Poster Presentation ANZSCDB National Scientific Meeting 2019

Heterozygous deleterious variants in WBP11 cause multiple congenital anomalies in humans and mice (#Poster 28)

Ella M. M. A. Martin 1 , Annabelle Enriquez 1 2 , Duncan B. Sparrow 3 , David T. Humphreys 1 2 , Kavitha R. Iyer 1 , Joelene A. Greasby 1 , Paul Leo 4 , Emma L. Duncan 4 , Clemantine Dimartino 5 6 , Jeanne Amiel 5 6 7 , Nara L. M. Sobreira 8 , Daphne Lehalle 9 , Hila M. Rasouly 10 , Ali G. Gharavi 10 , Robert D. Steiner 11 , Cathy Raggio 12 , Robert Blank 13 , Eleni Giannoulatou 1 , Christopher T. Gordon 5 6 , Rebekah Jobling 14 , Philip Giampietro 15 , Sally L. Dunwoodie 1 2 16 , Gavin Chapman 1 2
  1. Development and stem cell biology division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia
  2. Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
  3. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
  4. Queensland University of Technology, Brisbane, Queensland, Australia
  5. Laboratory of Embryology and Genetics of Human Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
  6. Paris Descartes-Sorbonne Paris Cité Université, Institut Imagine, Paris, France
  7. Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France
  8. Pediatric Clinical Research Unit, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, 21287, USA
  9. Centre Hospitalier Intercommunal Créteil, Créteil, 94000, France
  10. Division of Nephrology, Department of Medicine Columbia University, 1150 Saint Nicholas Avenue, New York 10032, USA
  11. Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Wisconsin, USA
  12. Hospital for Special Surgery, Pediatrics Orthopedic Surgery, New York, NY 10021, USA
  13. Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
  14. The Hospital for Sick Children, Totonto, Ontario, Canada
  15. Department of Pediatrics, Robert Wood Johnson School of Medicine/Rutgers University , New Brunswick, NJ 08901, USA
  16. Faculty of Science, UNSW Sydney, 2052, Sydney, NSW, Australia

Vertebral malformations are relatively common, affecting 1 in 2,000 live births and can result in abnormal curvature of the spine or, in severe cases, in neonatal death due to restrictive respiratory insufficiency. Although vertebral malformations often occur in isolation, 20% of cases have additional defects, most commonly congenital heart disease. Relatively few genes have been linked to vertebral malformations, mostly associated with rare and severe forms. In order to identify additional genetic causes of vertebral malformations we performed exome sequencing on the DNA of 45 trios and families. Several likely causative variants were identified in genes previously linked to vertebral defects in humans. In addition, two unrelated patients with Klippel-Feil Syndrome had novel heterozygous stop gain variants in the WBP11 gene. WBP11 encodes an evolutionarily conserved activator of splicing, which has not been previously linked to human disease. Similar truncated WBP11 constructs lack splicing activity, suggestive of a haploinsufficient mechanism of disease. Eight additional patients in five families were identified via GeneMatcher, four families with heterozygous truncating WBP11 variants and one with a predicted pathogenic variant in WBP11. Although patient phenotypes varied, common malformations included cervical vertebral fusions, oesophageal atresia, kidney and heart defects. We generated a mouse model of WBP11 haploinsufficiency by creating an 8bp deletion in exon 5 using CRISPR-Cas9 targeting. Wbp11 homozygous null mouse embryos died prior to E8.5 indicating that Wbp11 is an essential gene for development. Mice heterozygous for a Wbp11 null allele were not found in the expected Mendelian ratio with many dying either late in gestation, postnatally or as adults from hydrocephaly. Importantly, defects of the axial skeleton, brain and kidneys were common in Wbp11 heterozygous mice, similar to our patients, confirming WBP11 mutation as a cause of multiple congenital defects in humans and mice.