A NOTCH3 homozygous nonsense mutation in familial Sneddon syndrome with pediatric stroke

Elli Katharine Greisenegger, Sara Llufriu, Angel Chamorro, Alvaro Cervera, Adriano Jimenez-Escrig, Klemens Rappersberger, Wolfgang Marik, Stefan Greisenegger, Elisabeth Stögmann, Tamara Kopp, Tim M Strom, Jörg Henes, Anne Joutel, Alexander Zimprich

Research output: Journal article (peer-reviewed)Journal article

14 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)810-816
Number of pages7
JournalJournal of Neurology
Issue number3
Publication statusPublished - Mar 2021


  • Adult
  • Child
  • Codon, Nonsense
  • Consanguinity
  • Epidermal Growth Factor
  • Homozygote
  • Humans
  • Mutation
  • Receptor, Notch3/genetics
  • Sneddon Syndrome
  • Stroke/diagnostic imaging


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