, John W. Belmont, MD, PhD j, Nicholas L. Rider, DO b, c, i, Javier Chinen, MD, PhD c, i, Tram N. Cao, MS b, c, i, Eric A. Smith, BSc t, Maria Soledad Caldirola, BSc u, Liliana Bezrodnik, MD u, Saul Oswaldo Lugo Reyes, MD v, Francisco J. Espinosa Rosales, MD v, Nina Denisse Guerrero-Cursaru, BSc w, Luis Alberto Pedroza, PhD w, Cecilia M. Poli, MD b, x, Jose L. Franco, MD, PhD y, Claudia M. Trujillo Vargas, PhD y, Juan Carlos Aldave Becerra, MD z, Nicola Wright, MD aa, Thomas B. Issekutz, MD bb, Andrew C. Issekutz, MD bb, Jordan Abbott, MD cc, Jason W. Caldwell, DO dd, Diana K. Bayer, DO ee, Alice Y. Chan, MD, PhD ff, Alessandro Aiuti, MD, PhD gg, Caterina Cancrini, MD, PhD hh, Eva Holmberg, MD ii, Christina West, MD, PhD jj, Magnus Burstedt, MD, PhD ii, Ender Karaca, MD a, Gözde Yesil, MD a, kk, Hasibe Artac, MD ll, Yavuz Bayram, MD a, Mehmed Musa Atik, BSc a, Mohammad K. Eldomery, MD a, Mohammad S. Ehlayel, MD, PhD mm, Stephen Jolles, MD, PhD nn, Berit Flatø, MD, PhD oo, Alison A. Bertuch, MD, PhD i, l, I. Celine Hanson, MD b, c, i, Victor W. Zhang, PhD j, Lee-Jun Wong, PhD j, Jianhong Hu, PhD j, k, Magdalena Walkiewicz, PhD j, Yaping Yang, PhD j, Christine M. Eng, MD j, Eric Boerwinkle, PhD a, k, pp, Richard A. Gibbs, PhD a, j, k, William T. Shearer, MD, PhD c, i, Robert Lyle, PhD f, Jordan S. Orange, MD, PhD b, c, i, ⁎, ‡ , James R. Lupski, MD, PhD, DSc (Hon) a, i, j, k, ⁎, ‡ a Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex
b Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, Tex
j Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex
k Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex
l Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Tex
t Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Tex
c Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex
d Norwegian National Unit for Newborn Screening, Oslo University Hospital, Oslo, Norway
e Department of Pediatrics, Oslo University Hospital, Oslo, Norway
f Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
o Department of Hematology, Oslo University Hospital, Oslo, Norway
s Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway
oo Department of Rheumatology, Oslo University Hospital, Oslo, Norway
g Institute of Clinical Medicine, University of Oslo, Oslo, Norway
h Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland
i Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex
m Texas Children's Cancer and Hematology Center, Department of Pediatrics, Center for Cell and Gene Therapy, Texas Children's Hospital and Baylor College of Medicine, Houston, Tex
n Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
p Department of Hematology, St Olavs Hospital, Trondheim, Norway
q Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
r Department of Infectious Diseases, Medical Clinic, University Hospital of North-Norway, Tromsø, Norway
u Immunology Service, Ricardo Gutierrez Children's Hospital, Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina
v Immunodeficiencies Research Unit, National Institute of Pediatrics, Coyoacan, Mexico City, Mexico
w Universidad San Francisco de Quito, Quito, Ecuador
x Hospital Roberto del Rio, Universidad de Chile, Santiago, Chile
y Grupo de Inmunodeficiencias Primarias, Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad de Antioquia UdeA, Medellin, Colombia
z Allergy and Clinical Immunology, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru
aa Alberta Children's Hospital, Calgary, Alberta, Canada
bb Department of Pediatrics, Dalhousie University, Izaak Walton Killam Health Centre, Halifax, Nova Scotia, Canada
cc Department of Pediatrics, National Jewish Health, Denver, Colo
dd Section of Pulmonary, Critical Care, Allergic and Immunological Diseases, Wake Forest Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC
ee Department of Pediatrics, Division of Pediatric Allergy/Immunology and Pulmonology, University of Iowa Carver College of Medicine, Iowa City, Iowa
ff Department of Pediatrics, University of California, San Francisco, Calif
gg San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), and Vita-Salute San Raffaele University, Milan, Italy
hh University Department of Pediatrics, DPUO, Bambino Gesù Children's Hospital, and Tor Vergata University, Rome, Italy
ii Department of Clinical Genetics, University Hospital of Umeå, Umeå, Sweden
jj Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden
kk Department of Medical Genetics, Bezmi Alem Vakif University Faculty of Medicine, Istanbul, Turkey
ll Department of Pediatric Immunology and Allergy, Selcuk University Medical Faculty, Alaeddin Keykubat Kampusu, Konya, Turkey
mm Department of Pediatrics, Section of Pediatric Allergy and Immunology, Hamad Medical Corporation, Doha, Department of Paediatrics, Weill Cornell Medical College, Ar-Rayyan, Qatar
nn Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, Wales
pp Human Genetics Center, University of Texas School of Public Health, Houston, Tex
∗Corresponding authors: Asbjørg Stray-Pedersen, MD, PhD, Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Postbox 4950 Nydalen, N-0424 Oslo, Norway.Norwegian National Unit for Newborn ScreeningDivision of Pediatric and Adolescent MedicineOslo University HospitalPostbox 4950 NydalenOsloN-0424Norway∗Jordan S. Orange, MD, PhD, Feigin Center, 1102 Bates, Suite 330, Houston, TX 77030.Feigin Center, 1102 Bates, Suite 330HoustonTX77030∗James R. Lupski, MD, PhD, DSc (Hon), Baylor College of Medicine, Molecular and Human Genetics, Suite 604B, One Baylor Plaza, Houston, TX 77030.Baylor College of MedicineMolecular and Human GeneticsSuite 604B, One Baylor PlazaHoustonTX77030
Abstract |
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.
