Haploinsufficiency of ABL1 is associated with dominant isolated omphalocele

Caroline M. Kolvenbach^1,2,3*Öznur Yilmaz⁴Filipa M. Lopes⁵Jeshurun C Kalanithy⁶Katharina Lemberg^1,7Vineeta Sharma¹Amar Majmundar¹Matthias Geyer⁸Adrian S Woolf⁹Friedhelm Hildebrandt¹Benjamin Odermatt^2,4Heiko Martin Reutter^10*

• ¹Boston Children's Hospital, Harvard Medical School, Boston, United States
• ²Institute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, Bonn, Germany
• ³Department of Pediatrics I, University Children's Hospital Heidelberg, Medical Faculty, Heidelberg University, Heidelberg, Germany
• ⁴Institute of Neuroanatomy, Medical Faculty, University of Bonn, Bonn, Germany
• ⁵Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UK., Manchester, United Kingdom
• ⁶Department of Neonatology and Pediatric Intensive Care Medicine, University Children's Hospital Bonn, Bonn, Germany
• ⁷Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne and University Hospital Cologne, Cologne, Germany
• ⁸Institute of Structural Biology, Medical Faculty, University of Bonn, Bonn, Germany
• ⁹Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, United Kingdom
• ¹⁰Division of Neonatology and Pediatric Intensive Care, Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany

Omphalocele is a rare birth defect of the abdominal wall which results in the herniation of visceral organs through the umbilicus. To date, no genetic cause for non-syndromic isolated omphalocele has yet been defined. Exome sequencing in a four-generation multiplex family with isolated dominant omphalocele revealed a novel extended splice site variant (c.310+3A>C; p.?) in ABL1, encoding a non-receptor tyrosine kinase. Consistent with in silico predictions, in peripheral blood this variant leads to an alternatively spliced mRNA harboring a premature termination codon. Quantification of the ABL1 mRNA abundance showed a significant reduction of ABL1 mRNA in an affected allele carrier compared to a healthy control. These data indicate the degradation of the aberrantly spliced transcript by nonsense-mediated decay (NMD) consistent with haploinsufficiency as disease mechanism. Accordingly, pregnancy exposure with different tyrosine kinase inhibitors has been associated with a significantly increased risk for omphalocele in the exposed offspring. ABL1 is a causal gene for congenital heart defects and skeletal malformations syndrome (CHDSKM) and human ABL1 deficiency syndrome (HADS). CHDSKM has been associated with gain-of-function and HADS with 3’ truncating variants, likely escaping NMD. Therefore, allele-dependent mechanisms may explain phenotypic diversity. In human embryos, ABL1 was immunodetected in fibroblast-like cells in the umbilical cord and in abdominal wall surface ectoderm, both important sites for abdominal wall closure. In mouse embryos, wholemount in situ hybridization confirmed Abl1 expression in the umbilical cord. Our genetic and experimental findings provide evidence that ABL1 haploinsufficiency is the first monogenic cause for isolated dominant omphalocele.