Inheritance

Autosomal recessive / autosomal dominant / X-linked

Prevalence

 1/50,000-100,000

Source: ORPHA:2308

Rapid or full curation?

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

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Clinical Validity Points Total

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Clinical Validity Classification

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Molecular Mechanism

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

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

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

Case ID, Curator name, Date, Jira ticket link

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