Pathogenic variants causing ABL1 malformation syndrome cluster in a myristoyl-binding pocket and increase tyrosine kinase activity

Abstract

ABL1 is a proto-oncogene encoding a nonreceptor tyrosine kinase, best known in the somatic BCR-ABL fusion gene associated with chronic myeloid leukaemia. Recently, germline missense variants in ABL1 have been found to cause an autosomal dominant developmental syndrome with congenital heart disease, skeletal malformations and characteristic facies. Here, we describe a series of six new unrelated individuals with heterozygous missense variants in ABL1 (including four novel variants) identified via whole exome sequencing. All the affected individuals in this series recapitulate the phenotype of the ABL1 developmental syndrome and additionally we affirm that hearing impairment is a common feature of the condition. Four of the variants cluster in the myristoyl-binding pocket of ABL1, a region critical for auto-inhibitory regulation of the kinase domain. Bio-informatic analysis of transcript-wide conservation and germline/somatic variation reveals that this pocket region is subject to high missense constraint and evolutionary conservation. Functional work to investigate ABL1 kinase activity in vitro by transient transfection of HEK293T cells with variant ABL1 plasmid constructs revealed increased phosphorylation of ABL1-specific substrates compared to wild-type. The increased tyrosine kinase activity was suppressed by imatinib treatment. This case series of six new patients with germline heterozygous ABL1 missense variants further delineates the phenotypic spectrum of this condition and recognises microcephaly as a common finding. Our analysis supports an ABL1 gain-of-function mechanism due to loss of auto-inhibition, and demonstrates the potential for pharmacological inhibition using imatinib.

ABL1‐related congenital heart defects and skeletal malformations syndrome in a patient from Sub‐Saharan Africa: A case report highlighting novel cardiac features

“…Nine of the 29 previously reported cases of CHDSKM were noted to have aortic root dilatation. This was categorized simply as “mild” or “present” in five patients; in the remainder the Z‐scores varied between +3.31 to +4.5 (Blakes et al, 2021; Chen et al, 2020; Hildebrandt et al, 2021). These scores are substantially lower than the maximal Z ‐score of +8.1 in the current patient.…”

“…One patient did not have an age of onset noted. The progression of the aortic root dilatation is not well described and only two publications mention follow up echocardiograms; one was a teenager reported on by Blakes et al who had a normal aortic root at 25 years (Blakes et al, 2021), and Hildebrandt et al showed progression of the ascending aortic root from a Z ‐score of 2.39 at age 8 years to 3.31 at 23 years in one of their reported cases (Hildebrandt et al, 2021). The case presented here showed rapid progression of severe aortic root dilatation, with an increase in SOV Z ‐score from 7.1 to 8.1 over a 2‐year period in early adolescence which has not previously been reported.…”

“…Over time the face becomes elongated and narrow. The palate is described as high and arched (Blakes et al, 2021; Chen et al, 2020). Cardiac lesions reported range from structural lesions such as ventricular septal defect (VSD) and atrial septal defect (ASD), valvular pathology (mitral and pulmonary) as well aortic root dilatation in adulthood (Wang et al, 2017).…”

Nonreceptor Protein Kinases and Phosphatases Necessary for Auditory Function

“…Variants of ABL1 cause a syndromic disorder (Table 1) in which subsets of patients have outer ear abnormalities and hearing loss [40]. Recently, variants were reported in patients with a phenotype termed as ABL1 malformation syndrome, and it was shown that hearing loss in the patients occurred due to the increased tyrosine kinase activity of the protein [41]. Variants of BTK have been reported to cause otitis media and hearing loss in a few patients with agammaglobulinemia, X-linked 1, a disorder of B-lymphocyte maturation [42].…”

Congenital heart defects and skeletal malformation syndrome with congenital hemiplegia

“…1 This is rare syndrome mainly has autosomal dominant inheritance caused by germline mutation in ABL1 gene. 2,3…”