Cysteine-Altering NOTCH3 Variants Are Associated with an Increased Risk of Autoimmune Diseases
Open accessAbstract
Autoimmune conditions have been reported among patients with cysteine-altering NOTCH3 variants and CADASIL. This study aimed to investigate the occurrence of autoimmune illnesses and markers of inflammation in such populations. Cases were identified who had a NOTCH3 cysteine-altering variant from the Geisinger MyCode® Community Health Initiative (MyCode®). We further performed external validation using the UK Biobank cohort. A cohort of 121 individuals with a NOTCH3 cysteine-altering variant from MyCode® was compared to a control group with no non-synonymous variation in NOTCH3 (n = 184). Medical records were evaluated for inflammatory markers and autoimmune conditions, which were grouped by the organ systems involved. A similar analysis was conducted using data from the UK Biobank (n~450,000). An overall increase in inflammatory markers among participants with a NOTCH3 cysteine-altering variant was observed when compared to an age- and sex-matched MyCode® control group (out of participants with laboratory testing: 50.9% versus 26.7%; p = 0.0047; out of total participants: 23.1% versus 10.9%; p = 0.004). Analysis of UK Biobank data indicated any autoimmune diagnosis (1.63 [1.14, 2.09], p= 2.665 × 10−3) and multiple sclerosis (3.42 [1.67, 6.02], p = 9.681 × 10−4) are associated with a NOTCH3 cysteine-altering variant in any domain. Our findings suggest a possible association between NOTCH3 cysteine-altering variants and autoimmune conditions.
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Cysteine-altering NOTCH3 variants have been linked to increased susceptibility to autoimmune disorders, which may reinforce an erroneous MS diagnosis.
“In addition, cysteine-altering NOTCH3 variants have been linked to increased susceptibility to autoimmune disorders, which may reinforce an erroneous MS diagnosis.5”
From Multiple Sclerosis Misdiagnosis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (2026) · cites this paper as [5]
The Discussion reports more autoimmune diagnoses among NOTCH3-variant carriers in one cohort, though that difference was not statistically significant, and describes a possible association between the variants and immune dysregulation. It also mentions MS–CADASIL misdiagnosis, but attributes that possibility to similarities in imaging phenotype; it does not say increased autoimmune susceptibility reinforces an erroneous MS diagnosis. Page numbers were not available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCysteine-altering NOTCH3 variants could increase autoimmune susceptibility.
“This is supported by evidence that cysteine-altering NOTCH3 variants could increase autoimmune susceptibility.5”
From Multiple Sclerosis Misdiagnosis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (2026) · cites this paper as [5]
A subsequent CADASIL diagnosis is often made after progressive ischemic events, characteristic white matter changes, or as clear family history emerges.
“A subsequent CADASIL diagnosis is often made after progressive ischemic events, characteristic white matter changes, or as clear family history emerges.2-5”
From Multiple Sclerosis Misdiagnosis in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (2026) · cites this paper as [5]
The Discussion mentions possible misdiagnosis because CADASIL and multiple sclerosis can have similar imaging findings, but it does not describe when CADASIL is subsequently diagnosed. Searches for white matter changes, family history, ischemic events, and diagnosis found no passage establishing the claimed diagnostic pattern. (LLM, conf=0.76)
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References 15 · Cited by 2
Research works printed but not linked: 14
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- Authors
- Rieder, E., Li, J., Rodriguez-Flores, J. L., Taimur Malik, M., Abedi, V., & Zand, R.
- Affiliations
- Duke University (US)
- Geisinger Medical Center (US)
- Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA
- Neuroscience Institute, Geisinger Health System, Danville, PA 17822, USA
- Pennsylvania State University (US)
- Corresponding author
- Zand, Ramin
- Venue
- Journal of Clinical Medicine
- Publisher
- MDPI AG
- Published
- 2023-09-29
- Volume
- 12
- Issue
- 19
- Pages
- 6278
- ISSN
- 2077-0383 (ISSN-L)
- PMC
- PMC10573689
- OpenAlex
- W4387187006
- Cited by
- 2
- References
- 15
- Citations by year
- 2026: 2
- FWCI
- 0.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Clinical Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Vasculitis and related conditions
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Keywords
- Notch3, autoimmune disease, CADASIL, inflammatory markers, multiple sclerosis, genetic association, non-synonymous variants, UK Biobank
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