Thoracic aortic aneurysm or dissection (GMS)

Gene: ABL1

Green List (high evidence)

Submitted on behalf of the GMS Cardiology specialist group. This gene did not achieve a consensus Green rating; however, the group agreed that the existing evidence (published and in-house data) was sufficient to support inclusion in this panel.

Created: 9 Dec 2019, 1:19 p.m. | Last Modified: 9 Dec 2019, 1:19 p.m.

Panel Version: 0.55

I don't know

Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Amber on this panel.

Created: 18 Nov 2019, 4:33 p.m. | Last Modified: 18 Nov 2019, 4:33 p.m.

Panel Version: 0.35

I don't know

Gene not currently tested on Manchester cardiac gene panel. 6 variants listed on HGMD (accessed 24/09/2019), two of which from Wang et al Nature Genetics 2017. ClinGen Knowledge Base: gene not curated (accessed 24/09/2019).

Created: 25 Sep 2019, 9:07 a.m. | Last Modified: 25 Sep 2019, 9:07 a.m.

Panel Version: 0.30

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

Phenotypes
Congenital heart defects and skeletal malformations syndrome, 617602

Publications

• 28288113

Green List (high evidence)

617602 Congenital heart defects and skeletal malformations syndrome - includes ASD, VSD, aortic root dilation and coarctation of the aorta in addition to other syndromic connective tissue phenotypes; only two variants associated with this phenotype in HGMD, both from same publication

Created: 25 Mar 2019, 4:30 p.m.

Wang et al 2017 Nat Genet 49:613 PMID 28288113 describe two variants: c.734A>G (p.Tyr245Cys) found de novo in 5 individuals from 3 families (segregates with disease in two affected individuals from each of 2 families) and c.1066G>A (p.Ala356Thr) found de novo in a single family. Both variants are well conserved and affect the kinase domain. Neither have any gnomAD frequency and both are reported as pathogenic by more than one source on ClinVar.

Created: 25 Mar 2019, 4:27 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Added 'missense' tag.

Created: 6 Dec 2018, 8:46 p.m.

Comment on list classification: Updated rating from Grey to Green. Gene was added by Chris Buxton based on evidence in PMID:28288113. Although CB rated the gene Red, mild aortic root dilation/mild coarctation of the aorta is seen in patients from 3 families. Therefore phenotype is relevant to panel and sufficient unrelated cases to support diagnostic rating, as agreed by Helen Brittain, clinical fellow.

Created: 6 Dec 2018, 8:46 p.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).

Created: 6 Dec 2018, 8:43 p.m.

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. The variant c.734A>G (p.Tyr245Cys) was found to occur de novo in 3 individuals (families 1-2) and in family 3, the variant was seen in the affected father and daughter. Heart defects include aortic root dilatation and/or coarctation.

Created: 6 Dec 2018, 8:41 p.m.

Red List (low evidence)

Gain of function variants in this gene are described by Wang (2017, PMID 28288113) as a ddx for TGFB overexpression pathway disorders, eg Loeys Dietz, Shprintzen Goldberg, Marfan syndrome.

Wang X et al., Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations. Nat Genet. 2017 Apr;49(4):613-617.
Sources: Literature

Created: 22 Nov 2018, 9:53 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Congenital finger flexion contractures (HP:0005879); Congenital septal defect (HP:0004760); Generalized joint laxity (HP:0002761); Ascending aortic dilation (HP:0004970); Scoliosis (HP:0002650); Failure to thrive in infancy (HP:0001531); Hypospadias (HP:0000047); Pectus excavatum (HP:0000767)

Publications

• 28288113

Mode of pathogenicity
Other