Login to MyKarger

New to MyKarger? Click here to sign up.

Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Original Article

Editor's Choice - Free Access

A Novel de novo Mutation in CEACAM16 Associated with Postlingual Hearing Impairment

Hofrichter M.A.H.a · Nanda I.a · Gräf J.a · Schröder J.a · Shehata-Dieler W.b · Vona B.a · Haaf T.a

Author affiliations

aDepartment of Human Genetics, Julius Maximilian University, and bDepartment of Otorhinolaryngology, Comprehensive Hearing Center, University Hospitals, Würzburg, Germany

Corresponding Author

Barbara Vona

Institute of Human Genetics, Julius Maximilian University

Biozentrum, Am Hubland

DE-97074 Würzburg (Germany)

E-Mail barbara.vona@uni-wuerzburg.de

Related Articles for ""

Mol Syndromol 2015;6:156-163

Do you have an account?

Login Information

Contact Information

By signing up for MyKarger you will automatically participate in our year-End raffle.
If you Then Do Not wish To participate, please uncheck the following box.

Yes, I wish To participate In the year-End raffle And Get the chance To win some Of our most interesting books, And other attractive prizes.

I have read the Karger Terms and Conditions and agree.


Mutations in CEACAM16 cause autosomal dominant nonsyndromic hearing loss (DFNA4B). So far, 2 families have been reported with segregating missense mutations, both in the immunoglobulin constant domain A of the CEACAM16 protein. In this study, we used the TruSight One panel to investigate a parent-child trio without familial history of hearing loss and one affected child. When filtering for recessive inheritance and de novo events, we discovered a de novo CEACAM16 mutation (c.1094T>G, p.Leu365Arg) as the sole likely pathogenic variant. The de novo mutation was confirmed by Sanger sequencing and STR analysis. The proband's hearing loss closely matches the described onset and severity for DFNA4B. We present the third CEACAM16 variant and the first de novo mutation in CEACAM16. This de novo mutation is robustly described as a pathogenic mutation according to in silico mutation prediction tools and affects a highly conserved amino acid in the most strongly conserved CEACAM16 N2 domain. Our strategy of screening family trios enhances de novo mutation discovery and the exclusion of other variants of potential interest through pedigree filtering.

