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WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitulate 10p11.23 microdeletion syndrome
  1. Cori DeSanto1,
  2. Kristin D'Aco2,
  3. Gabriel C Araujo3,
  4. Nora Shannon4,
  5. DDD Study5,
  6. Hilary Vernon6,7,
  7. April Rahrig8,
  8. Kristin G Monaghan9,
  9. Zhiyv Niu10,
  10. Patrik Vitazka9,
  11. Jonathan Dodd3,
  12. Sha Tang11,
  13. Linda Manwaring1,
  14. Arelis Martir-Negron8,12,
  15. Rhonda E Schnur9,
  16. Jane Juusola9,
  17. Audrey Schroeder2,
  18. Vivian Pan8,
  19. Katherine L Helbig11,
  20. Bethany Friedman9,
  21. Marwan Shinawi1
  1. 1Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA
  2. 2Division of Genetics, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
  3. 3Department of Psychology, St Louis Children's Hospital, St Louis, Missouri, USA
  4. 4Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK
  5. 5Wellcome Trust Sanger Institute, Cambridge, UK
  6. 6Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland, USA
  7. 7McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA
  8. 8Department of Pediatrics, Advocate Children's Hospital, Park Ridge, Illinois, USA
  9. 9GeneDx, Gaithersburg, Maryland, USA
  10. 10Department of Molecular and Human Genetics, Whole Genome Laboratory and Medical Genetics Laboratories, Baylor College of Medicine, Houston, Texas, USA
  11. 11Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA
  12. 12Division of Clinical Genetics & Metabolic Disorders, Palm Beach Gardens Outpatient Center, Nicklaus Children's Hospital, Miami, Florida, USA
  1. Correspondence to Dr Marwan Shinawi, Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, One Children's Place, Northwest Tower, 9132, Campus Box 8116, St Louis, MO 63110, USA; Shinawi_M{at}


Background Rare de novo mutations have been implicated as a significant cause of idiopathic intellectual disability. Large deletions encompassing 10p11.23 have been implicated in developmental delay, behavioural abnormalities and dysmorphic features, but the genotype–phenotype correlation was not delineated. Mutations in WAC have been recently reported in large screening cohorts of patients with intellectual disability or autism, but no full phenotypic characterisation was described.

Methods Clinical and molecular characterisation of six patients with loss-of-function WAC mutations identified by whole exome sequencing was performed. Clinical data were obtained by retrospective chart review, parental interviews, direct patient interaction and formal neuropsychological evaluation.

Results Five heterozygous de novo WAC mutations were identified in six patients. Three of the mutations were nonsense, and two were frameshift; all are predicted to cause loss of function either through nonsense-mediated mRNA decay or protein truncation. Clinical findings included developmental delay (6/6), hypotonia (6/6), behavioural problems (5/6), eye abnormalities (5/6), constipation (5/6), feeding difficulties (4/6), seizures (2/6) and sleep problems (2/6). All patients exhibited common dysmorphic features, including broad/prominent forehead, synophrys and/or bushy eyebrows, depressed nasal bridge and bulbous nasal tip. Posteriorly rotated ears, hirsutism, deep-set eyes, thin upper lip, inverted nipples, hearing loss and branchial cleft anomalies were also noted.

Conclusions Our case series show that loss-of-function mutations in WAC cause a recognisable genetic syndrome characterised by a neurocognitive phenotype and facial dysmorphism. Our data highly suggest that WAC haploinsufficiency is responsible for most of the phenotypic features associated with deletions encompassing 10p11.23.

  • Clinical genetics
  • Genetics

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