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Nonsense mutation in the WDR73 gene is associated with Galloway-Mowat syndrome
  1. Tawfeg Ben-Omran1,
  2. Somayyeh Fahiminiya2,3,
  3. Natalie Sorfazlian4,
  4. Mariam Almuriekhi1,
  5. Zafar Nawaz5,
  6. Javad Nadaf2,3,
  7. Kitam Abu Khadija5,
  8. Samiha Zaineddin5,
  9. Hussein Kamel6,
  10. Jacek Majewski2,3,
  11. Vincent Tropepe4,7
  1. 1Section of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Weill-Cornell Medical College, Doha, Qatar
  2. 2Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
  3. 3McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada
  4. 4Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario, Canada
  5. 5Cytogenetic and Molecular Cytogenetic Laboratory, Department of Laboratory, Medicine and Pathology, Hamad Medical Corporation, Doha, Qatar
  6. 6Department of Radiology, Hamad Medical Corporation, Weill-Cornell Medical College, Doha, Qatar
  7. 7Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Professor Vincent Tropepe, Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario, Canada M5S 3G5; v.tropepe{at}utoronto.ca

Abstract

Background Neuroanatomical defects are often present in children with severe developmental delay and intellectual disabilities. Few genetic loci have been associated with disorders of neurodevelopment. Our objective of the present study was to analyse a consanguineous Arab family showing some of the hallmark signs of a rare cerebellar hypoplasia-related neurodevelopmental syndrome as a strategy for discovering a causative genetic mutation.

Methods We used whole exome sequencing to identify the causative mutation in two female siblings of a consanguineous Arab family showing some of the hallmark signs of a cerebellar-hypoplasia-related neurodevelopmental disorder. Direct Sanger sequencing was used to validate the candidate mutations that cosegregated with the phenotype. Gene expression and loss of function studies were carried out in the zebrafish model system to examine the role of the candidate gene in neurodevelopment.

Results Patients presented with severe global developmental delay, intellectual disability, hypoplasia of the cerebellum and biochemical findings suggestive of nephrotic disease. Whole exome sequencing of the two patients revealed a shared nonsense homozygous variant in WDR73 (p.Q235X (c.703C>T)) resulting in loss of the last 144 amino acids of the protein. The variant segregated according to a recessive mode of inheritance in this family and was absent from public and our inhouse databases. We examined the developmental role of WDR73 using a loss-of-function paradigm in zebrafish. There was a significant brain growth and morphogenesis defect in wdr73 knockdown embryos resulting in a poorly differentiated midbrain and cerebellum.

Conclusions The results provide new insight into the functional role of WDR73 in brain development and show that perturbation of its function in an inherited disorder in humans is associated with cerebellar hypoplasia as well as nephrotic disease, consistent with Galloway-Mowat Syndrome.

  • Clinical genetics
  • Developmental
  • Molecular genetics

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