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

Hum Mol Genet. 2020 Dec 4;29(22):3662-3678. doi: 10.1093/hmg/ddaa258.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Anal Canal / abnormalities
  • Anal Canal / pathology
  • Animals
  • DNA-Binding Proteins / genetics*
  • Esophagus / abnormalities
  • Esophagus / metabolism
  • Esophagus / pathology
  • Haploinsufficiency / genetics*
  • Heart Defects, Congenital / genetics
  • Heart Defects, Congenital / pathology
  • Heterozygote
  • Humans
  • Kidney / abnormalities
  • Kidney / metabolism*
  • Kidney / pathology
  • Limb Deformities, Congenital / genetics
  • Limb Deformities, Congenital / pathology
  • Loss of Function Mutation / genetics
  • Mice
  • RNA Splicing / genetics
  • RNA Splicing Factors / genetics*
  • Spine / abnormalities
  • Spine / pathology
  • Trachea / abnormalities
  • Trachea / pathology


  • DNA-Binding Proteins
  • RNA Splicing Factors
  • WBP11 protein, human

Supplementary concepts

  • VACTERL association