Heterozygous NOTCH1 Variants Cause CNS Immune Activation and Microangiopathy

Guy Helman^#^{1

2}, Parand Zarekiani^#^{3

4}, Samantha A M Tromp^#^{5

6}, Ashley Andrews⁷, Lorenzo D Botto⁷, Joshua L Bonkowsky⁸, Anna Chassevent⁹, Elisa Giorgio^{10

11}, Tommaso Pippucci¹², Shen Wei¹³, Constance Smith-Hicks^{14

15}, Giovanna Vaula¹⁶, Michèl A A P Willemsen¹⁷, Mareike Schimmel¹⁸, Kurt Vollert¹⁹, Fumitaka Shimizu²⁰, Takashi Kanda²⁰, Matthew Lynch^{21

22}, Tony Roscioli^{23

24

25}, Ryan J Taft²⁶, Cas Simons^{1

2}, Marianna Bugiani^{3

4}, Taco W Kuijpers^{5

6}, Marjo S van der Knaap^{4

27

28}

Affiliations

¹ Murdoch Children's Research Institute, The Royal Children's Hospital, Victoria, Australia.
² Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia.
³ Department of Pathology, Amsterdam University Medical Centers, VU University Amsterdam and Amsterdam Neuroscience, Amsterdam, HV, The Netherlands.
⁴ Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, Amsterdam, DD, The Netherlands.
⁵ Department of Pediatric Immunology, Rheumatology and Infectious Disease, Emma Children's Hospital, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, DD, The Netherlands.
⁶ Department of Experimental Immunology, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, DD, The Netherlands.
⁷ Division of Medical Genetics, University of Utah, Salt Lake City, UT.
⁸ Division of Pediatric Neurology, Department of Pediatrics, University of Utah, Salt Lake City, UT.
⁹ Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland.
¹⁰ Department of Molecular Medicine, University of Pavia, Pavia, Italy.
¹¹ Medical Genetics Unit, IRCCS Mondino Foundation, Pavia, Italy.
¹² U.O. Genetica Medica, IRCCS Azienda Ospedaliero - Universitaria di Bologna, Policlinico di Sant'Orsola, Bologna, Italy.
¹³ Clinical Genome Sequencing Laboratory, Mayo Clinic, Rochester, MN.
¹⁴ The Hugo Moser Research Institute at Kennedy Krieger, Baltimore, MD.
¹⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.
¹⁶ Department of Neuroscience, Azienda Ospedaliera-Universitaria Città della Salute e della Scienza, Turin, Italy.
¹⁷ Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁸ Division of Pediatric Neurology, Childrens's Hospital, University Hospital Augsburg, Augsburg, Germany.
¹⁹ Department of Diagnostic Radiology and Neuroradiology - Pediatric Radiology Section, University Hospital Augsburg, Augsburg, Germany.
²⁰ Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
²¹ Neurosciences Unit, Queensland Children's Hospital, Brisbane, Australia.
²² Queensland Lifespan Metabolic Medicine Service, Queensland Children's Hospital, Brisbane, Australia.
²³ New South Wales Health Pathology Randwick Genomics Laboratory, Sydney, New South Wales, Australia.
²⁴ Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, New South Wales, Australia.
²⁵ Neuroscience Research Australia (NeuRA), University of New South Wales, Sydney, New South Wales, Australia.
²⁶ Illumina Inc., San Diego, California.
²⁷ Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, VU University Amsterdam and Amsterdam Neuroscience, Amsterdam, The Netherlands.
²⁸ Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands.

^# Contributed equally.

PMID: 35947102
DOI: 10.1002/ana.26477

Heterozygous NOTCH1 Variants Cause CNS Immune Activation and Microangiopathy

Guy Helman et al. Ann Neurol. 2022 Nov.

. 2022 Nov;92(5):895-901.

doi: 10.1002/ana.26477. Epub 2022 Aug 20.

