title: WDR73 Mutations Cause Infantile Neurodegeneration and Variable Glomerular Kidney Disease.
abstract: Infantile-onset cerebellar atrophy (CA) is a clinically and genetically heterogeneous trait. Galloway-Mowat syndrome (GMS) is a rare autosomal recessive disease, characterized by microcephaly with brain anomalies including CA in some cases, intellectual disability, and early-infantile-onset nephrotic syndrome. Very recently, WDR73 deficiency was identified as the cause of GMS in five individuals. To evaluate the role of WDR73 mutations as a cause of GMS and other forms of syndromic CA, we performed Sanger or exome sequencing in 51 unrelated patients with CA and variable brain anomalies and in 40 unrelated patients with a diagnosis of GMS. We identified 10 patients from three CA and from two GMS families with WDR73 mutations including the original family described with CA, mental retardation, optic atrophy, and skin abnormalities (CAMOS). There were five novel mutations, of which two were truncating and three were missense mutations affecting highly conserved residues. Individuals carrying homozygous WDR73 mutations mainly presented with a pattern of neurological and neuroimaging findings as well as intellectual disability, while kidney involvement was variable. We document postnatal onset of CA, a retinopathy, basal ganglia degeneration, and short stature as novel features of WDR73-related disease, and define WDR73-related disease as a new entity of infantile neurodegeneration.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Vodopiutz
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Austria.
authors.forename: Rainer
authors.initials: R
authors.lastname: Seidl
authors.affiliation: Division of Neuroradiology and Musculoskeletal Radiology, Medical University of Vienna, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Prayer
authors.affiliation: Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: M Imran
authors.initials: MI
authors.lastname: Khan
authors.affiliation: Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Mayr
authors.affiliation: Department of Obstetrics and Feto-Maternal Medicine, Medical University of Vienna, Austria.
authors.forename: Berthold
authors.initials: B
authors.lastname: Streubel
authors.affiliation: Department of Pediatrics, Justus-Liebig-University, Gießen, Germany.
authors.forename: Jens-Oliver
authors.initials: JO
authors.lastname: Steiß
authors.affiliation: Department of Child Neurology, Justus-Liebig-University, Gießen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hahn
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Csaicsich
authors.affiliation: Inserm, UMR_S 910, 13385, Marseille, France.|Aix Marseille Université, GMGF, Marseille, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Castro
authors.affiliation: Inserm, UMR_S 910, 13385, Marseille, France.|Aix Marseille Université, GMGF, Marseille, France.
authors.forename: Mirna
authors.initials: M
authors.lastname: Assoum
authors.affiliation: Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.affiliation: Institute of Human Genetics, University of Essen, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Grazia M S
authors.initials: GM
authors.lastname: Mancini
authors.affiliation: Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts.|Department of Gynecology and Obstetrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
authors.forename: Carolin E
authors.initials: CE
authors.lastname: Sadowski
authors.affiliation: Inserm, UMR_S 910, 13385, Marseille, France.|Aix Marseille Université, GMGF, Marseille, France.|Département de Génétique Médicale, Hôpital d'Enfants de la Timone, AP-HM, Marseille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lévy
authors.affiliation: Université Saint Joseph, Campus des Sciences Médicales, Unité de génétique médicale, Lebanon.|Institut Jérôme Lejeune, Paris, France.
authors.forename: André
authors.initials: A
authors.lastname: Mégarbané
authors.affiliation: Deenanath Mangeshkar Hospital & Research Center, Erandawane, Pune, India.
authors.forename: Koumudi
authors.initials: K
authors.lastname: Godbole
authors.affiliation: Institute of Human Genetics, University Hospital, Magdeburg, Germany.
authors.forename: Denny
authors.initials: D
authors.lastname: Schanze
authors.affiliation: Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.affiliation: Inserm, UMR_S 910, 13385, Marseille, France.|Aix Marseille Université, GMGF, Marseille, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Delague
authors.affiliation: Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.|Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.affiliation: Institute of Human Genetics, University Hospital, Magdeburg, Germany.|Institute of Human Genetics, University of Erlangen, Erlangen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001706:Biopsy; D001921:Brain / Q000002:abnormalities / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D005921:Glomerulonephritis / Q000175:diagnosis / Q000235:genetics*; D020271:Heredodegenerative Disorders, Nervous System / Q000175:diagnosis / Q000235:genetics*; D006551:Hernia, Hiatal / Q000175:diagnosis / Q000235:genetics; D006801:Humans; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D009401:Nephrosis / Q000175:diagnosis / Q000235:genetics*; D059906:Neuroimaging; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment; D055815:Young Adult
chemical_list: D011506:Proteins; C000595586:WDR73 protein, human
keywords: Galloway-Mowat; SCAR5; WDR73; basal ganglia; cerebellar atrophy; intellectual disability; optic atrophy; retinopathy