The DOI matches its Crossref record; 61 of the 61 references it cites were found in a registry or an index.
Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases
Abstract
Genetic studies of human disease have traditionally focused on the detection of disease-causing mutations in afflicted individuals. Here we describe a complementary approach that seeks to identify healthy individuals resilient to highly penetrant forms of genetic childhood disorders. A comprehensive screen of 874 genes in 589,306 genomes led to the identification of 13 adults harboring mutations for 8 severe Mendelian conditions, with no reported clinical manifestation of the indicated disease. Our findings demonstrate the promise of broadening genetic studies to systematically search for well individuals who are buffering the effects of rare, highly penetrant, deleterious mutations. They also indicate that incomplete penetrance for Mendelian diseases is likely more common than previously believed. The identification of resilient individuals may provide a first step toward uncovering protective genetic variants that could help elucidate the mechanisms of Mendelian diseases and new therapeutic strategies.
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“However, erroneous results from SNP chips used in research biobanks can also lead to false associations and wasted resource in the development of new treatments against the wrong targets.33 34 35”
From Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation (2021) · cites this paper as [34]
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Metadata
- Authors
- Chen, R., Shi, L., Hakenberg, J., Naughton, B., Sklar, P., Zhang, J., Zhou, H., Tian, L., Prakash, O., Lemire, M., Sleiman, P., Cheng, W.-Y., Chen, W., Shah, H., Shen, Y., Fromer, M., Omberg, L., Deardorff, M. A., Zackai, E., Bobe, J. R., Levin, E., Hudson, T. J., Groop, L., Wang, J., Hakonarson, H., Wojcicki, A., Diaz, G. A., Edelmann, L., Schadt, E. E., & Friend, S. H.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- 23andMe (United States) (US)
- BGI Group (China) (CN)
- Children's Hospital of Philadelphia (US)
- Lund University (SE)
- Ontario Institute for Cancer Research (CA)
- Sage Bionetworks (US)
- Corresponding author
- Chen, Rong
- Schadt, Eric E
- Friend, Stephen H
- ORCID
- Chen, Rong
- Shi, Lisong
- Hakenberg, Jörg
- Sklar, Pamela
- Zhang, Jianguo
- Zhou, Hanlin
- Tian, Lifeng
- Prakash, Om
- Lemire, Mathieu
- Cheng, Wei-yi
- Chen, Wanting
- Shen, Yulan
- Fromer, Menachem
- Omberg, Larsson
- Deardorff, Matthew A
- Zackai, Elaine
- Bobe, Jason R
- Hudson, Thomas J
- Groop, Leif
- Wang, Jun
- Hakonarson, Hakon
- Edelmann, Lisa
- Schadt, Eric E
- Friend, Stephen H
- Venue
- Nature Biotechnology
- Published
- 2016-04-11
- Volume
- 34
- Issue
- 5
- Pages
- 531-538
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W2326403029
- Cited by
- 310
- References
- 59
- Citations by year
- 2026: 14 · 2025: 19 · 2024: 13 · 2023: 33 · 2022: 24 · 2021: 26 · 2020: 38 · 2019: 33 · 2018: 32 · 2017: 45 · 2016: 33
- FWCI
- 38.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- disease resilience, asymptomatic carriers, incomplete penetrance, protective genetic variants, pathogenic variants
- MeSH terms
- Child, Child, Preschool, Chromosome Mapping, DNA Mutational Analysis, Female, Genetic Testing, Humans, Infant, Infant, Newborn, Male, Sensitivity and Specificity, Reproducibility of Results, Genome, Human, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genetic Diseases, Inborn, Mendelian Randomization Analysis, Disease Resistance
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