Haploinsufficiency of ABL1 is associated with dominant isolated omphalocele
Omphalocele is a rare birth defect of the abdominal wall that results in herniation of the visceral organs through the umbilicus. To date, there are no identified genetic causes for non-syndromic isolated omphalocele. Exome sequencing in a four-generation multiplex family with isolated dominant omph...
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Frontiers Media S.A.
2025-08-01
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| author | Caroline M. Kolvenbach Caroline M. Kolvenbach Caroline M. Kolvenbach Öznur Yilmaz Filipa M. Lopes Jeshurun C. Kalanithy Jeshurun C. Kalanithy Katharina Lemberg Katharina Lemberg Vineeta Sharma Amar J. Majmundar Matthias Geyer Adrian S. Woolf Friedhelm Hildebrandt Benjamin Odermatt Benjamin Odermatt Heiko Reutter |
| author_facet | Caroline M. Kolvenbach Caroline M. Kolvenbach Caroline M. Kolvenbach Öznur Yilmaz Filipa M. Lopes Jeshurun C. Kalanithy Jeshurun C. Kalanithy Katharina Lemberg Katharina Lemberg Vineeta Sharma Amar J. Majmundar Matthias Geyer Adrian S. Woolf Friedhelm Hildebrandt Benjamin Odermatt Benjamin Odermatt Heiko Reutter |
| author_sort | Caroline M. Kolvenbach |
| collection | DOAJ |
| description | Omphalocele is a rare birth defect of the abdominal wall that results in herniation of the visceral organs through the umbilicus. To date, there are no identified genetic causes for non-syndromic isolated omphalocele. 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 that encoded 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 its significant reduction in an affected allele carrier compared to a healthy control. These data indicate degradation of the aberrantly spliced transcript by non-sense-mediated decay (NMD), consistent with haploinsufficiency as the disease mechanism. Accordingly, exposure to different tyrosine kinase inhibitors during pregnancy is associated with a significantly higher risk of omphalocele in the exposed offspring. ABL1 is a causative gene for congenital heart defect and skeletal malformation syndrome (CHDSKM) and human ABL1 deficiency syndrome (HADS); CHDSKM is associated with gain-of-function while HADS is associated with 3′ truncating variants, likely escaping NMD. Therefore, allele-dependent mechanisms may explain the phenotypic diversity. In human embryos (45–47 days post fertilization), ABL1 was immunodetected in fibroblast-like cells in the umbilical cord as well as abdominal wall surface ectoderm, both of which are important sites for abdominal wall closure. In mouse embryos (embryonic days 14.5–15.5), 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. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
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| spelling | doaj-art-5d937e7c8d6944309a0dcc68c1315d9c2025-08-20T03:44:32ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2025-08-011310.3389/fcell.2025.16308941630894Haploinsufficiency of ABL1 is associated with dominant isolated omphaloceleCaroline M. Kolvenbach0Caroline M. Kolvenbach1Caroline M. Kolvenbach2Öznur Yilmaz3Filipa M. Lopes4Jeshurun C. Kalanithy5Jeshurun C. Kalanithy6Katharina Lemberg7Katharina Lemberg8Vineeta Sharma9Amar J. Majmundar10Matthias Geyer11Adrian S. Woolf12Friedhelm Hildebrandt13Benjamin Odermatt14Benjamin Odermatt15Heiko Reutter16Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United StatesMedical Faculty, Institute of Anatomy and Cell Biology, University of Bonn, Bonn, GermanyDepartment of Pediatrics I, University Children’s Hospital Heidelberg, Medical Faculty, Heidelberg University, Heidelberg, GermanyMedical Faculty, Institute of Neuroanatomy, University of Bonn, Bonn, GermanyDivision of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, MA, United KingdomMedical Faculty, Institute of Anatomy and Cell Biology, University of Bonn, Bonn, GermanyDepartment of Neonatology and Pediatric Intensive Care Medicine, University Children’s Hospital Bonn, Bonn, GermanyDepartment of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United StatesDepartment II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne and University Hospital Cologne, Cologne, GermanyDepartment of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United StatesDepartment of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United StatesMedical Faculty, Institute of Structural Biology, University of Bonn, Bonn, GermanyDivision of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, MA, United KingdomDepartment of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United StatesMedical Faculty, Institute of Anatomy and Cell Biology, University of Bonn, Bonn, GermanyMedical Faculty, Institute of Neuroanatomy, University of Bonn, Bonn, GermanyDivision of Neonatology and Pediatric Intensive Care, Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, GermanyOmphalocele is a rare birth defect of the abdominal wall that results in herniation of the visceral organs through the umbilicus. To date, there are no identified genetic causes for non-syndromic isolated omphalocele. 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 that encoded 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 its significant reduction in an affected allele carrier compared to a healthy control. These data indicate degradation of the aberrantly spliced transcript by non-sense-mediated decay (NMD), consistent with haploinsufficiency as the disease mechanism. Accordingly, exposure to different tyrosine kinase inhibitors during pregnancy is associated with a significantly higher risk of omphalocele in the exposed offspring. ABL1 is a causative gene for congenital heart defect and skeletal malformation syndrome (CHDSKM) and human ABL1 deficiency syndrome (HADS); CHDSKM is associated with gain-of-function while HADS is associated with 3′ truncating variants, likely escaping NMD. Therefore, allele-dependent mechanisms may explain the phenotypic diversity. In human embryos (45–47 days post fertilization), ABL1 was immunodetected in fibroblast-like cells in the umbilical cord as well as abdominal wall surface ectoderm, both of which are important sites for abdominal wall closure. In mouse embryos (embryonic days 14.5–15.5), 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.https://www.frontiersin.org/articles/10.3389/fcell.2025.1630894/fullomphaloceleABL1dominantexome sequencinghaploinsufficiency |
| spellingShingle | Caroline M. Kolvenbach Caroline M. Kolvenbach Caroline M. Kolvenbach Öznur Yilmaz Filipa M. Lopes Jeshurun C. Kalanithy Jeshurun C. Kalanithy Katharina Lemberg Katharina Lemberg Vineeta Sharma Amar J. Majmundar Matthias Geyer Adrian S. Woolf Friedhelm Hildebrandt Benjamin Odermatt Benjamin Odermatt Heiko Reutter Haploinsufficiency of ABL1 is associated with dominant isolated omphalocele Frontiers in Cell and Developmental Biology omphalocele ABL1 dominant exome sequencing haploinsufficiency |
| title | Haploinsufficiency of ABL1 is associated with dominant isolated omphalocele |
| title_full | Haploinsufficiency of ABL1 is associated with dominant isolated omphalocele |
| title_fullStr | Haploinsufficiency of ABL1 is associated with dominant isolated omphalocele |
| title_full_unstemmed | Haploinsufficiency of ABL1 is associated with dominant isolated omphalocele |
| title_short | Haploinsufficiency of ABL1 is associated with dominant isolated omphalocele |
| title_sort | haploinsufficiency of abl1 is associated with dominant isolated omphalocele |
| topic | omphalocele ABL1 dominant exome sequencing haploinsufficiency |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2025.1630894/full |
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