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Cited by 97Immunodeficiency and Autoimmune DisordersGenomics and Rare DiseasesBlood disorders and treatments

Incomplete penetrance in primary immunodeficiency: a skeleton in the closet

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Gruber, Conor, Bogunovic, Dusan·2020·Human Genetics
DOI 10.1007/s00439-020-02131-9PMC PMC7275875
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Abstract

Primary immunodeficiencies (PIDs) comprise a diverse group of over 400 genetic disorders that result in clinically apparent immune dysfunction. Although PIDs are classically considered as Mendelian disorders with complete penetrance, we now understand that absent or partial clinical disease is often noted in individuals harboring disease-causing genotypes. Despite the frequency of incomplete penetrance in PID, no conceptual framework exists to categorize and explain these occurrences. Here, by reviewing decades of reports on incomplete penetrance in PID we identify four recurrent themes of incomplete penetrance, namely genotype quality, (epi)genetic modification, environmental influence, and mosaicism. For each of these principles, we review what is known, underscore what remains unknown, and propose future experimental approaches to fill the gaps in our understanding. Although the content herein relates specifically to inborn errors of immunity, the concepts are generalizable across genetic diseases.

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  • The study could not correctly assess the influence of environmental factors and modifier genes on penetrance of APOE mutations.

    “Meanwhile, it also prevents the correct and comprehensive assessment of the influence of environmental factors and modifier genes on the penetrance of APOE mutations9,18, 19, 20, 21”

    From The First Case of Lipoprotein Glomerulopathy in a Patient With Male Infertility (2026) · cites this paper as [19]

    The Conclusions (page unavailable) identify environmental influences and genetic modifiers as factors that affect penetrance in primary immunodeficiency. The paper does not assess APOE mutations or say that a study could not adequately assess those factors for APOE; a search for APOE found no matching passage. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Gruber, C., & Bogunovic, D.
Affiliations
Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Bogunovic, Dusan
ORCID
Venue
Human Genetics
Publisher
Springer Science and Business Media LLC
Published
2020-02-17
Volume
139
Issue
6-7
Pages
745-757
ISSN
  • 0018-7348 (ISSN-L)
  • 0340-6717
  • 1432-1203
DOI
10.1007/s00439-020-02131-9
PMC
PMC7275875
OpenAlex
W3008036448
Cited by
97
References
4
Citations by year
2026: 13 · 2025: 16 · 2024: 12 · 2023: 13 · 2022: 14 · 2021: 24 · 2020: 5
FWCI
1.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Human Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Allergy and Infectious Diseases (R01AI127372, R21 AI134366, R21AI129827)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
Keywords
incomplete penetrance, primary immunodeficiency, genotype-phenotype discordance, epigenetic modifications, mosaicism, Mendelian inheritance, genetic heterogeneity
MeSH terms
Primary Immunodeficiency Diseases, Humans, Mosaicism, Genetic Variation, Penetrance, Genetic Predisposition to Disease, Epigenesis, Genetic, Gene-Environment Interaction

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