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

Abstract

ABL1 is a proto-oncogene well known as part of the fusion gene BCR-ABL in the Philadelphia chromosome of leukemia cancer cells1. Inherited germline ABL1 changes have not been associated with genetic disorders. Here we report ABL1 germline variants co-segregating 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 as de novo or co-segregating with disease in five individuals (families 1-3). Additionally, a de novo c.1066G>A (p.Ala356Thr) variant was identified in the 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 p.Tyr245Cys and p.Ala356Thr substitutions. Our clinical and laboratory findings, together with previously reported teratogenic effects of selective BCR-ABL inhibitors in humans2-5 and developmental defects in Abl1 knock-out mice6,7, suggest ABL1 plays an important role during organismal development.

Phenotypic expansion in DDX3X – a common cause of intellectual disability in females

“…However, pathway analysis for the highest 5% and lowest 5% genes expressed in RNAseq data from dermal fibroblasts obtained in one subject (Female 13) showed enrichment in cell cycle control of chromosomal replication and double‐strand break repair pathways (Table S2). Future studies will elucidate whether individuals carrying DDX3X variants are at risk for the development of malignancies 21. In summary, we identified 31 unrelated patients with causal variants in DDX3X and expanded the genotypic and phenotypic spectrum of DDX3X ‐related disorders.…”

The expanding clinical phenotype of germline ABL1 ‐associated congenital heart defects and skeletal malformations syndrome

“…This study reports six patients carrying de novo heterozygous missense variants with phenotypes overlapping with the original study (Wang et al, 2017). ABL1 has two isoforms, 1a (NM_005157.5) and 1b (NM_007313.2), as a result of an alternatively spliced first exon.…”

“…He had global developmental delay, failure to thrive, hypotonia, and severe feeding difficulties requiring gastrostomy tube for insertion, tetralogy of Fallot, and microcephaly (50.5 cm; <3rd centile at 9 years of age based on Norwegian growth charts (Juliusson et al, 2009(Juliusson et al, , 2013 Complementary DNA (cDNA) constructs, cell culture, and immunoblotting in the functional studies were performed as previously described (Wang et al, 2017). The antiphospho-ABL1 antibody (#5300, Cell Signaling Technology, Danvers, MA) used in the original study (Wang et al, 2017) All reported heterozygous missense variants identified by exome sequencing in this study were found to be de novo ( Figure S1; Tables S1 and S2). We identified the variant c. 407C>T (p.Thr136Met) (Figure 1).…”

Truncating variants in UBAP1 associated with childhood‐onset nonsyndromic hereditary spastic paraplegia

“…Variants reported in this study were deposited to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/). Clinical trio exome sequencing for Families 1 and 3 at Baylor was performed as previously described (Wang et al, ; Yang et al, ). Briefly, genomic DNA samples were fragmented, ligated to Illumina multiplexing paired‐end adaptors, amplified with indexes added, and hybridized to exome capture reagent (Roche NimbleGen).…”

“…Variants reported in this study were deposited to ClinVar (https:// www.ncbi.nlm.nih.gov/clinvar/). Clinical trio exome sequencing for Families 1 and 3 at Baylor was performed as previously described (Wang et al, 2017;Yang et al, 2013) (Yang et al, 2013). Reads were aligned to human genome build GRCh37/UCSC hg19 and analyzed for sequence variants using a custom-developed analysis tool.…”