© 2015 S. Karger AG, Basel


  1. Abe S, Katagiri T, Saito-Hisaminato A, Usami S, Inoue Y, et al: Identification of CRYM as a candidate responsible for nonsyndromic deafness, through cDNA microarray analysis of human cochlear and vestibular tissues. Am J Hum Genet 72:73-82 (2003).
  2. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, et al: A method and server for predicting damaging missense mutations. Nat Methods 7:248-249 (2010).
  3. Campbell CD, Eichler EE: Properties and rates of germline mutations in humans. Trends Genet 29:575-584 (2013).
  4. Cheatham MA, Goodyear RJ, Homma K, Legan PK, Korchagina J, et al: Loss of the tectorial membrane protein CEACAM16 enhances spontaneous, stimulus-frequency, and transiently evoked otoacoustic emissions. J Neurosci 34:10325-10338 (2014).
  5. Chen AH, Ni L, Fukushima K, Marietta J, O'Neill M, et al: Linkage of a gene for dominant non-syndromic deafness to chromosome 19. Hum Mol Genet 4:1073-1076 (1995).
  6. Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Beroud C: Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37:e67 (2009).
  7. Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT: LOVD v.2.0: the next generation in gene variant databases. Hum Mutat 557-563 (2011).
  8. Jang MA, Lee SH, Kim N, Ki CS: Frequency and spectrum of actionable pathogenic secondary findings in 196 Korean exomes. Genet Med, Epub ahead of print (2015).
  9. Jones GP, Elliott SJ, Russell IJ, Lukashkin AN: Modified protein expression in the tectorial membrane of the cochlea reveals roles for the striated sheet matrix. Biophys J 108:203-210 (2015).
  10. Kammerer R, Zimmermann W: Coevolution of activating and inhibitory receptors within mammalian carcinoembryonic antigen families. BMC Biol 8:12 (2010).
  11. Kammerer R, Rüttiger L, Riesenberg R, Schäuble C, Krupar R, et al: Loss of mammal-specific tectorial membrane component carcinoembryonic antigen cell adhesion molecule 16 (CEACAM16) leads to hearing impairment at low and high frequencies. J Biol Chem 287:21584-21598 (2012).
  12. Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, et al: Rate of de novo mutations and the importance of father's age to disease risk. Nature 488:471-475 (2012).
  13. Ku CS, Vasiliou V, Cooper DN: A new era in the discovery of de novo mutations underlying human genetic disease. Hum Genomics 6:27 (2012).
  14. Legan PK, Goodyear RJ, Morín M, Mencia A, Pollard H, et al: Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane. Hum Mol Genet 23:2551-2568 (2014).
  15. Mustapha M, Weil D, Chardenoux S, Elias S, El-Zir E, et al: An alpha-tectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre-lingual non-syndromic deafness, DFNB21. Hum Mol Genet 8:409-412 (1999).
  16. Ng PC, Henikoff S: Predicting deleterious amino acid substitutions. Genome Res 11:863-874 (2001).
  17. Pertea M, Lin X, Salzberg SL: GeneSplicer: a new computational method for splice site prediction. Nucleic Acids Res 29:1185-1190 (2001).
  18. Petersen MB: Non-syndromic autosomal-dominant deafness. Clin Genet 62:1-13 (2002).
  19. Rau A, Legan PK, Richardson GP: Tectorin mRNA expression is spatially and temporally restricted during mouse inner ear development. J Comp Neurol 405:271-280 (1999).
  20. Reese MG, Eeckman FH, Kulp D, Haussler D: Improved splice site detection in Genie. J Comput Biol 4:311-323 (1997).
  21. Reva B, Antipin Y, Sander C: Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res 39:e118 (2011).
  22. Samocha KE, Robinson EB, Sanders SJ, Stevens C, Sabo A, et al: A framework for the interpretation of de novo mutation in human disease. Nat Genet 46:944-950 (2014).
  23. Schraders M, Ruiz-Palmero L, Kalay E, Oostrik J, del Castillo FJ, et al: Mutations of the gene encoding otogelin are a cause of autosomal-recessive nonsyndromic moderate hearing impairment. Am J Hum Genet 91:883-889 (2012).
  24. Schultz JM, Khan SN, Ahmed ZM, Riazuddin S, Waryah AM, et al: Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39. Am J Hum Genet 85:25-39 (2009).
  25. Schwarz JM, Cooper DN, Schuelke M, Seelow D: MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 11:361-362 (2014).
  26. Shearer AE, Eppsteiner RW, Booth KT, Ephraim SS, Gurrola J 2nd, et al: Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. Am J Hum Genet 95:445-453 (2014).
  27. Shihab HA, Gough J, Cooper DN, Stenson PD, Barker GL, et al: Predicting the functional, molecular, and phenotypic consequences of amino acid substitutions using hidden Markov models. Hum Mutat 34:57-65 (2013).
  28. Smith CM, Finger JH, Hayamizu TF, McCright IJ, Xu J, et al: The mouse Gene Expression Database (GXD): 2014 update. Nucleic Acids Res 42:D818-D824 (2014).
  29. Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN: The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet 133:1-9 (2014).
  30. Untergasser A, Cutcutache I, Koressaar T, Ye J, Faircloth BC, et al: Primer3 - new capabilities and interfaces. Nucleic Acids Res 40:e115 (2012).
  31. Veltman JA, Brunner HG: De novo mutations in human genetic disease. Nat Rev Genet 13:565-575 (2012).
  32. Verhoeven K, Van Laer L, Kirschhofer K, Legan PK, Hughes DC, et al: Mutations in the human alpha-tectorin gene cause autosomal dominant non-syndromic hearing impairment. Nat Genet 19:60-62 (1998).
  33. Wang H, Wang X, He C, Li H, Qing J, et al: Exome sequencing identifies a novel CEACAM16 mutation associated with autosomal dominant nonsyndromic hearing loss DFNA4B in a Chinese family. J Hum Genet 60:119-126 (2015).
  34. Yariz KO, Duman D, Seco CZ, Dallman J, Huang M, et al: Mutations in OTOGL, encoding the inner ear protein otogelin-like, cause moderate sensorineural hearing loss. Am J Hum Genet 91:872-882 (2012).
  35. Yeo G, Burge CB: Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 11:377-394 (2004).
  36. Zheng J, Miller KK, Yang T, Hildebrand MS, Shearer AE, et al: Carcinoembryonic antigen-related cell adhesion molecule 16 interacts with alpha-tectorin and is mutated in autosomal dominant hearing loss (DFNA4). Proc Natl Acad Sci USA 108:4218-4223 (2011).

Article / Publication Details

First-Page Preview
Abstract of Original Article

Accepted: August 13, 2015
Published online: September 03, 2015
Issue release date: October 2015

Number of Print Pages: 8
Number of Figures: 2
Number of Tables: 1

ISSN: 1661-8769 (Print)
eISSN: 1661-8777 (Online)

For additional information: https://www.karger.com/MSY

Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.