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Variable brain phenotype primarily affects the brainstem and cerebellum in patients with osteogenesis imperfecta caused by recessive WNT1 mutations
  1. Kimberly A Aldinger1,
  2. Nancy J Mendelsohn2,3,
  3. Brian HY Chung4,
  4. Wenjuan Zhang5,
  5. Daniel H Cohn5,
  6. Bridget Fernandez6,
  7. Fowzan S Alkuraya7,8,
  8. William B Dobyns1,9,10,
  9. Cynthia J Curry11,12
  1. 1Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA
  2. 2Medical Genetics Division, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA
  3. 3Division of Genetics, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
  4. 4Department of Paediatrics and Adolescent Medicine, Department of Obstetrics and Gynaecology, Centre for Genomic Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
  5. 5Department of Molecular, Cell and Developmental Biology, Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, California, USA
  6. 6Disciplines of Genetics and Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
  7. 7Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  8. 8Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
  9. 9Department of Pediatrics, University of Washington, Seattle, Washington, USA
  10. 10Department of Neurology, University of Washington, Seattle, Washington, USA
  11. 11Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA
  12. 12Genetic Medicine Central California, Fresno, California, USA
  1. Correspondence to Dr Cynthia J Curry, University of California, San Francisco/Genetic Medicine Central California, 155N Fresno St., Fresno CA 93701, USA; Cynthia.curry{at}

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Autosomal recessively inherited mutations in WNT1 were recently identified as a cause of severe osteogenesis imperfecta (OI).1–6 This finding does not address the critical role of Wnt1 in mid-hindbrain development that is well described in model organisms.7 ,8 Severe intellectual and motor deficits were noted in 4 of 16 families reported to date, but few details were provided. We reviewed developmental outcomes and brain-imaging studies for one new and five previously reported individuals with WNT1-associated OI. All six have brain malformations, with prominent brainstem and cerebellar hypoplasia in five of these six individuals.

Homozygous or compound heterozygous mutations in WNT1 were recently described as a novel cause for severe autosomal-recessive OI in 25 individuals from 16 families in a series of six papers.1–6 Brain-imaging studies in two individuals were reported to show unilateral cerebellar hypoplasia,2 ,4 and another was reported to have Chiari malformation type 1.5 However, only limited data were presented regarding the brain and neurological phenotypes, including only a single MRI image. This is an important issue to address, as the WNT family of secreted signalling proteins play key roles in many developmental and homeostatic processes.9 Indeed, prominent defects in early brain development were described in two mouse lines with Wnt1 mutations long before WNT1 mutations were identified as a cause of bone fragility in humans.7 ,8

To examine the human brain phenotype associated with mutations in WNT1, we reviewed all available brain-imaging studies from one new and five previously reported individuals including one sibling pair,1–5 which consisted of five brain MRI (figure 1) and one cranial CT scan (see online supplementary figure S1). We found significant malformations in all six individuals (table 1). Hippocampal malformations were found in three affected individuals for whom coronal MRI …

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  • Contributors KAA, WBD and CJC participated in the design of the study. NJM, BHYC, WZ, DHC, BF, FSA and CJC collected and/or generated data. KAA, WBD and CJC analysed and interpreted the data. KAA, WBD, DHC and CJC drafted the manuscript. All coauthors read and approved the final manuscript.

  • Funding Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke (NINDS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institute of Dental and Craniofacial Research (NIDCR) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH) under award numbers 1R01NS092772 to WBD, P01HD070394 to DHC, R01DE019567 to DHC and R01AR062651 to DHC, and by the SK Yee Medical Foundation and Orthopaedic Hospital Research Center at UCLA.

  • Competing interests None declared.

  • Ethics approval The Institutional Review Board at Seattle Children's Hospital, Seattle, Washington, USA.

  • Provenance and peer review Not commissioned; externally peer reviewed.