Le texte complet de cet article est disponible en PDF.Key words : Primary immunodeficiency disease, whole-exome sequencing, copy number variants
Abbreviations used : AD, ALPS, AR, BCM, BHCMG, CMA, CNV, CVID, ExAC, HGMD, HSCT, MAF, MLPA, OMIM, PIDD, RIDDLE, SCID, SNV, WES, WGS
Plan
| Funding for the work performed in Oslo was provided by the South-Eastern Norway Health Authority, and A.S.-P. received research scholarship from the American Women's club of Oslo. The BHCMG is supported by the National Human Genome Research Institute and the National Heart, Lung, and Blood (U54HG006542). Funding was also provided by the Jeffrey Modell Foundation and NIH AI-120989 (to J.S.O.). |
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| Disclosure of potential conflict of interest: A. Stray-Pedersen has received grants from the South-Eastern Norway Healthy Authority, the National Human Genome Research Institute, and the National Heart, Lung, and Blood Institute. H. S. Sorte has received a grant from the South-Eastern Norway Health Authority. P. Samarakoon has received a grant from the Norwegian South-Eastern Regional Health Authority (project 2013038). T. Gambin has received a grant from the National Human Genome Research Institute. I. K. Chinn has received grants from the National Institutes of Health (NIH) and the Jeffrey Modell Foundation. L. R. Forbes has board memberships with Baxlata and Horizon, has received grants from Baylor, has received payment for lectures from Horizon, and has received travel support from the Clinical Immunology Society. S. N. Jhangiani has received a grant from the National Human Genome Research Institute. D. M. Muzny has received a grant from the National Human Genome Research Institute. S. K. Nicholas is employed by Baylor College of Medicine. C. Davis has consultant arrangements with Aimmune Therapeutics Advisory Board and Intrommune Advisory Board; has received grants from Thermo Fisher Scientific, Nutricia North America, Aimmune Therapeutics, and DBV Technologies, SA; and has received payment for development of educational presentations from PriMed. T. Vece has received royalties from UpToDate. C. E. Allen is employed by the Baylor College of Medicine, has received grants from the NIH/National Cancer Institute, St Baldrick's Foundation, Cookies for Kids Cancer, and the HistioCure Foundation; and has received travel support from NovImmune. P. Boone has received grants from the NIH. H. Hjorth-Hansen has consultant arrangements with and has received payment for lectures from Ariad. J. W. Belmont is an employee of Illumina and has provided expert testimony for Baker, Botts, LLC. N. Rider has received royalties from UpToDate. F. J. Espinosa Rosales is a board member for Baxalta, Octapharma, GlaxoSmithKline, and Nestle Nutrition; has consultant arrangements with Baxalta, CSL Behring, Abbott Nutrition, and Nestle Nutrition; has received payment for lectures from CSL Behring, Octapharma, Nestle Nutrition, Abbott Nutrition, and Sanofi; has received payment for development of educational presentations from Sanofi and Abbott; and has received travel support from UCB Pharma, CSL Behring, Octapharma, and Grifols. J. W, Caldwell is employed by Wake Forest University School of Medicine and has provided expert testimony for independent contracts. A. Aiuti has received grants from Fondazione Telethon Rome, the Italian Ministry of Health, the European Union (CELL PID and EURO-CID), and funding from GlaxoSmithKline. E. Boerwinkle and R. A. Gibbs have received a grant from the National Human Genome Research Institute. W. T. Shearer has received a grant from the NIH, is employed by the Baylor College of Medicine, and has received royalties from a textbook on clinical immunology. R. Lyle has received a grant from Helse Sør-Øst. J. S. Orange has consultant arrangements with Baxalta, CSL Behring, and Grifols; has a patent through the Children's Hospital of Philadelphia; has received royalties from UpToDate; and funding was also provided by the Jeffrey Modell Foundation and NIH AI-120989. J. R. Lupski has received grants from the National Human Genome Research Institute, the National Institute of Neurological Disorders, the National Institute of General Medical Sciences, the National Eye Institute, and the National Heart, Lung, and Blood Institute; has consultant arrangements with Regeneron Pharmaceuticals; is employed by Baylor College of Medicine; is coinventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting and receives royalties for these patents; and has stock/stock options in 23andMe. The rest of the authors declare that they have no relevant conflicts of interest. |
© 2016
American Academy of Allergy, Asthma & Immunology. Publié par Elsevier Masson SAS. Tous droits réservés.
Vol 139 - N° 1
P. 232-245 - janvier 2017 Retour au numéro
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