Skeletal dysplasia

Gene: ABL1

Green List (high evidence)

>3 families reported - Y245C in several. Skeletal defects are variable and include pectus excavatum, scoliosis, and finger contractures, and some patient exhibit joint laxity. Rating: green if SD; Review on behalf of Tracy Lester

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Congenital heart defects and skeletal malformations syndrome, 617602

Publications

• 28288113

I don't know

Comment on list classification: Leaving this gene as amber just now. Question as to whether this is considered a skeletal dysplasia. The broader skeletal manifestations (scoliosis / pectus) are classically thought of as part of the Marfan / FTAAD spectrum rather than a skeletal dysplasia.

Created: 11 Dec 2019, 5:02 p.m. | Last Modified: 11 Dec 2019, 5:02 p.m.

Panel Version: 1.282

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: ABL1; Initial rating suggestion: green if SD

Created: 6 Mar 2019, 11:36 a.m.

Comment on mode of pathogenicity: Seleced 'LOF do not cause this phenotype' on advice from Helen Brittain, Clinical Fellow, in view of the postulated gain of function mechanism (two recurent missense variants in PMID:28288113).

Created: 6 Dec 2018, 9:29 p.m.

Added to Skeletal dysplasia panel with Amber rating as suggested by Helen Brittain. Wang et al, 2017 (PMID:28288113) report ABL1 germline variants cosegregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities and failure to thrive. They report 2 variants in 4 families (6 individuals). Helen Brittain, clinical fellow, notes that: "the broader skeletal manifestations (scoliosis / pectus) are classically thought of as part of the Marfan / FTAAD spectrum rather than a skeletal dysplasia. Therefore do not think that skeletal dysplasia (or limb panel) would be the primary route for diagnosis here and would opt for amber on the basis that we need to see the phenotype across other cases first."
Sources: Literature

Created: 6 Dec 2018, 9:28 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Congenital heart defects and skeletal malformations syndrome, 617602

Publications

• 28288113

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments