Thoracic aortic aneurysm or dissection (GMS)
Gene: ABL1
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
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
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
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 publicationCreated: 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.
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: LiteratureCreated: 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
Mode of pathogenicity
Other
Gene: abl1 has been classified as Green List (High Evidence).
Publications for gene: ABL1 were set to
gene: ABL1 was added gene: ABL1 was added to GMS FTAAD placeholder panel. Sources: Expert Review Amber,South West GLH Mode of inheritance for gene: ABL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: ABL1 were set to Failure to thrive in infancy (HP:0001531); Generalized joint laxity (HP:0002761); Ascending aortic dilation (HP:0004970); Congenital finger flexion contractures (HP:0005879); Hypospadias (HP:0000047); Pectus excavatum (HP:0000767); Congenital heart defects and skeletal malformations syndrome, 617602; Scoliosis (HP:0002650); Congenital septal defect (HP:0004760)