title: Horizontal gaze palsy with progressive scoliosis: three novel ROBO3 mutations and descriptions of the phenotypes of four patients.
abstract: OBJECTIVE
  Clinical and molecular characterization of patients with horizontal gaze palsy with progressive scoliosis (HGPPS) to extend existing knowledge of the phenotype caused by mutations in the Roundabout homolog of Drosophila 3 (ROBO3) gene.
  
  
  METHODS
  Four patients (aged 6 months to 13 years), two of them siblings, with features of horizontal gaze palsy and their parents were examined clinically and by molecular testing of the ROBO3 gene. The three families were unrelated, but parents in each family were consanguineous.
  
  
  RESULTS
  We identified three novel homozygous ROBO3 mutations in four patients with typical ophthalmologic signs of HGPPS. We found an exonic insertion/deletion mutation (c.913delAinsTGC; p.Ile305CysfsX13), a 31 bp deletion including the donor splice site of exon 17 and adjacent exonic and intronic sequences (c.2769_2779del11, 2779+1_+20del20), and a missense mutation located next to a splice donor site (c.3319A>C) resulting in skipping of exon 22, as shown by cDNA analysis.
  
  
  CONCLUSIONS
  We describe three novel mutations in the ROBO3 gene and the detailed clinical phenotype of HGPPS. One patient displayed marked convergence upon attempting smooth pursuits to both sides. In one patient, the typical ophthalmologic phenotype, the neuroradiologic findings, and molecular testing led to the diagnosis even before scoliosis developed. In addition to the typical magnetic resonance imaging brain signs of HGPPS, this patient had marked hypoplasia of the frontal lobes and corpus callosum. In summary, diagnosis of HGPPS may be established by ophthalmologic and molecular investigation early in life, allowing ongoing orthopedic surveillance from an early stage.
authors.affiliation: Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany. alexander.volk@uni-ulm.de
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Volk
authors.forename: Oliver
authors.initials: O
authors.lastname: Carter
authors.forename: Julia
authors.initials: J
authors.lastname: Fricke
authors.forename: Peter
authors.initials: P
authors.lastname: Herkenrath
authors.forename: Jörg
authors.initials: J
authors.lastname: Poggenborg
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
authors.forename: Andre W
authors.initials: AW
authors.lastname: Demant
authors.forename: Roland
authors.initials: R
authors.lastname: Ivo
authors.forename: Peer
authors.initials: P
authors.lastname: Eysel
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.forename: Antje
authors.initials: A
authors.lastname: Neugebauer
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002648:Child; D003241:Consanguinity; D004252:DNA Mutational Analysis; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D015835:Ocular Motility Disorders / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic / Q000235:genetics*; D012529:Saudi Arabia; D012600:Scoliosis / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D035781:Siblings; D014421:Turkey; D014787:Vision Tests; D000097905:Roundabout Proteins
chemical_list: D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C499630:ROBO3 protein, human; D000097905:Roundabout Proteins