CBL – CBL-related disorder

CBL-related disorder is an autosomal dominant RASopathy characterized by heterogeneous features including global developmental delay, cardiovascular malformations, lymphatic abnormalities, and predisposition to juvenile myelomonocytic leukemia (JMML). The disorder arises from heterozygous germline variants in the CBL gene, encoding an E3 ubiquitin ligase that downregulates receptor tyrosine kinases and controls RAS/MAPK signaling (Gene Symbol; Disease Name).

Inheritance is autosomal dominant, with most pathogenic variants arising de novo or transmitted from mosaic or unaffected parents. Patients often present in early childhood with splenomegaly, thrombocytopenia, and mild dysmorphic features, while a minority develop transient or progressive JMML requiring hematopoietic stem cell transplantation.

Over 50 unrelated individuals have been reported, including a cohort of 25 patients with prenatal hydrops fetalis, chylothorax and pleural effusions bearing CBL mutations, 20 of whom developed JMML (PMID:25358541). Single-case reports further expand the spectrum to include Takayasu arteritis, central nervous system vasculitis, severe EBV infection with panuveitis, and dilute cardiomyopathy manifestations.

Pathogenic variants cluster in the linker helix and RING domains, disrupting ubiquitin ligase activity. A recurrent variant, c.1111T>C (p.Tyr371His), has been identified in multiple patients and impairs CBL’s regulatory conformation (PMID:25358541). Other recurrent alleles include c.1141T>C (p.Cys381Arg) and c.1194C>G (p.His398Gln).

Segregation analysis in a large pedigree harboring the CBL p.Tyr371Cys variant showed eight carriers with three individuals developing JMML over 35 years, indicating incomplete penetrance but clear co-segregation with leukemia predisposition (PMID:25939664).

Functional studies demonstrate that RASopathy-associated CBL variants fail to ubiquitylate and internalize epidermal growth factor receptor (EGFR), leading to prolonged surface signaling and elevated ERK phosphorylation (PMID:25178484). Cellular models further reveal loss of E3 activity, enhanced GM-CSF hypersensitivity, and hyperactivation of downstream kinases, recapitulating JMML pathogenesis.

CBL-related disorder represents a definitive gene–disease relationship, supported by robust genetic and experimental data. Genetic testing for CBL variants is clinically actionable for diagnostic confirmation, risk stratification, and surveillance of leukemia and vascular complications.

Key Take-home: Germline CBL mutations define a RASopathy with leukemia predisposition, and targeted molecular assays enable early diagnosis and tailored management.

References

• American Journal of Medical Genetics Part A | 2015 | Hydrops, fetal pleural effusions and chylothorax in three patients with CBL mutations. PMID:25358541
• Human Genetics | 2015 | Juvenile myelomonocytic leukemia due to a germline CBL Y371C mutation: 35-year follow-up of a large family. PMID:25939664
• Human Mutation | 2014 | RASopathy-associated CBL germline mutations cause aberrant ubiquitylation and trafficking of EGFR. PMID:25178484

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