Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations.

TitleGermline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations.
Publication TypeJournal Article
Year of Publication2017
AuthorsWang, X, Charng, W-L, Chen, C-A, Rosenfeld, JA, Shamsi, AAl, Al-Gazali, L, McGuire, M, Mew, NAh, Arnold, GL, Qu, C, Ding, Y, Muzny, DM, Gibbs, RA, Eng, CM, Walkiewicz, M, Xia, F, Plon, SE, Lupski, JR, Schaaf, CP, Yang, Y
JournalNat Genet
Volume49
Issue4
Pagination613-617
Date Published2017 Apr
ISSN1546-1718
Abstract

ABL1 is a proto-oncogene well known as part of the fusion gene BCR-ABL1 in the Philadelphia chromosome of leukemia cancer cells. Inherited germline ABL1 changes have not been associated with genetic disorders. Here we 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 or cosegregate with disease in five individuals (families 1-3). Additionally, a de novo c.1066G>A (p.Ala356Thr) variant was identified in a sixth individual (family 4). We overexpressed the mutant constructs in HEK 293T cells and observed increased tyrosine phosphorylation, suggesting increased ABL1 kinase activities associated with both the p.Tyr245Cys and p.Ala356Thr substitutions. Our clinical and experimental findings, together with previously reported teratogenic effects of selective BCR-ABL inhibitors in humans and developmental defects in Abl1 knockout mice, suggest that ABL1 has an important role during organismal development.

DOI10.1038/ng.3815
Alternate JournalNat. Genet.
PubMed ID28288113
PubMed Central IDPMC5373987
Grant ListU01 HG007709 / HG / NHGRI NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States