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CBL Gene Curation

CBL Gene Curation

Owned by Andrea Oza
2023-09-28
3 min read

Gene-disease assertions not curated here (add link or write note): CBL-related disorder (Noonan syndrome) - Definitive by RASopathy GCEP.

Disease

Jacobsen syndrome aka 11q terminal deletion syndrome

Disease

Jacobsen syndrome aka 11q terminal deletion syndrome

Inheritance

Autosomal recessive / autosomal dominant / X-linked

Prevalence

Orphanet

Medline Plus Genetics

 1/50,000-100,000

Source: ORPHA:2308

Rapid or full curation?

Rapid
Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - under group reviewhttps://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37499

Clinical Validity Scoring Notes and points

200 cases reported to date: PMID: 19267933

Source:

Clinical Validity Points Total

 

Source:

Clinical Validity Classification

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

 

Source:

Molecular Mechanism

Loss of function

Gain of function

Dominant negative

Unknown

Other

This is a microdeletion, per ClinGen the region is GRCh38/hg38 chr11:110729277-135067522

Curated for repeat expansions. Evidence is limited.

Summary - 2 families only with CCG repeat expansion close to fragile site FRA11B showing that expansions led to the fragile site, which in subsequent generations could lead to deletion of the Jacobsen syndrome region. The logic makes sense and this is a rare condition.

  • Jones 1995 PMID: 7603564 - A CCG repeat expansion located close to the fragile site FRA11B. Three families described here with Jacobsen syndrome. They propose that the repeat expansion acts like a premutation that can lead to subsequent development of the fragile site in subsequent generations. The presence of a fragile site predisposes to deletion of the Jacobsen syndrome region. In total, all nine of the known FRA11B-expressing individuals were found to have expansions in the CBL2 repeat region of >100 repeats.

  • No gnomAD data.

  • PMID: 19267933 - In a minority (~10%) of cases, the breakpoint for Jacobsen syndrome is at the FRA11B fragile site. Most 11q deletions occur distally to FRA11B.

  • PMID: 10767345 (same authors as Jones 1995, same 2 families)- 24 Jacobsen patients studied. They found CCG repeats in a number of loci. Essentially these are CpG islands. Two individuals have expansions at the FRA11B which is in the 5' UTR of CBL.

Penetrance

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

 

Source:

Age of Onset

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

 

Severity

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

 

Clinical Features

pre- and postnatal physical growth retardation, psychomotor retardation, and characteristic facial dysmorphism (skull deformities, hypertelorism, ptosis, coloboma, downslanting palpebral fissures, epicanthal folds, broad nasal bridge, short nose, v-shaped mouth, small ears, low set posteriorly rotated ears). Abnormal platelet function, thrombocytopenia or pancytopenia are usually present at birth. Patients commonly have malformations of the heart, kidney, gastrointestinal tract, genitalia, central nervous system and skeleton

Sources:

HPO Terms

https://hpo.jax.org/app/

 

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

 

Case ID, Curator name, Date, Jira ticket link

Andrea Oza, 09.28.2023 https://broadinstitute.atlassian.net/browse/BCL-168

 

 

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