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是一种编码非受体酪氨酸激酶的原癌基因，最著名的是与慢性粒细胞白血病相关的体细胞BCR-ABL融合基因。最近， ABL1种系错义变异被发现可引起常染色体显性发育综合征，伴有先天性心脏病、骨骼畸形和特征性相貌。在这里，我们描述了通过全外显子组测序鉴定出的一系列六个新的无关个体，它们在ABL1中具有杂合错义变异（包括四个新变异）。本系列中所有受影响的个体都概括了ABL1发育综合征的表型，此外我们确认听力障碍是该病症的一个共同特征。其中四个变体聚集在 ABL1 的肉豆蔻酰结合口袋中，该区域对于激酶结构域的自抑制调节至关重要。对全转录本保守性和种系/体细胞变异的生物信息学分析表明，该口袋区域受到高度错义约束和进化保守性的影响。通过用变体ABL1质粒构建体瞬时转染 HEK293T 细胞来研究体外 ABL1 激酶活性的功能性工作表明，与野生型相比，ABL1 特异性底物的磷酸化增加。伊马替尼治疗抑制了酪氨酸激酶活性的增加。该病例系列由 6 名携带种系杂合ABL1错义变异的新患者组成，进一步描绘了这种疾病的表型谱，并认识到小头畸形是一种常见的发现。 我们的分析支持由于自动抑制丧失而导致的 ABL1 功能获得机制，并证明了使用伊马替尼进行药理学抑制的潜力。