Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Genetic heterogeneity in hereditary hearing loss: Potential role of kinociliary protein TOGARAM2

European Journal of Human Genetics (2024)Cite this article

Subjects

Abstract

Hearing loss (HL) is a heterogenous trait with pathogenic variants in more than 200 genes that have been discovered in studies involving small and large HL families. Over one-third of families with hereditary HL remain etiologically undiagnosed after screening for mutations in the recognized genes. Genetic heterogeneity complicates the analysis in multiplex families where variants in more than one gene can be causal in different individuals even in the same sibship. We employed exome or genome sequencing in at least two affected individuals with congenital or prelingual-onset, severe to profound, non-syndromic, bilateral sensorineural HL from four multiplex families. Bioinformatic analysis was performed to identify variants in known and candidate deafness genes. Our results show that in these four families, variants in a single HL gene do not explain HL in all affected family members, and variants in another known or candidate HL gene were detected to clarify HL in the entire family. We also present a variant in TOGARAM2 as a potential cause underlying autosomal recessive non-syndromic HL by showing its presence in a family with HL, its expression in the cochlea and the localization of the protein to cochlear hair cells. Conclusively, analyzing all affected family members separately can serve as a good source for the identification of variants in known and novel candidate genes for HL.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Pedigrees depicting genetic heterogeneity and variants identified in deafness genes.
Fig. 2: In vitro analysis of c.1543C > T variant in TOGARAM2.
Fig. 3: Localization of TOGARAM2 in the cochlea from a P1 wild type mouse.

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this article and its supplementary information files. The genetic variants are submitted to ClinVar database; accession IDs SCV004022367 and SCV004022368.

References

  1. McGinniss MJ, Kaback MM. Heterozygote testing and carrier screening. Emery and Rimoin’s principles and practice of medical genetics: Elsevier; 2013. p. 1–10.

  2. Pandya A, O’Brien A, Kovasala M, Bademci G, Tekin M, Arnos KS. Analyses of del (GJB6‐D13S1830) and del (GJB6‐D13S1834) deletions in a large cohort with hearing loss: Caveats to interpretation of molecular test results in multiplex families. Mol Genet Genom Med. 2020;8:e1171.

    Article  Google Scholar 

  3. Mazzoli M, Van Camp G, Newton V, Giarbini N, Declau F, Parving A. Recommendations for the description of genetic and audiological data for families with nonsyndromic hereditary hearing impairment. Audiol Med. 2003;1:148–50.

    Article  Google Scholar 

  4. Krumm N, Sudmant PH, Ko A, O’Roak BJ, Malig M, Coe BP, et al. Copy number variation detection and genotyping from exome sequence data. Genome Res. 2012;22:1525–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Chen X, Schulz-Trieglaff O, Shaw R, Barnes B, Schlesinger F, Källberg M, et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics. 2016;32:1220–2.

    Article  PubMed  CAS  Google Scholar 

  6. Rausch T, Zichner T, Schlattl A, Stütz AM, Benes V, Korbel JO. DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics. 2012;28:i333–i9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Abyzov A, Urban AE, Snyder M, Gerstein M. CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. Genome Res. 2011;21:974–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–23.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Oza AM, DiStefano MT, Hemphill SE, Cushman BJ, Grant AR, Siegert RK, et al. Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss. Hum Mutat. 2018;39:1593–613.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Tavtigian SV, Harrison SM, Boucher KM, Biesecker LG. Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines. Hum Mutat.2020;41:1734–7.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36:928–30.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Tollefson MR, Gogal RA, Weaver AM, Schaefer AM, Marini RJ, Azaiez H, et al. Assessing variants of uncertain significance implicated in hearing loss using a comprehensive deafness proteome. Hum Genet. 2023;142:819–34.

  13. Conant D, Hsiau T, Rossi N, Oki J, Maures T, Waite K, et al. Inference of CRISPR edits from Sanger trace data. CRISPR J. 2022;5:123–30.

