RT Journal Article SR Electronic T1 Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 686 OP 691 DO 10.1136/jmg.2010.076836 VO 47 IS 10 A1 B Pérez A1 F Mechinaud A1 C Galambrun A1 N Ben Romdhane A1 B Isidor A1 N Philip A1 J Derain-Court A1 B Cassinat A1 J Lachenaud A1 S Kaltenbach A1 A Salmon A1 C Désirée A1 S Pereira A1 M L Menot A1 N Royer A1 O Fenneteau A1 A Baruchel A1 C Chomienne A1 A Verloes A1 H Cavé YR 2010 UL http://jmg.bmj.com/content/47/10/686.abstract AB Background CBL missense mutations have recently been associated with juvenile myelomonocytic leukaemia (JMML), an aggressive myeloproliferative and myelodysplastic neoplasm of early childhood characterised by excessive macrophage/monocyte proliferation. CBL, an E3 ubiquitin ligase and a multi-adaptor protein, controls proliferative signalling networks by downregulating the growth factor receptor signalling cascades in various cell types.Methods and results CBL mutations were screened in 65 patients with JMML. A homozygous mutation of CBL was found in leukaemic cells of 4/65 (6%) patients. In all cases, copy neutral loss of heterozygosity of the 11q23 chromosomal region, encompassing the CBL locus, was demonstrated. Three of these four patients displayed additional features suggestive of an underlying developmental condition. A heterozygous germline CBL p.Y371H substitution was found in each of them and was inherited from the father in one patient. The germline mutation represents the first hit, with somatic loss of heterozygosity being the second hit positively selected in JMML cells. The three patients display a variable combination of dysmorphic features, hyperpigmented skin lesions and microcephaly that enable a ‘CBL syndrome’ to be tentatively delineated. Learning difficulties and postnatal growth retardation may be part of the phenotype.Conclusion A report of germline mutations of CBL in three patients with JMML is presented here, confirming the existence of an unreported inheritable condition associated with a predisposition to JMML.