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Journal Reference
J Med Genet. 2015 Jun;52(6):381-90.
Ben-Omran T1, Fahiminiya S2, Sorfazlian N3, Almuriekhi M1, Nawaz Z4, Nadaf J2, Khadija KA4, Zaineddin S4, Kamel H5, Majewski J2, Tropepe V6.
[expand title=”Show Affiliations”]- Section of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Weill-Cornell Medical College, Doha, Qatar.
- Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
- Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario, Canada.
- Cytogenetic and Molecular Cytogenetic Laboratory, Department of Laboratory, Medicine and Pathology, Hamad Medical Corporation, Doha, Qatar.
- Department of Radiology, Hamad Medical Corporation, Weill-Cornell Medical College, Doha, Qatar.
- Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario, Canada Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, Ontario, Canada.
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.