    Article  PubMed  CAS  Google Scholar 

  14. Ikenouchi J, Furuse M, Furuse K, Sasaki H, Tsukita S, Tsukita S. Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. J Cell Biol. 2005;171:939–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Cheng J, Novati G, Pan J, Bycroft C, Žemgulytė A, Applebaum T, et al. Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science. 2023;381:eadg7492.

    Article  PubMed  CAS  Google Scholar 

  16. Danzi MC, Dohrn MF, Fazal S, Beijer D, Rebelo AP, Cintra V, et al. Deep structured learning for variant prioritization in Mendelian diseases. Nat Commun. 2023;14:4167.

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  17. Bonthron DT, Brady N, Donaldson LA, Steinmann B. Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase). Hum Mol Genet. 1994;3:1627–31.

    Article  PubMed  CAS  Google Scholar 

  18. Petit C. From deafness genes to hearing mechanisms: harmony and counterpoint. Trends Mol Med. 2006;12:57–64.

    Article  PubMed  CAS  Google Scholar 

  19. Sirmaci A, Edwards YJ, Akay H, Tekin M. Challenges in whole exome sequencing: an example from hereditary deafness. PLoS One. 2012;7:e32000.

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  20. Chong JX, Buckingham KJ, Jhangiani SN, Boehm C, Sobreira N, Smith JD, et al. The genetic basis of Mendelian phenotypes: discoveries, challenges, and opportunities. Am J Hum Genet. 2015;97:199–215.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Ramzan M, Duman D, Hendricks LCP, Guo S, Mutlu A, Kalcioglu MT, et al. Genome sequencing identifies coding and non-coding variants for non-syndromic hearing loss. J. Hum. Genet. 2023;68:1–13.

  22. Rehman AU, Santos-Cortez RLP, Drummond MC, Shahzad M, Lee K, Morell RJ, et al. Challenges and solutions for gene identification in the presence of familial locus heterogeneity. Eur J Hum Genet 2015;23:1207–15.

    Article  PubMed  CAS  Google Scholar 

  23. Naz S, Imtiaz A, Mujtaba G, Maqsood A, Bashir R, Bukhari I, et al. Genetic causes of moderate to severe hearing loss point to modifiers. Clin Genet 2017;91:589–98.

    Article  PubMed  CAS  Google Scholar 

  24. Richard EM, Santos‐Cortez RLP, Faridi R, Rehman AU, Lee K, Shahzad M, et al. Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss. Hum Mutat 2019;40:53–72.

    Article  PubMed  CAS  Google Scholar 

  25. Lu Y, Zhou X, Jin Z, Cheng J, Shen W, Ji F, et al. Resolving the genetic heterogeneity of prelingual hearing loss within one family: Performance comparison and application of two targeted next-generation sequencing approaches. J Hum Genet. 2014;59:599–607.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Das A, Dickinson DJ, Wood CC, Goldstein B, Slep KC. Crescerin uses a TOG domain array to regulate microtubules in the primary cilium. Mol Biol Cell 2015;26:4248–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Perlaza K, Mirvis M, Ishikawa H, Marshall W. The short flagella 1 (SHF1) gene in Chlamydomonas encodes a Crescerin TOG-domain protein required for late stages of flagellar growth. Mol Bio Cell 2022;33:ar12.

    Article  CAS  Google Scholar 

  28. Belyantseva IA, Labay V, Boger ET, Griffith AJ, Friedman TB. Stereocilia: the long and the short of it. Trends Mol Med 2003;9:458–61.

    Article  PubMed  CAS  Google Scholar 

  29. Miyoshi T, Belyantseva IA, Kitajiri S-I, Miyajima H, Nishio S-Y, Usami S-I, et al. Human deafness-associated variants alter the dynamics of key molecules in hair cell stereocilia F-actin cores. Hum. Genet. 2021;141:1-20.

  30. Riazuddin S, Ahmed ZM, Fanning AS, Lagziel A, Kitajiri S, Ramzan K, et al. Tricellulin is a tight-junction protein necessary for hearing. Am. J. Hum. Genet. 2006;79:1040–51.

