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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| Hauptverfasser: | , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
06 August 2025
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| In: |
Frontiers in cell and developmental biology
Year: 2025, Jahrgang: 13, Pages: 1-9 |
| ISSN: | 2296-634X |
| DOI: | 10.3389/fcell.2025.1630894 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.3389/fcell.2025.1630894 Verlag, kostenfrei, Volltext: https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2025.1630894/full 
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| Verfasserangaben: | Caroline M. Kolvenbach, Öznur Yilmaz, Filipa M. Lopes, Jeshurun C. Kalanithy, Katharina Lemberg, Vineeta Sharma, Amar J. Majmundar, Matthias Geyer, Adrian S. Woolf, Friedhelm Hildebrandt, Benjamin Odermatt and Heiko Reutter |
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| 245 | 1 | 0 | |a Haploinsufficiency of ABL1 is associated with dominant isolated omphalocele |c Caroline M. Kolvenbach, Öznur Yilmaz, Filipa M. Lopes, Jeshurun C. Kalanithy, Katharina Lemberg, Vineeta Sharma, Amar J. Majmundar, Matthias Geyer, Adrian S. Woolf, Friedhelm Hildebrandt, Benjamin Odermatt and Heiko Reutter |
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| 520 | |a 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. | ||
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| 650 | 4 | |a dominant | |
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| 650 | 4 | |a haploinsufficiency | |
| 650 | 4 | |a omphalocele | |
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