RT Journal Article
SR Electronic
T1 De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 550
OP 557
DO 10.1136/jmedgenet-2016-104432
VO 54
IS 8
A1 Stéphanie Guey
A1 Lou Grangeon
A1 Francis Brunelle
A1 Françoise Bergametti
A1 Jeanne Amiel
A1 Stanislas Lyonnet
A1 Audrey Delaforge
A1 Minh Arnould
A1 Béatrice Desnous
A1 Céline Bellesme
A1 Dominique Hervé
A1 Jan C Schwitalla
A1 Markus Kraemer
A1 Elisabeth Tournier-Lasserve
A1 Manoelle Kossorotoff
YR 2017
UL http://jmg.bmj.com/content/54/8/550.abstract
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.