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A founder mutation in COL4A3 causes autosomal recessive Alport syndrome in the Ashkenazi Jewish population
Author(s) -
Webb B.D.,
Brandt T.,
Liu L.,
Jalas C.,
Liao J.,
Fedick A.,
Linderman M.D.,
Diaz G.A.,
Kornreich R.,
Trachtman H.,
Mehta L.,
Edelmann L.
Publication year - 2014
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.12247
Subject(s) - alport syndrome , genetics , haplotype , population , founder effect , mutation , genetic linkage , allele , medicine , biology , glomerulonephritis , gene , kidney , environmental health
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.