title: Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies.
abstract: 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.
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065 Howard Hughes Medical Institute, New York, NY 10065 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France Paris Descartes University, Imagine Institute, 75015 Paris, France Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Jean-Laurent.Casanova@mail.rockefeller.edu.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Conley
authors.affiliation: Department of Microbiology and Immunology, New York Medical College, Valhalla, NY 10595.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Seligman
authors.affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065 Howard Hughes Medical Institute, New York, NY 10065 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, MA 02115 Department of Pediatrics and Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
mesh_terms: D056726:Genetic Association Studies; D036281:Genetic Research / Q000331:legislation & jurisprudence; D005820:Genetic Testing; D017408:Guidelines as Topic; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis / Q000235:genetics*