Haploinsufficiency of 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 omphalocele revealed a novel extended splice site variant (c.310 + 3A>C; p.?) in that encoded a non-receptor tyrosine kinase. Consistent with predictions, in peripheral blood, this variant leads to an alternatively spliced mRNA harboring a premature termination codon. Quantification of the 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. 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 hybridization confirmed expression in the umbilical cord. Our genetic and experimental findings provide evidence that haploinsufficiency is the first monogenic cause for isolated dominant omphalocele.

Copyright © 2025 Kolvenbach, Yilmaz, Lopes, Kalanithy, Lemberg, Sharma, Majmundar, Geyer, Woolf, Hildebrandt, Odermatt and Reutter.

PMID: 40843169