A NOTCH3 homozygous nonsense mutation in familial Sneddon syndrome with pediatric stroke
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ORIGINAL COMMUNICATION
A NOTCH3 homozygous nonsense mutation in familial Sneddon syndrome with pediatric stroke Elli Katharine Greisenegger1,2 · Sara Llufriu3 · Angel Chamorro4,5 · Alvaro Cervera6 · Adriano Jimenez‑Escrig7 · Klemens Rappersberger8 · Wolfgang Marik9 · Stefan Greisenegger2 · Elisabeth Stögmann2 · Tamara Kopp10 · Tim M. Strom11,12 · Jörg Henes12 · Anne Joutel13 · Alexander Zimprich2 Received: 6 April 2020 / Revised: 5 June 2020 / Accepted: 13 July 2020 © The Author(s) 2020
Abstract Sneddon syndrome is a rare disorder affecting small and medium-sized blood vessels that is characterized by the association of livedo reticularis and stroke. We performed whole-exome sequencing (WES) in 2 affected siblings of a consanguineous family with childhood-onset stroke and identified a homozygous nonsense mutation within the epidermal growth factor repeat (EGFr) 19 of NOTCH3, p.(Arg735Ter). WES of 6 additional cases with adult-onset stroke revealed 2 patients carrying heterozygous loss-of-function variants in putative NOTCH3 downstream genes, ANGPTL4, and PALLD. Our findings suggest that impaired NOTCH3 signaling is one underlying disease mechanism and that bi-allelic loss-of-function mutation in NOTCH3 is a cause of familial Sneddon syndrome with pediatric stroke. Keywords NOTCH3 · CADASIL · Sneddon syndrome · Homozygous nonsense mutation
Introduction Sneddon syndrome (SS) is a rare disorder (about 4 patients per million), affecting mainly young and predominately female adults [1,2]. It is characterized by recurrent strokes and livedo reticularis, a violaceous, netlike patterning of the * Alexander Zimprich [email protected] 1
Department of Dermatology and Venereology, University Hospital of St. Pölten, Karl Landsteiner University of Health Sciences, St. Pölten, Austria
Department of Neurology, Medical University of Vienna, Währinger Gürtel 18‑20, 1090 Vienna, Austria
2
3
Laboratory of Advanced Imaging in Neuroimmunological Diseases, Center of Neuroimmunology, Hospital Clinic Barcelona, IDIBAPS and Universitat de Barcelona, Barcelona, Spain
4
Department of Neuroscience, Comprehensive Stroke Center, Hospital Clinic Barcelona, Barcelona, Spain
5
Institure Investigacions Biomèdicas August Pi I Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
6
Royal Darwin Hospital, Darwin, NT, Australia
7
Department of Neurology, Hospital Ramon Y Cajal, 28034 Madrid, Spain
skin [3]. Skin biopsies often display distinct histopathological findings consisting in sequential stage-specific changes in small to medium- sized arteries at the border between dermis and subcutis such as a possibly short-lived endotheliitis, followed by inflammatory obstruction, subendothelial cell proliferation and fibrosis of the occluded artery and shrinkage 8
Department of Dermatology, Rudolfstiftung Hospital, Vienna, Austria
9
Division of Neuroradiology and Musculoskeletal Radiology, Department of Biomedical Imaging and Image‑Guided Therapy, Medical University of Vienna, Vienna, Austria
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