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J Allergy Clin Immunol. 2017 Jan;139(1):232-245. doi: 10.1016/j.jaci.2016.05.042. Epub 2016 Jul 16.

Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.

Author information

1
Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Norwegian National Unit for Newborn Screening, Oslo University Hospital, Oslo, Norway; Department of Pediatrics, Oslo University Hospital, Oslo, Norway. Electronic address: astraype@ous-hf.no.
2
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
3
Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland.
4
Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
5
Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
6
Department of Pediatrics, Oslo University Hospital, Oslo, Norway.
7
Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
8
Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex.
9
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
10
Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
11
Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
12
Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex.
13
Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Tex; 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.
14
Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
15
Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Hematology, Oslo University Hospital, Oslo, Norway.
16
Department of Hematology, Oslo University Hospital, Oslo, Norway.
17
Department of Hematology, St Olavs Hospital, Trondheim, Norway; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
18
Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
19
Department of Pediatrics, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
20
Department of Infectious Diseases, Medical Clinic, University Hospital of North-Norway, Tromsø, Norway.
21
Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway.
22
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex.
23
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Tex.
24
Immunology Service, Ricardo Gutierrez Children's Hospital, Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina.
25
Immunodeficiencies Research Unit, National Institute of Pediatrics, Coyoacan, Mexico City, Mexico.
26
Universidad San Francisco de Quito, Quito, Ecuador.
27
Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Hospital Roberto del Rio, Universidad de Chile, Santiago, Chile.
28
Grupo de Inmunodeficiencias Primarias, Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad de Antioquia UdeA, Medellin, Colombia.
29
Allergy and Clinical Immunology, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru.
30
Alberta Children's Hospital, Calgary, Alberta, Canada.
31
Department of Pediatrics, Dalhousie University, Izaak Walton Killam Health Centre, Halifax, Nova Scotia, Canada.
32
Department of Pediatrics, National Jewish Health, Denver, Colo.
33
Section of Pulmonary, Critical Care, Allergic and Immunological Diseases, Wake Forest Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC.
34
Department of Pediatrics, Division of Pediatric Allergy/Immunology and Pulmonology, University of Iowa Carver College of Medicine, Iowa City, Iowa.
35
Department of Pediatrics, University of California, San Francisco, Calif.
36
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), and Vita-Salute San Raffaele University, Milan, Italy.
37
University Department of Pediatrics, DPUO, Bambino Gesù Children's Hospital, and Tor Vergata University, Rome, Italy.
38
Department of Clinical Genetics, University Hospital of Umeå, Umeå, Sweden.
39
Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden.
40
Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Department of Medical Genetics, Bezmi Alem Vakif University Faculty of Medicine, Istanbul, Turkey.
41
Department of Pediatric Immunology and Allergy, Selcuk University Medical Faculty, Alaeddin Keykubat Kampusu, Konya, Turkey.
42
Department of Pediatrics, Section of Pediatric Allergy and Immunology, Hamad Medical Corporation, Doha, Department of Paediatrics, Weill Cornell Medical College, Ar-Rayyan, Qatar.
43
Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, Wales.
44
Department of Rheumatology, Oslo University Hospital, Oslo, Norway.
45
Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Tex.
46
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex.
47
Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex; Human Genetics Center, University of Texas School of Public Health, Houston, Tex.
48
Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex. Electronic address: orange@bcm.edu.
49
Baylor-Hopkins Center for Mendelian Genomics of the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Tex; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex. Electronic address: jlupski@bcm.tmc.edu.

Erratum in

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.

KEYWORDS:

Primary immunodeficiency disease; copy number variants; whole-exome sequencing

PMID:
27577878
PMCID:
PMC5222743
DOI:
10.1016/j.jaci.2016.05.042
[Indexed for MEDLINE]
Free PMC Article

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