title: Genome-wide linkage study suggests a susceptibility locus for isolated bilateral microtia on 4p15.32-4p16.2.
abstract: Microtia is a congenital deformity where the external ear is underdeveloped. Genetic investigations have identified many susceptibility genes of microtia-related syndromes. However, no causal genes were reported for isolated microtia, the main form of microtia. We conducted a genome-wide linkage analysis on a 5-generation Chinese pedigree with isolated bilateral microtia. We identified a suggestive linkage locus on 4p15.32-4p16.2 with parametric LOD score of 2.70 and nonparametric linkage score (Zmean) of 12.28 (simulated occurrence per genome scan equal to 0.46 and 0.47, respectively). Haplotype reconstruction analysis of the 4p15.32-4p16.2 region further confined the linkage signal to a 10-Mb segment located between rs12505562 and rs12649803 (9.65-30.24 cM; 5.54-15.58 Mb). Various human organ developmental genes reside in this 10-Mb susceptibility region, such as EVC, EVC2, SLC2A9, NKX3-2, and HMX1. The coding regions of three genes, EVC known for cartilage development and NKX3-2, HMX1 involved in microtia, were selected for sequencing with 5 individuals from the pedigree. Of the 38 identified sequence variants, none segregates along with the disease phenotype. Other genes or DNA sequences of the 10-Mb region warrant for further investigation. In conclusion, we report a susceptibility locus of isolated microtia, and this finding will encourage future studies on the genetic basis of ear deformity.
authors.affiliation: Beijing Institute of Genomics, Chinese Academy of Sciences and Key Laboratory of Genome Science and Information, Chinese Academy of Sciences, Beijing, P. R. China; Department of Cardiology, Beijing Anzhen Hospital of the Capital University of Medical Sciences, Beijing, P. R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Ear Reconstruction, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Beijing, P.R. China.
authors.forename: Jintian
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Ear Reconstruction, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Beijing, P.R. China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Ear Reconstruction, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Beijing, P.R. China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Jin
authors.affiliation: Beijing Institute of Genomics, Chinese Academy of Sciences and Key Laboratory of Genome Science and Information, Chinese Academy of Sciences, Beijing, P. R. China.
authors.forename: Duen-Mei
authors.initials: DM
authors.lastname: Wang
authors.affiliation: Beijing Institute of Genomics, Chinese Academy of Sciences and Key Laboratory of Genome Science and Information, Chinese Academy of Sciences, Beijing, P. R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Ear Reconstruction, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Beijing, P.R. China.
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Beijing Institute of Genomics, Chinese Academy of Sciences and Key Laboratory of Genome Science and Information, Chinese Academy of Sciences, Beijing, P. R. China.
authors.forename: Yong-Biao
authors.initials: YB
authors.lastname: Zhang
mesh_terms: D002648:Child; D002894:Chromosomes, Human, Pair 4; D065817:Congenital Microtia / Q000235:genetics*; D056915:DNA Copy Number Variations; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide