Exome sequencing identifies a novel CEACAM16 mutation associated with autosomal dominant nonsyndromic hearing loss DFNA4B in a Chinese family

  • J Hum Genet. 2015 Mar;60(3):119-126. doi: 10.1038/jhg.2014.114.
Honghan Wang  #  1  2  3 ,  Xinwei Wang  #  1  3 ,  Chufeng He  1  3 ,  Haibo Li  4 ,  Jie Qing  5 ,  Mhamed Grati  5 ,  Zhengmao Hu  4 ,  Jiada Li  4 ,  Yiqiao Hu  4 ,  Kun Xia  4 ,  Lingyun Mei  1  3 ,  Xingwei Wang  1  3 ,  Jianjun Yu  2 ,  Hongsheng Chen  1  3 ,  Lu Jiang  1  3 ,  Yalan Liu  1  3 ,  Meichao Men  1  6 ,  Hailin Zhang  2 ,  Liping Guan  7 ,  Jingjing Xiao  7 ,  Jianguo Zhang  7 ,  Xuezhong Liu  5 ,  Yong Feng  1  4  3
Affiliations
  • 1. Department of Otolaryngology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, China.
  • 2. Department of Head and Neck Surgery, Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan, China.
  • 3. Province Key Laboratory of Otolaryngology Critical Diseases, Changsha, Hunan, China.
  • 4. State Key Laboratory of Medical Genetics of China, Changsha, Hunan, China.
  • 5. Department of Otorhinolaryngology, University of Miami, Miller School of Medicine, Miami, FL, USA.
  • 6. Health Management Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 7. BGI-Shenzhen, Shenzhen, Guangdong, China.
  • # Contributed equally.
PMID: 25589040 DOI: 10.1038/jhg.2014.114
Abstract

Autosomal dominant nonsyndromic hearing loss (ADNSHL/DFNA) is a highly genetically heterogeneous disorder. Hitherto only about 30 ADNSHL-causing genes have been identified and many unknown genes remain to be discovered. In this research, genome-wide linkage analysis mapped the disease locus to a 4.3 Mb region on chromosome 19q13 in SY-026, a five-generation nonconsanguineous Chinese family affected by late-onset and progressive ADNSHL. This linkage region showed partial overlap with the previously reported DFNA4. Simultaneously, probands were analyzed using exome capture followed by next-generation Sequencing. Encouragingly, a heterozygous missense mutation, c.505G>A (p.G169R) in exon 3 of the CEACAM16 gene (carcinoembryonic antigen-related cell adhesion molecule 16), was identified via this combined strategy. Sanger Sequencing verified that the mutation co-segregated with hearing loss in the family and that it was not present in 200 unrelated control subjects with matched ancestry. This is the second report in the literature of a family with ADNSHL caused by CEACAM16 mutation. Immunofluorescence staining and western blots also prove CEACAM16 to be a secreted protein. Furthermore, our studies in transfected HEK293T cells show that the secretion efficacy of the mutant CEACAM16 is much lower than that of the wild type, suggesting a deleterious effect of the sequence variant.