TY - JOUR T1 - Variable brain phenotype primarily affects the brainstem and cerebellum in patients with osteogenesis imperfecta caused by recessive <em>WNT1</em> mutations JF - Journal of Medical Genetics JO - J Med Genet SP - 427 LP - 430 DO - 10.1136/jmedgenet-2015-103476 VL - 53 IS - 6 AU - Kimberly A Aldinger AU - Nancy J Mendelsohn AU - Brian HY Chung AU - Wenjuan Zhang AU - Daniel H Cohn AU - Bridget Fernandez AU - Fowzan S Alkuraya AU - William B Dobyns AU - Cynthia J Curry Y1 - 2016/06/01 UR - http://jmg.bmj.com/content/53/6/427.abstract N2 - 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 ,8To 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 … ER -