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Hum Mutat. 2015 Nov;36(11):1021-8. doi: 10.1002/humu.22828. Epub 2015 Aug 6.

WDR73 Mutations Cause Infantile Neurodegeneration and Variable Glomerular Kidney Disease.

Author information

1
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Austria.
2
Division of Neuroradiology and Musculoskeletal Radiology, Medical University of Vienna, Austria.
3
Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
4
Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria.
5
Department of Obstetrics and Feto-Maternal Medicine, Medical University of Vienna, Austria.
6
Department of Pediatrics, Justus-Liebig-University, Gießen, Germany.
7
Department of Child Neurology, Justus-Liebig-University, Gießen, Germany.
8
Inserm, UMR_S 910, 13385, Marseille, France.
9
Aix Marseille Université, GMGF, Marseille, France.
10
Institute of Human Genetics, University of Essen, Germany.
11
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
12
Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts.
13
Department of Gynecology and Obstetrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
14
Département de Génétique Médicale, Hôpital d'Enfants de la Timone, AP-HM, Marseille, France.
15
Université Saint Joseph, Campus des Sciences Médicales, Unité de génétique médicale, Lebanon.
16
Institut Jérôme Lejeune, Paris, France.
17
Deenanath Mangeshkar Hospital & Research Center, Erandawane, Pune, India.
18
Institute of Human Genetics, University Hospital, Magdeburg, Germany.
19
Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
20
Institute of Human Genetics, University of Erlangen, Erlangen, Germany.

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.

KEYWORDS:

Galloway-Mowat; SCAR5; WDR73; basal ganglia; cerebellar atrophy; intellectual disability; optic atrophy; retinopathy

PMID:
26123727
PMCID:
PMC4616260
DOI:
10.1002/humu.22828
[Indexed for MEDLINE]
Free PMC Article

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