  31. Van Hauwe P, Everett LA, Coucke P, Scott DA, Kraft ML, Ris-Stalpers C, et al. Two frequent missense mutations in Pendred syndrome. Hum. Mol. Genet. 1998;7:1099–104.

  32. Cassatella D, Howard SR, Acierno JS, Xu C, Papadakis GE, Santoni FA, et al. Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures. Eur. J. Endocrinol. 2018;178:377–88.

  33. Vona B, Maroofian R, Mendiratta G, Croken M, Peng S, Ye X, et al. Dual Diagnosis of Ellis-van Creveld Syndrome and Hearing Loss in a Consanguineous Family. Mol. Syndromol. 2017;9:5–14.

  34. Yoshimura H, Miyagawa M, Kumakawa K, Nishio SY, Usami S. Frequency of Usher syndrome type 1 in deaf children by massively parallel DNA sequencing. J. Hum. Genet. 2016;61:419–22.

  35. Cengiz FB, Duman D, Sirmaci A, Tokgöz-Yilmaz S, Erbek S, Oztürkmen-Akay H, et al. Recurrent and private MYO15A mutations are associated with deafness in the Turkish population. Genet. Test. Mol. Biomarkers. 2010;14:543–50.

Download references

Acknowledgements

The authors thank all the members of hearing loss families for their participation and cooperation in the study.

Funding

This work was supported by NIH R01DC009645 and R01DC012836 to MT and the German Research Foundation DFG VO 2138/7-1 grant 469177153 to BV and ANPCyT Argentina PICT-2021 GRF-TI-00422 to KW.

Author information

Authors and Affiliations

  1. John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA

    Memoona Ramzan, Mohammad Faraz Zafeer, Clemer Abad, Shengru Guo, Guney Bademci, Katherina Walz & Mustafa Tekin

  2. Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany

    Daniel Owrang & Barbara Vona

  3. Institute for Auditory Neuroscience and Inner Ear Lab, University Medical Center Göttingen, Göttingen, Germany

    Daniel Owrang & Barbara Vona

  4. Department of Medical Genetics, Antalya University Medical School, Antalya, Turkey

    Ozgul Alper

  5. Departmet of Otolaryngology, Istanbul Medeniyet University School of Medicine, Istanbul, Turkey

    Ahmet Mutlu & Mahmut Tayyar Kalcioglu

  6. Otorhinolaryngology Clinic of Goztepe Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey

    Ahmet Mutlu & Mahmut Tayyar Kalcioglu

  7. Division of Pediatric Genetics, Ege University School of Medicine, Izmir, Turkey

    Tahir Atik

  8. Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

    Duygu Duman

  9. Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA

    Katherina Walz & Mustafa Tekin

  10. IQUIBICEN CONICET, Faculty of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina

    Katherina Walz

Authors
  1. Memoona Ramzan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad Faraz Zafeer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Clemer Abad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shengru Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel Owrang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ozgul Alper
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ahmet Mutlu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tahir Atik
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Duygu Duman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Guney Bademci
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Barbara Vona
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mahmut Tayyar Kalcioglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Katherina Walz
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Mustafa Tekin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: MR and MT, Data collection: MR, OA, AM, MFZ, CA, MT, Formal analysis: MR, GB, DD, Funding acquisition: MT, BV, KW, Writing original draft: MR and MT, Writing-review and editing: MR, OA, AM, MFZ, CA, GB, DD, TA, TK, KW, BV, DO, MT.

Corresponding author

Correspondence to Mustafa Tekin.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics declaration

The study was approved by the Institutional Review Board at the University of Miami, USA, Ankara University Medical School Ethics Committee, Turkiye, Local Ethics Committee of Istanbul Medeniyet University, and Goztepe Training and Research Hospital Istanbul, Turkiye.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ramzan, M., Zafeer, M.F., Abad, C. et al. Genetic heterogeneity in hereditary hearing loss: Potential role of kinociliary protein TOGARAM2. Eur J Hum Genet (2024). https://doi.org/10.1038/s41431-024-01562-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41431-024-01562-6

Search

Advanced search

Quick links