Journal article

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

Alexander JM Blakes, Emily Gaul, Wayne Lam, Nora Shannon, Karen M Knapp, Louise S Bicknell, Meremaihi R Jackson, Emma M Wade, Stephen Robertson, Susan M White, Raoul Heller, Andrew Chase, Diana Baralle, Andrew GL Douglas

European Journal of Human Genetics | SPRINGERNATURE | Published : 2020


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 featur..

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Awarded by Health Innovation Challenge Fund

Awarded by Wellcome Sanger Institute

Awarded by Lung GO Sequencing Project

Awarded by WHI Sequencing Project

Awarded by Broad GO Sequencing Project

Awarded by Seattle GO Sequencing Project

Awarded by Heart GO Sequencing Project

Awarded by NIHR Research Professorship grant

Awarded by Bloodwise Specialist Programme

Funding Acknowledgements

The authors would like to thank the individuals and families described in this paper. This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from and via email from Funding for the project was provided by the Wellcome Trust. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute [grant number WT098051]. The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. Particular acknowledgements go to the following DDD clinicians who helped clarify which patients had pathogenic ABL1 variants: Julia Rankin (Royal Devon & Exeter NHS Foundation Trust), Michael Parker (Sheffield Children's NHS Foundation Trust), Pradeep Vasudevan (University Hospitals of Leicester NHS Trust), Ingrid Scurr (University Hospitals Bristol NHS Foundation Trust), Vinod Varghese (University Hospital of Wales), Vani Jain (University Hospital of Wales), Elisabeth Rosser (Great Ormond Street Hospital for Children NHS Foundation Trust), Shane McKee (Belfast Health and Social Care Trust), Gillian Rea (Belfast Health and Social Care Trust). The authors would like to thank the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at https://gnomad.broa The authors would also like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010). LSB is supported by a Rutherford Discovery Fellowship, administered by the Royal Society of New Zealand; the Bicknell lab is supported by the Neurological Foundation of New Zealand. DB and AGLD are supported by an NIHR Research Professorship grant awarded to DB (RP-2016-07-011). AC's research on this project was funded by Bloodwise Specialist Programme Grant no. 18007.