Juvenile myelomonocytic leukemia due to a germline CBL Y371C mutation: 35-year follow-up of a large family.
Juvenile myelomonocytic leukemia (JMML) is a pediatric myeloproliferative neoplasm that arises from malignant transformation of the stem cell compartment and results in increased production of myeloid cells. Somatic and germline variants in CBL (Casitas B-lineage lymphoma proto-oncogene) have been associated with JMML. We report an incompletely penetrant CBL Y371C mutation discovered by whole-exome sequencing in three individuals with JMML in a large pedigree with 35 years of follow-up. The Y371 residue is highly evolutionarily conserved among CBL orthologs and paralogs. In silico bioinformatics prediction programs suggested that the Y371C mutation is highly deleterious. Protein structural modeling revealed that the Y371C mutation abrogated the ability of the CBL protein to adopt a conformation that is required for ubiquitination. Clinically, the three mutation-positive JMML individuals exhibited variable clinical courses; in two out of three, primary hematologic abnormalities persisted into adulthood with minimal clinical symptoms. The penetrance of the CBL Y371C mutation was 30% for JMML and 40% for all leukemia. Of the 8 mutation carriers in the family with available photographs, only one had significant dysmorphic features; we found no evidence of a clinical phenotype consistent with a "CBL syndrome". Although CBL Y371C has been previously reported in familial JMML, we are the first group to follow a complete pedigree harboring this mutation for an extended period, revealing additional information about this variant's penetrance, function and natural history.
Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive Rm 6E450, Bethesda, MD, 20892, USA, pathaka@mail.nih.gov.
Anand
A
Pathak
Alexander
A
Pemov
Mary L
ML
McMaster
Ramita
R
Dewan
Sarangan
S
Ravichandran
Evgenia
E
Pak
Amalia
A
Dutra
Hyo Jung
HJ
Lee
Aurelie
A
Vogt
Xijun
X
Zhang
Meredith
M
Yeager
Stacie
S
Anderson
Martha
M
Kirby
Neil
N
Caporaso
Mark H
MH
Greene
Lynn R
LR
Goldin
Douglas R
DR
Stewart
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005260:Female; D005500:Follow-Up Studies; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D010375:Pedigree; D019683:Penetrance; D017434:Protein Structure, Tertiary; D000090063:Proto-Oncogene Mas; D050721:Proto-Oncogene Proteins c-cbl / Q000737:chemistry / Q000235:genetics*; D054875:Ubiquitination / Q000235:genetics*
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human