Thoracic aortic aneurysm or dissection
Gene: ABL1
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: 24 Sep 2019, 1:33 p.m. | Last Modified: 24 Sep 2019, 1:33 p.m.
Panel Version: 1.93
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
Source South West GLH was added to ABL1. Mode of inheritance for gene ABL1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Rating Changed from Green List (high evidence) to Green List (high evidence)
Phenotypes for gene: ABL1 were changed from 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) to Congenital heart defects and skeletal malformations syndrome, 617602; 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)
Tag missense tag was added to gene: ABL1.
Gene: abl1 has been classified as Green List (High Evidence).
Mode of pathogenicity for gene: ABL1 was changed from Other to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mode of inheritance for gene: ABL1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
gene: ABL1 was added gene: ABL1 was added to Thoracic aortic aneurysm or dissection. Sources: Literature Mode of inheritance for gene: ABL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ABL1 were set to 28288113 Phenotypes for gene: ABL1 were set to 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) Penetrance for gene: ABL1 were set to unknown Mode of pathogenicity for gene: ABL1 was set to Other Review for gene: ABL1 was set to RED