title: Compound Heterozygous Variants in ROBO1 Cause a Neurodevelopmental Disorder With Absence of Transverse Pontine Fibers and Thinning of the Anterior Commissure and Corpus Callosum.
abstract: Axonal guidance disorders are characterized by white matter tracts with an anomalous course, failure to cross the midline, or presence of anomalous white matter tracts. Diffusion tensor imaging (DTI) is a suitable noninvasive, in vivo neuroimaging tool to study axonal guidance disorders. We describe a novel disorder in a boy with compound heterozygous variants in the ROBO1 gene.
  
  
  
  The child was referred at age 13 months because of developmental delay. At age nine years, he had severe intellectual disability and hyperactivity. He was nonverbal and wheelchair dependent because of spastic diplegia and ataxia. Brain magnetic resonance imaging with DTI revealed marked pontine hypoplasia, thinning of the anterior commissure and corpus callosum, and absence of the transverse pontine fibers. In addition, at the level of the pons the corticospinal tracts and medial lemnisci were not clearly separated from each other. Whole exome sequencing revealed compound heterozygous variants in the ROBO1 gene.
  
  
  
  This child's neuroimaging phenotype (absence of the transverse pontine fibers and thinning of the anterior commissure and corpus callosum as shown by DTI) is suggestive of an axonal guidance disorder and supports a pathogenic role of the compound heterozygous variants in the ROBO1 gene.
authors.affiliation: Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Università degli Studi di Milano, Postgraduation School in Radiodiagnostics, Milan, Italy.
authors.forename: Sonia F
authors.initials: SF
authors.lastname: Calloni
authors.affiliation: Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland.
authors.forename: Julie S
authors.initials: JS
authors.lastname: Cohen
authors.affiliation: Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Pediatric Radiology and Pediatric Neuroradiology, Johns Hopkins All Children's Hospital, St. Petersburg, Florida.
authors.forename: Avner
authors.initials: A
authors.lastname: Meoded
authors.affiliation: Whole Exome Sequencing Program, GeneDx, Gaithersburg, Maryland.
authors.forename: Jane
authors.initials: J
authors.lastname: Juusola
authors.affiliation: Department of Neuroradiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Fabio M
authors.initials: FM
authors.lastname: Triulzi
authors.affiliation: Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Thierry A G M
authors.initials: TAGM
authors.lastname: Huisman
authors.affiliation: Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: aporett1@jhmi.edu.
authors.forename: Andrea
authors.initials: A
authors.lastname: Poretti
authors.affiliation: Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Ali
authors.initials: A
authors.lastname: Fatemi
mesh_terms: D016880:Anisotropy; D002648:Child; D003337:Corpus Callosum / Q000000981:diagnostic imaging / Q000473:pathology*; D056324:Diffusion Tensor Imaging; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008137:Longitudinal Studies; D008297:Male; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D065886:Neurodevelopmental Disorders / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D011149:Pons / Q000000981:diagnostic imaging / Q000473:pathology*; D011971:Receptors, Immunologic / Q000235:genetics*; D066127:White Matter / Q000000981:diagnostic imaging / Q000473:pathology*; D000097905:Roundabout Proteins
chemical_list: D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins
keywords: ROBO1; anterior commissure; axonal guidance disorder; developmental delay; diffusion tensor imaging; magnetic resonance imaging; transverse pontine fibers