Fetal hydrops
Gene: CBLComment on mode of pathogenicity: Activating mutations are reported in G2P.Created: 21 Dec 2016, 2:48 p.m.
Comment when marking as ready: Rated as green, and mode of inheritance complete.Created: 19 Dec 2016, 1:47 p.m.
Although G2P and Decipher list CBL mutations in NSSL disorder (OMIM:613563) as 'activating', CBL is a negative regulator of RTK (and thereby RAS) signaling. Therefore inhibiting CBL activity enhances RAS signaling as seen in the RASopathies. PMID:20619386 also report that CBL mutations impair CBL ligase activity. Therefore not recorded a non-LOF mode of pathogenicity.Created: 19 Dec 2016, 11:33 a.m.
Comment on list classification: Expert review Green plus >3 CBL variants reported in OMIM for NSLL (OMIM:613563), in which some patients present with hydrops fetalis. Confirmed DD gene for NSLL (OMIM:613563). Plus 3 unrelated patients reported in PMID:25358541 with CBL and Fetal hydrops.Created: 19 Dec 2016, 11:08 a.m.
PMID:25358541 (Bulow et al., 2015) report on three unrelated patients with CBL mutations manifesting with hydrops fetalis, fetal pleural effusions and/or congenital hydro-/chylothorax. Fetal chylothorax may progress to hydrops fetalis. Patient 1 was born to a healthy 35 year and a nonconsanguineous 36-year old father. Patient two was born to unrelated European parents. Patient 3 is the second child of nonconsanguineous parents.Created: 15 Dec 2016, 4:52 p.m.
Comment on mode of inheritance: Mode of inheritance confirmed by OMIM and G2P.Created: 15 Dec 2016, 4:30 p.m.
CBL is included in the Fetal hydrops gene panel based on the presence of Fetal hydrops in some patients diagnosed with NSLL (Noonan Syndrome-like disorder with our without Juvenile Myelomonocytic Leukemia, OMIM:#613563), a disorder caused by heterozygous mutations in CBL.Created: 10 Oct 2016, 9:09 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Noonan syndrome-like disorder associated with JMML
Publications
21 December 2016. External reviews were assessed, and panel was revised according to expert review, internal discussion and additional curation. Following internal discussion, all genes from the V1.14 'RASopathies' panel were added as green EXCLUDING NF1 and SPRED1- a cautious approach was taken because Fetal hydrops is a fetal panel. All relevant genes from the 'Mucopolysaccharideosis, Gaucher, Fabry' V1.0 panel (lysosomal storage disorders) were also added to the Fetal hydrops panel as green together with genes from the literature where there is a reasonable link between the corresponding lysosomal storage disorder (LSD) and Fetal hydrops. All PEX genes from the V1.2 'Peroxisomal disorders' panel were added as green based on a link between peroxisomal biogenesis disorders and Fetal hydrops.
Mode of pathogenicity for CBL was changed to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
CBL was added to Fetal hydropspanel. Sources: Eligibility statement prior genetic testing
This gene has been classified as Green List (High Evidence).
This gene has been classified as Green List (High Evidence).
Mode of inheritance for CBL was changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for CBL were set to Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia, 613563; NSLL; Noonan syndrome-like disorder associated with JMML; Fetal hydrops (in some patients)
Phenotypes for CBL were set to Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia, 613563; NSLL; Noonan syndrome-like disorder associated with JMML
CBL was added to Fetal hydropspanel. Sources: Other
CBL was created by rfoulger