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The genetic causes of multiple congenital anomalies are incompletely understood. Here, we report novel heterozygous predicted loss-of-function (LoF) and predicted damaging missense variants in the WW domain binding protein 11 ( WBP11 ) gene in seven unrelated families with a variety of overlapping congenital malformations, including cardiac, vertebral, tracheo-esophageal, renal and limb defects.  WBP11  encodes a component of the spliceosome with the ability to activate pre-messenger RNA splicing. We generated a  Wbp11  null allele in mouse using CRISPR-Cas9 targeting.  Wbp11  homozygous null embryos die prior to E8.5, indicating that  Wbp11  is essential for development. Fewer  Wbp11  heterozygous null mice are found than expected due to embryonic and postnatal death. Importantly,  Wbp11  heterozygous null mice are small and exhibit defects in axial skeleton, kidneys and esophagus, similar to the affected individuals, supporting the role of  WBP11  haploinsufficiency in the development of congenital malformations in humans. LoF  WBP11  variants should be considered as a possible cause of VACTERL association as well as isolated Klippel-Feil syndrome, renal agenesis or esophageal atresia.

Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice