Genome-wide linkage study suggests a susceptibility locus for isolated bilateral microtia on 4p15.32-4p16.2

PLoS One. 2014 Jul 1;9(7):e101152. doi: 10.1371/journal.pone.0101152. eCollection 2014.

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • Chromosomes, Human, Pair 4*
  • Congenital Microtia / genetics*
  • DNA Copy Number Variations
  • Female
  • Genetic Linkage
  • Genetic Predisposition to Disease*
  • Genome, Human*
  • Humans
  • Male
  • Pedigree
  • Polymorphism, Single Nucleotide

Grant support

This study was supported by grants from the National Natural Science Foundation of China (31201006, 31371347 to Y-B.Z., 81372085 to Q.Z. 81300863 to J.H.) and PUMC Youth Fund and the Fundamental Research Funds for the Central Universities (3332013091 to J.H.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.