TY - JOUR T1 - Germline mutations of the <em>CBL</em> gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia JF - Journal of Medical Genetics JO - J Med Genet SP - 686 LP - 691 DO - 10.1136/jmg.2010.076836 VL - 47 IS - 10 AU - B Pérez AU - F Mechinaud AU - C Galambrun AU - N Ben Romdhane AU - B Isidor AU - N Philip AU - J Derain-Court AU - B Cassinat AU - J Lachenaud AU - S Kaltenbach AU - A Salmon AU - C Désirée AU - S Pereira AU - M L Menot AU - N Royer AU - O Fenneteau AU - A Baruchel AU - C Chomienne AU - A Verloes AU - H Cavé Y1 - 2010/10/01 UR - http://jmg.bmj.com/content/47/10/686.abstract N2 - 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. ER -