A novel rearrangement of occludin causes brain calcification and renal dysfunction
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Pediatric intracranial calcification may be caused by inherited or acquired factors. We describe the identification of a novel rearrangement in which a downstream pseudogene translocates into exon 9 of OCLN, resulting in band-like brain calcification and advanced chronic kidney disease in early childhood. SNP genotyping and read-depth variation from whole exome sequencing initially pointed to a mutation in the OCLN gene. The high degree of identity between OCLN and two pseudogenes required a combination of multiplex ligation-dependent probe amplification, PCR, and Sanger sequencing to identify the genomic rearrangement that was the underlying genetic cause of the disease. Mutations in exon 3, or at the 5–6 intron splice site, of OCLN have been reported to cause brain calcification and polymicrogyria with no evidence of extra-cranial phenotypes. Of the OCLN splice variants described, all make use of exon 9, while OCLN variants that use exons 3, 5, and 6 are tissue specific. The genetic rearrangement we identified in exon 9 provides a plausible explanation for the expanded clinical phenotype observed in our individuals. Furthermore, the lack of polymicrogyria associated with the rearrangement of OCLN in our patients extends the range of cranial defects that can be observed due to OCLN mutations.
KeywordsCopy Number Variation Sanger Sequencing Chronic Kidney Disease Stage Single Nucleotide Polymorphism Genotyping Homozygosity Mapping
We are grateful to the family members who generously contributed their time and materials for this research. The authors would like to acknowledge the significant contributions to this work that were made by Dr. Duane Guernsey. Dr. Guernsey was a valued member of our research team who passed during the completion of this project. The following agencies provided funding for this project: Genome Canada, Genome Atlantic, Nova Scotia Health Research Foundation, Nova Scotia Research and Innovation Trust, Dalhousie Faculty of Medicine, Capital District Health Authority, IWK Health Centre Foundation, and Capital Health Research Fund. The authors would like to acknowledge the contribution of the Genome Quebec High Throughput Sequencing Platform. M.A.L is supported by a trainee award from the Beatrice Hunter Cancer Research Institute with funds provided by The Terry Fox Strategic Health Research Training Program in Cancer Research from CIHR. M.E.S is supported by the Centre de Recherche du CHU Ste-Justine.
Conflict of interest
The authors declare that there are no conflicts of interest.
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