期刊
HUMAN MOLECULAR GENETICS
卷 29, 期 22, 页码 3662-3678出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddaa258
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资金
- National Health and Medical Research Council (NHMRC) [ID1044543, ID1135886, ID1042002]
- Office of Health and Medical Research New South Wales Government - New South Wales Government
- Victor Chang Cardiac Research Institute Innovation Centre - New South Wales Government
- Agence Nationale de la Recherche [CranioRespiro project and `Investissements d'avenir' program] [ANR-10-IAHU-01]
- Merck Sharp and Dohme ameliorer la vie ensemble par l'innovation et la recherche (Devo-Decode project)
- National Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases [R01DK080099]
- Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health [R03HD099516]
- Baylor-Hopkins Center for Mendelian Genomics (NHGRI) [UM1 HG006542]
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.
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