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Novel Variants in COL4A3 and COL4A4 are Causes of Alport Syndrome in Rio Grande do Norte, Brazil

de Araujo, W. C.; Falcao, R. M.; Uchoa, R.; Garcia, C. A.; de Souza, J. E. S.; Jeronimo, S. M. B.

2019-12-17 genomics
10.1101/2019.12.17.878918 bioRxiv
Show abstract

BackgroundAlport syndrome is a progressive and hereditary nephropathy, characterized by hematuria and proteinuria, and extrarenal manifestations as hearing loss and eye abnormalities. The disease can be expressed as autosomal recessive or dominant, caused by variants in COL4A3 and COL4A4 loci, respectively, or X-linked caused by variants in COL4A5 locus. MethodsTwo unrelated families with Alport Syndrome from northeast of Brazil were studied and whole exome sequencing were performed. DNA sequences were mapped against the human genome (GRCh38/hg38 build) to identify associated mutations. ResultsVariant analysis showed deleterious variants in COL4A3 and COL4A4 loci in chromosome 2. Two variants were detected with alternative alleles in a homozygous state in the probands. One novel premature stop codon at position 481 of COL4A3 protein is present in one family and one frameshift mutation leading to a premature stop codon at position 786 of COL4A4 protein in the other family. Both Alport cases presented their variants surrounded by a broad runs of homozygosity (ROH). ConclusionsThe autosome recessive inheritance coupled with the runs of homozygosity in both families suggest inbreeding.

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