{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:04:00Z","timestamp":1791295440771,"version":"4.1.0"},"reference-count":27,"publisher":"BMJ","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2010,2,23]]},"published-print":{"date-parts":[[2010,10]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                     <jats:italic>CBL<\/jats:italic> 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>\n                     <jats:italic>CBL<\/jats:italic> mutations were screened in 65 patients with JMML. A homozygous mutation of <jats:italic>CBL<\/jats:italic> 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 <jats:italic>CBL<\/jats:italic> locus, was demonstrated. Three of these four patients displayed additional features suggestive of an underlying developmental condition. A heterozygous germline <jats:italic>CBL<\/jats:italic> 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 \u2018CBL syndrome\u2019 to be tentatively delineated. Learning difficulties and postnatal growth retardation may be part of the phenotype.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>A report of germline mutations of <jats:italic>CBL<\/jats:italic> in three patients with JMML is presented here, confirming the existence of an unreported inheritable condition associated with a predisposition to JMML.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg.2010.076836","type":"journal-article","created":{"date-parts":[[2010,6,12]],"date-time":"2010-06-12T20:14:09Z","timestamp":1276373649000},"page":"686-691","source":"Crossref","is-referenced-by-count":138,"title":["Germline mutations of the <i>CBL<\/i> gene define a new genetic syndrome with predisposition to juvenile myelomonocytic 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