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

The genetic causes of multiple congenital anomalies are incompletely understood. Here we report novel heterozygous predicted loss-of-function and predicted damaging missense variants in the WBP11 gene, in seven unrelated families with a variety of overlapping congenital malformations including cardiac, vertebral, tracheo-oesophageal, renal and limb defects. WBP11 encodes a component of the spliceosome with the ability to activate pre-mRNA 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 oesophagus, similar to the affected individuals, supporting the role of WBP11 haploinsufficiency in the development of congenital malformations in humans. Loss-of-function WBP11 variants should be considered as a possible cause of VACTERL association as well as isolated Klippel-Feil syndrome, renal agenesis or oesophageal atresia.