De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy.
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.



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.



We identified two germline de novo mutations inCBLin 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 germlineCBLmutations 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.



These data suggest thatCBLgene screening should be considered in early-onset moyamoya, even in the absence of obvious signs of RASopathy.
INSERM UMR-S1161, Génétique et physiopathologie des maladies cérébro-vasculaires, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
Stéphanie
S
Guey
INSERM UMR-S1161, Génétique et physiopathologie des maladies cérébro-vasculaires, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
Lou
L
Grangeon
AP-HP Department of Pediatric Radiology, University Hospital Necker-Enfants malades, Paris Descartes University, Paris, France.|Department of Neuroradiology, University Hospital Necker-Enfants malades, Paris Descartes University, Paris, France.
Francis
F
Brunelle
INSERM UMR-S1161, Génétique et physiopathologie des maladies cérébro-vasculaires, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
Françoise
F
Bergametti
AP-HP, Department of Genetic, University Hospital Necker-Enfants malades, Paris, France.|Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France.
Jeanne
J
Amiel
AP-HP, Department of Genetic, University Hospital Necker-Enfants malades, Paris, France.|Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, Paris, France.
Stanislas
S
Lyonnet
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.
Audrey
A
Delaforge
INSERM UMR-S1161, Génétique et physiopathologie des maladies cérébro-vasculaires, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
Minh
M
Arnould
AP-HP, Department of Pediatric Neurology, Robert-Debré University Hospital, Paris, France.
Béatrice
B
Desnous
AP-HP, Department of Pediatric Neurology, Bicêtre University Hospital, Le Kremlin Bicêtre, France.
Céline
C
Bellesme
INSERM UMR-S1161, Génétique et physiopathologie des maladies cérébro-vasculaires, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|AP-HP, Groupe Hospitalier Saint-Louis Lariboisière, Service de Neurologie, Paris, France.
Dominique
D
Hervé
Department of Neurology, Alfried-Krupp-Hospital Essen, Essen, Germany.
Jan C
JC
Schwitalla
Department of Neurology, Alfried-Krupp-Hospital Essen, Essen, Germany.
Markus
M
Kraemer
INSERM UMR-S1161, Génétique et physiopathologie des maladies cérébro-vasculaires, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|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.
Elisabeth
E
Tournier-Lasserve
French Center for Pediatric Stroke, University Hospital Necker-Enfants malades, Paris, France.|AP-HP, French Center for Pediatric Stroke and Pediatric Neurology Department, University Hospital Necker-Enfants malades, Paris, France.
Manoelle
M
Kossorotoff
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D008297:Male; D009072:Moyamoya Disease / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D000073359:Exome Sequencing
D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human
CBL E3 Ubiquition Liqase; Moyamoya; Paediatrics; RASopathy; Stroke