The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies
Open accessAbstract
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.
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Cites
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De novo mutations revealed by whole-exome sequencing are strongly associated with autism
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Targeted capture and massively parallel sequencing of 12 human exomes
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Exome sequencing identifies the cause of a mendelian disorder
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Cited by
Tangye, S. G., Al-Herz, W., Bousfiha, A., Cunningham-Rundles, C., Franco, J. L., Holland, S. M., Klein, C., Morio, T., Oksenhendler, E., Picard, C., et al. (2022) · Journal of Clinical Immunology · doi:10.1007/s10875-022-01289-3 · Cited by 1,156
The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities
Chong, J. X., Buckingham, K. J., Jhangiani, S. N., Boehm, C., Sobreira, N., Smith, J. D., Harrell, T. M., McMillin, M. J., Wiszniewski, W., Gambin, T., et al. (2015) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2015.06.009 · Cited by 643
Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis
Khajuria, R. K., Munschauer, M., Ulirsch, J. C., Fiorini, C., Ludwig, L. S., McFarland, S. K., Abdulhay, N. J., Specht, H., Keshishian, H., Mani, D. R., et al. (2018) · Cell · doi:10.1016/j.cell.2018.02.036 · Cited by 416
“In addition, the key advances occurring in the field of human genetics will enable us to better understand how such process can be perturbed in human disease (Casanova et al., 2014), as we have been able to study here for DBA.”
BackgroundCharacterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery
Greater Middle East Variome Consortium, Scott, E. M., Halees, A., Itan, Y., Spencer, E. G., He, Y., Azab, M. A., Gabriel, S. B., Belkadi, A., Boisson, B., et al. (2016) · Nature Genetics · doi:10.1038/ng.3592 · Cited by 376
Self-citationPoli, M. C., Aksentijevich, I., Bousfiha, A. A., Cunningham-Rundles, C., Hambleton, S., Klein, C., Morio, T., Picard, C., Puel, A., Rezaei, N., et al. (2025) · Journal of Human Immunity · doi:10.70962/jhi.20250003 · Cited by 341
Metadata
- Authors
- Casanova, J.-L., Conley, M. E., Seligman, S. J., Abel, L., & Notarangelo, L. D.
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2014-10-13
- Volume
- 211
- Issue
- 11
- Pages
- 2137-2149
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- OpenAlex
- W2105275733
- Cited by
- 257
- References
- 13
- FWCI
- 10.11
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Casanova, J.-L., Conley, M. E., Seligman, S. J., Abel, L., & Notarangelo, L. D. (2014). Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies. Journal of Experimental Medicine. https://doi.org/10.1084/jem.20140520
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