A founder mutation in COL4A3 causes autosomal recessive Alport syndrome in the Ashkenazi Jewish population |
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| Authors: | BD Webb T Brandt L Liu C Jalas J Liao A Fedick MD Linderman GA Diaz R Kornreich H Trachtman L Mehta L Edelmann |
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| Institution: | 1. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, , New York, NY, USA;2. Department of Pediatrics, Icahn School of Medicine at Mount Sinai, , New York, NY, USA;3. Bonei Olam, Center for Rare Jewish Genetic Disorders, , Brooklyn, NY, USA;4. Department of Microbiology and Molecular Genetics, UMDNJ‐Robert Wood Johnson Medical School, , Piscataway, NJ, USA;5. Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, , New York, NY, USA;6. Department of Pediatrics, New York University School of Medicine, , New York, NY, USA |
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| Abstract: | Alport syndrome is an inherited progressive nephropathy arising from mutations in the type IV collagen genes, COL4A3, COL4A4, and COL4A5. Symptoms also include sensorineural hearing loss and ocular lesions. We determined the molecular basis of Alport syndrome in a non‐consanguineous Ashkenazi Jewish family with multiple affected females using linkage analysis and next generation sequencing. We identified a homozygous COL4A3 mutation, c.40_63del, in affected individuals with mutant alleles inherited from each parent on partially conserved haplotypes. Large‐scale population screening of 2017 unrelated Ashkenazi Jewish samples revealed a carrier frequency of 1 in 183 indicating that COL4A3 c.40_63del is a founder mutation which may be a common cause of Alport syndrome in this population. Additionally, we determined that heterozygous mutation carriers in this family do not meet criteria for a diagnosis of Thin Basement Membrane Nephropathy and concluded that carriers of c.40_63del are not likely to develop benign familial hematuria. |
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| Keywords: | Alport syndrome Ashkenazi Jewish COL4A3 founder mutation |
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