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De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy
  1. Stéphanie Guey1,
  2. Lou Grangeon1,
  3. Francis Brunelle2,3,
  4. Françoise Bergametti1,
  5. Jeanne Amiel4,5,
  6. Stanislas Lyonnet4,5,
  7. Audrey Delaforge6,
  8. Minh Arnould1,
  9. Béatrice Desnous7,
  10. Céline Bellesme8,
  11. Dominique Hervé1,9,
  12. Jan C Schwitalla10,
  13. Markus Kraemer10,
  14. Elisabeth Tournier-Lasserve1,6,
  15. Manoelle Kossorotoff11,12
  1. 1 INSERM UMR-S1161, Génétique et physiopathologie des maladies cérébro-vasculaires, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
  2. 2 AP-HP Department of Pediatric Radiology, University Hospital Necker-Enfants malades, Paris Descartes University, Paris, France
  3. 3 Department of Neuroradiology, University Hospital Necker-Enfants malades, Paris Descartes University, Paris, France
  4. 4 AP-HP, Department of Genetic, University Hospital Necker-Enfants malades, Paris, France
  5. 5 Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France
  6. 6 AP-HP, Service de génétique moléculaire neurovasculaire, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l’œil, Groupe Hospitalier Saint-Louis Lariboisière, Paris, France
  7. 7 AP-HP, Department of Pediatric Neurology, Robert-Debré University Hospital, Paris, France
  8. 8 AP-HP, Department of Pediatric Neurology, Bicêtre University Hospital, Le Kremlin Bicêtre, France
  9. 9 AP-HP, Groupe Hospitalier Saint-Louis Lariboisière, Service de Neurologie, Paris, France
  10. 10 Department of Neurology, Alfried-Krupp-Hospital Essen, Essen, Germany
  11. 12 AP-HP, French Center for Pediatric Stroke and Pediatric Neurology Department, University Hospital Necker-Enfants malades, Paris, France
  12. 11 French Center for Pediatric Stroke, University Hospital Necker-Enfants malades, Paris, France
  1. Correspondence to Dr Manoelle Kossorotoff, AP-HP, French Center for Pediatric Stroke and Pediatric Neurology Department, University Hospital Necker-Enfants malades, Paris 75014, France; manoelle.kossorotoff{at}


Background Moyamoya angiopathy (MMA) is characterised by a progressive stenosis of the terminal part of the internal carotid arteries and the development of abnormal collateral deep vessels. Its pathophysiology is unknown. MMA can be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions (moyamoya syndrome) including some Mendelian diseases. We aimed to investigate the genetic basis of moyamoya using a whole exome sequencing (WES) approach conducted in sporadic cases without any overt symptom suggestive of a known Mendelian moyamoya syndrome.

Methods A WES was performed in four unrelated early-onset moyamoya sporadic cases and their parents (trios). Exome data were analysed under dominant de novo, autosomal recessive and X-linked hypotheses. A panel of 17 additional sporadic cases with early-onset moyamoya was available for mutation recurrence analysis.

Results We identified two germline de novo mutations in CBL in two out of the four trio probands, two girls presenting with an infancy-onset severe MMA. Both mutations were predicted to alter the ubiquitin ligase activity of the CBL protein that acts as a negative regulator of the RAS pathway. These two germline CBL mutations have previously been described in association with a developmental Noonan-like syndrome and susceptibility to juvenile myelomonocytic leukaemia (JMML). Notably, the two mutated girls never developed JMML and presented only subtle signs of RASopathy that did not lead to evoke this diagnosis during follow-up.

Conclusions These data suggest that CBL gene screening should be considered in early-onset moyamoya, even in the absence of obvious signs of RASopathy.

  • Moyamoya
  • CBL E3 Ubiquition Liqase
  • RASopathy
  • Stroke
  • Paediatrics

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  • Contributors SG, ET-L: study design. MK, FBrunelle, JA, SL, BD, CB, JCS, MK, DH: clinical investigation and sample collection. SG, LG, FBergametti, AD, MA: experimental work, preparation of samples and direct sequencing. SG, LG, ET-L: exome data interpretation and analysis. SG, MK, ET-L: first draft of the manuscript.

  • Funding The authors acknowledge support from INSERM funding to U1161 and from Fondation pourla Recherche Médicale (SG, PhD student grant).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.