Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies

被引:181
作者
Casanova, Jean-Laurent [1 ,2 ,3 ,4 ,5 ]
Conley, Mary Ellen [1 ]
Seligman, Stephen J. [6 ]
Abel, Laurent [1 ,2 ,3 ,4 ]
Notarangelo, Luigi D. [7 ,8 ]
机构
[1] Rockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, New York, NY 10065 USA
[2] Howard Hughes Med Inst, New York, NY 10065 USA
[3] Necker Hosp Sick Children, INSERM U1163, Necker Branch, Lab Human Genet Infect Dis, F-75015 Paris, France
[4] Paris Descartes Univ, Imagine Inst, F-75015 Paris, France
[5] Necker Hosp Sick Children, Pediat Hematol Immunol Unit, F-75015 Paris, France
[6] New York Med Coll, Dept Microbiol & Immunol, Valhalla, NY 10595 USA
[7] Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA
[8] Harvard Univ, Sch Med, Dept Pediat & Pathol, Boston, MA 02115 USA
关键词
INTERFERON-GAMMA-RECEPTOR; SYSTEMIC-LUPUS-ERYTHEMATOSUS; BACILLE CALMETTE-GUERIN; PLURIPOTENT STEM-CELLS; AUTOINFLAMMATORY DISEASE; MOLECULAR-BASIS; MUTATION CAUSES; 11; CARD11; DEFICIENCY; IMMUNITY;
D O I
10.1084/jem.20140520
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Can genetic and clinical findings made in a single patient be considered sufficient to establish a causal relationship between genotype and phenotype? We report that up to 49 of the 232 monogenic etiologies (21%) of human primary immunodeficiencies (PIDs) were initially reported in single patients. The ability to incriminate single-gene inborn errors in immunodeficient patients results from the relative ease in validating the disease-causing role of the genotype by in-depth mechanistic studies demonstrating the structural and functional consequences of the mutations using blood samples. The candidate genotype can be causally connected to a clinical phenotype using cellular (leukocytes) or molecular (plasma) substrates. The recent advent of next generation sequencing (NGS), with whole exome and whole genome sequencing, induced pluripotent stem cell (iPSC) technology, and gene editing technologies-including in particular the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology-offer new and exciting possibilities for the genetic exploration of single patients not only in hematology and immunology but also in other fields. We propose three criteria for deciding if the clinical and experimental data suffice to establish a causal relationship based on only one case. The patient's candidate genotype must not occur in individuals without the clinical phenotype. Experimental studies must indicate that the genetic variant impairs, destroys, or alters the expression or function of the gene product (or two genetic variants for compound heterozygosity). The causal relationship between the candidate genotype and the clinical phenotype must be confirmed via a relevant cellular phenotype, or by default via a relevant animal phenotype. When supported by satisfaction of rigorous criteria, the report of single patient-based discovery of Mendelian disorders should be encouraged, as it can provide the first step in the understanding of a group of human diseases, thereby revealing crucial pathways underlying physiological and pathological processes.
引用
收藏
页码:2137 / 2149
页数:13
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