PT  - JOURNAL ARTICLE
AU  - Stéphanie Guey
AU  - Lou Grangeon
AU  - Francis Brunelle
AU  - Françoise Bergametti
AU  - Jeanne Amiel
AU  - Stanislas Lyonnet
AU  - Audrey Delaforge
AU  - Minh Arnould
AU  - Béatrice Desnous
AU  - Céline Bellesme
AU  - Dominique Hervé
AU  - Jan C Schwitalla
AU  - Markus Kraemer
AU  - Elisabeth Tournier-Lasserve
AU  - Manoelle Kossorotoff
TI  - De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy
AID  - 10.1136/jmedgenet-2016-104432
DP  - 2017 Aug 01
TA  - Journal of Medical Genetics
PG  - 550--557
VI  - 54
IP  - 8
4099  - http://jmg.bmj.com/content/54/8/550.short
4100  - http://jmg.bmj.com/content/54/8/550.full
SO  - J Med Genet2017 Aug 01; 54
AB  - 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.