Authors

Affiliations

¹ Murdoch Children's Research Institute, The Royal Children's Hospital, Victoria, Australia.
² Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia.
³ Department of Pathology, Amsterdam University Medical Centers, VU University Amsterdam and Amsterdam Neuroscience, Amsterdam, HV, The Netherlands.
⁴ Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, Amsterdam, DD, The Netherlands.
⁵ Department of Pediatric Immunology, Rheumatology and Infectious Disease, Emma Children's Hospital, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, DD, The Netherlands.
⁶ Department of Experimental Immunology, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, DD, The Netherlands.
⁷ Division of Medical Genetics, University of Utah, Salt Lake City, UT.
⁸ Division of Pediatric Neurology, Department of Pediatrics, University of Utah, Salt Lake City, UT.
⁹ Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland.
¹⁰ Department of Molecular Medicine, University of Pavia, Pavia, Italy.
¹¹ Medical Genetics Unit, IRCCS Mondino Foundation, Pavia, Italy.
¹² U.O. Genetica Medica, IRCCS Azienda Ospedaliero - Universitaria di Bologna, Policlinico di Sant'Orsola, Bologna, Italy.
¹³ Clinical Genome Sequencing Laboratory, Mayo Clinic, Rochester, MN.
¹⁴ The Hugo Moser Research Institute at Kennedy Krieger, Baltimore, MD.
¹⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.
¹⁶ Department of Neuroscience, Azienda Ospedaliera-Universitaria Città della Salute e della Scienza, Turin, Italy.
¹⁷ Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁸ Division of Pediatric Neurology, Childrens's Hospital, University Hospital Augsburg, Augsburg, Germany.
¹⁹ Department of Diagnostic Radiology and Neuroradiology - Pediatric Radiology Section, University Hospital Augsburg, Augsburg, Germany.
²⁰ Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
²¹ Neurosciences Unit, Queensland Children's Hospital, Brisbane, Australia.
²² Queensland Lifespan Metabolic Medicine Service, Queensland Children's Hospital, Brisbane, Australia.
²³ New South Wales Health Pathology Randwick Genomics Laboratory, Sydney, New South Wales, Australia.
²⁴ Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, New South Wales, Australia.
²⁵ Neuroscience Research Australia (NeuRA), University of New South Wales, Sydney, New South Wales, Australia.
²⁶ Illumina Inc., San Diego, California.
²⁷ Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, VU University Amsterdam and Amsterdam Neuroscience, Amsterdam, The Netherlands.
²⁸ Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands.

^# Contributed equally.

PMID: 35947102
DOI: 10.1002/ana.26477

Abstract

NOTCH1 belongs to the NOTCH family of proteins that regulate cell fate and inflammatory responses. Somatic and germline NOTCH1 variants have been implicated in cancer, Adams-Oliver syndrome, and cardiovascular defects. We describe 7 unrelated patients grouped by the presence of leukoencephalopathy with calcifications and heterozygous de novo gain-of-function variants in NOTCH1. Immunologic profiling showed upregulated CSF IP-10, a cytokine secreted downstream of NOTCH1 signaling. Autopsy revealed extensive leukoencephalopathy and microangiopathy with vascular calcifications. This evidence implicates that heterozygous gain-of-function variants in NOTCH1 lead to a chronic central nervous system (CNS) inflammatory response resulting in a calcifying microangiopathy with leukoencephalopathy. ANN NEUROL 2022;92:895-901.

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Reply to "Type I IFN Signature in NOTCH1-Related Leukoencephalopathy".
Verhoeven D, Tromp SAM, van der Knaap MS, Kuijpers TW. Verhoeven D, et al. Ann Neurol. 2023 May;93(5):1043-1045. doi: 10.1002/ana.26629. Epub 2023 Mar 20. Ann Neurol. 2023. PMID: 36891671 No abstract available.
Type I Interferon Signature in NOTCH1-Related Leukoencephalopathy.
Nicita F, Travaglini L, Matteo V, Aiello C, Longo D, Insalaco A, Bertini E, Prencipe G. Nicita F, et al. Ann Neurol. 2023 May;93(5):1041-1043. doi: 10.1002/ana.26631. Epub 2023 Mar 21. Ann Neurol. 2023. PMID: 36892079 No abstract available.

References

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1. Stittrich AB, Lehman A, Bodian DL, et al. Mutations in NOTCH1 cause Adams-Oliver syndrome. Am J Hum Genet 2014;95:275-284.
1. Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004;306:269-271.
1. Hack RJ, Rutten J, Lesnik Oberstein SAJ. Cadasil. In: Adam MP, Mirzaa GM, Pagon RA, et al., eds. GeneReviews((R)). Seattle (WA): University of Washington, Seattle, 2019.
1. Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat 2015;36:928-930.

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Heterozygous NOTCH1 Variants Cause CNS Immune Activation and Microangiopathy

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Heterozygous NOTCH1 Variants Cause CNS Immune Activation and Microangiopathy

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