title: Refinement of the DFNA41 locus and candidate genes analysis.
abstract: We previously mapped the 41rst gene locus (DFNA41) for autosomal dominant hearing loss on chromosome 12q24-qter in a large multi-generational Chinese family. We determined that DFNA41 is located in a 15 cM region, proximal to the marker D12S1609. A maximum two point LOD score of 6.56 at theta = 0.0 was obtained with marker D12S343. In the current study, screening of eight candidate genes within the DFNA41 interval did not reveal the mutation causing deafness in this family. Eight highly informative single nucleotide polymorphisms (SNPs) in the region of D12S343 were selected for linkage and association study. Because the pedigree studied here is a large family with many founders, we applied the transmission/disequilibrium (TDT) test. To account for the dependence of small families and the relatively small sample size, simulations were performed to obtain P-values. For three nearby SNPs spanning a 7 kb interval, we found significant evidence of linkage and association. The highest Z score of linkage and association of 3.6 (P < or = 0.0001) was obtained for SNP rs1566667. Haplotype analysis revealed that affected individuals were heterozygous for one core SNP (rs1027560-rs1027557-rs1566667-rs1463865-rs2078105) CAGTC haplotype, confirming location and autosomal dominant inheritance of the DFNA41 locus. Examination of pairwise LD calculation identified a major haplotype block defined by the four most centromeric SNPs. This study represents a significant refinement of the DFNA41 locus and should facilitate positional cloning of the disease gene.
authors.affiliation: Department of Otolaryngology (D-48), University of Miami, 1666 NW 12th Avenue, Miami, FL, 33136, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Yan
authors.affiliation: Department of Otolaryngology (D-48), University of Miami, 1666 NW 12th Avenue, Miami, FL, 33136, USA.
authors.forename: Xiao Mei
authors.initials: XM
authors.lastname: Ouyang
authors.affiliation: Department of Preventive Medicine and Epidemiology, Loyola Stritch School of Medicine, Maywood, IL, 60153, USA.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Otolaryngology (D-48), University of Miami, 1666 NW 12th Avenue, Miami, FL, 33136, USA.
authors.forename: Li Lin
authors.initials: LL
authors.lastname: Du
authors.affiliation: Neurology Department, Massachusetts General Hospital and Neurobiology Department, Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Zheng Yi
authors.initials: ZY
authors.lastname: Chen
authors.affiliation: Department of Otolaryngology (D-48), University of Miami, 1666 NW 12th Avenue, Miami, FL, 33136, USA. xliu@med.miami.edu.
authors.forename: Xue Zhong
authors.initials: XZ
authors.lastname: Liu
mesh_terms: D002503:Centromere / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*