Limb disordersGene: ABL1
Comment on list classification: Downgraded to Amber on advice from Genomics England clinical team. Although there are several dactyly phenotypes, they are not very severe / specific. Clinodactyly is very common in the population as a whole and non-specific. Only one case is reported to have 2-3 toe syndactyly. The limb panel would not 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.
Created: 6 Dec 2018, 1:38 p.m.
Comment on mode of pathogenicity: Both variants reported so far in PMID:28288113 are missense.
Created: 4 Dec 2018, 11:43 a.m.
Comment on list classification: Updated rating from Red to Green: ABL1 was originally added to the TAAD panel by the external reviewer Chris Buxton. The phenotypes reported in PMID:28288113 are appropriate for inclusion on the limb panel (including clinodactyly, arachnodactyly, camptodactylyly) and seen in sufficient cases (>3 families, 2 missense variants) for a diagnostic rating.
Created: 4 Dec 2018, 11:42 a.m.
Digit anomalies were seen in all four families from PMID:28288113: Subject 1 (family 1) had a hindfoot deformity. Subject 2 (family 1) had long fingers and toes. Subject 3 (family 2), had 5th finger clinodactyly bilaterally. Subject 4 (family 3) had clinodactyly of the 5th fingers. Subject 5 (family 3) had arachnodactyly (Spider hands), Subject 6 (family 4) had bilateral camptodactylyly of little fingers and bilateral 2-3 toe syndactyly.
Created: 4 Dec 2018, 11:40 a.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. Additionally, a de novo c.1066G>A (p.Ala356Thr) variant was identified in a sixth individual (family 4). Functional assays show that both missense variants cause increased phosphorylation, suggesting increased ABL1 kinase activity.
Created: 4 Dec 2018, 11:37 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
congential heart disease, skeletal abnormalities and failure to thrive; clinodactyly; syndactyly; arachnodactyly
Rebecca Foulger: Wang et al.,2017 (PMID:2828811
Gene: abl1 has been classified as Amber List (Moderate Evidence).
Mode of pathogenicity for gene: ABL1 was changed from None to Other
Gene: abl1 has been classified as Green List (High Evidence).
gene: ABL1 was added gene: ABL1 was added to Limb disorders. Sources: Literature Mode of inheritance for gene: ABL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ABL1 were set to 28288113 Phenotypes for gene: ABL1 were set to congential heart disease, skeletal abnormalities and failure to thrive; clinodactyly; syndactyly; arachnodactyly