Identification of Novel Candidate Genes and Variants for Hearing Loss and Temporal Bone Anomalies

doi:10.3390/genes12040566

. 2021 Apr 13;12(4):566.

doi: 10.3390/genes12040566.

Identification of Novel Candidate Genes and Variants for Hearing Loss and Temporal Bone Anomalies

Regie Lyn P Santos-Cortez^{1

2

3}, Talitha Karisse L Yarza^{3

4}, Tori C Bootpetch¹, Ma Leah C Tantoco^{3

4

5}, Karen L Mohlke⁶, Teresa Luisa G Cruz^{3

5}, Mary Ellen Chiong Perez⁷, Abner L Chan^{3

5}, Nanette R Lee⁸, Celina Ann M Tobias-Grasso⁹, Maria Rina T Reyes-Quintos^{3

4

5}, Eva Maria Cutiongco-de la Paz^{10

11}, Charlotte M Chiong^{3

4

5

12}

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
² Center for Children's Surgery, Children's Hospital Colorado, Aurora, CO 80045, USA.
³ Philippine National Ear Institute, University of the Philippines (UP) Manila-National Institutes of Health (NIH), Manila 1000, Philippines.
⁴ Newborn Hearing Screening Reference Center, UP Manila-NIH, Manila 1000, Philippines.
⁵ Department of Otorhinolaryngology, UP Manila College of Medicine-Philippine General Hospital (UP-PGH), Manila 1000, Philippines.
⁶ Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
⁷ Department of Anesthesiology, UP Manila College of Medicine, Manila 1000, Philippines.
⁸ Office of Population Studies and Department of Anthropology, Sociology and History, University of San Carlos, Cebu City 6000, Philippines.
⁹ MED-EL, 6020 Innsbruck, Austria.
¹⁰ Institute of Human Genetics, UP Manila-NIH, Manila 1000, Philippines.
¹¹ Philippine Genome Center, UP Diliman Campus, Quezon City 1101, Philippines.
¹² UP Manila College of Medicine, Manila 1000, Philippines.

PMID: 33924653
PMCID: PMC8069784
DOI: 10.3390/genes12040566

Identification of Novel Candidate Genes and Variants for Hearing Loss and Temporal Bone Anomalies

Regie Lyn P Santos-Cortez et al. Genes (Basel). 2021.

. 2021 Apr 13;12(4):566.

doi: 10.3390/genes12040566.

Authors

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
² Center for Children's Surgery, Children's Hospital Colorado, Aurora, CO 80045, USA.
³ Philippine National Ear Institute, University of the Philippines (UP) Manila-National Institutes of Health (NIH), Manila 1000, Philippines.
⁴ Newborn Hearing Screening Reference Center, UP Manila-NIH, Manila 1000, Philippines.
⁵ Department of Otorhinolaryngology, UP Manila College of Medicine-Philippine General Hospital (UP-PGH), Manila 1000, Philippines.
⁶ Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
⁷ Department of Anesthesiology, UP Manila College of Medicine, Manila 1000, Philippines.
⁸ Office of Population Studies and Department of Anthropology, Sociology and History, University of San Carlos, Cebu City 6000, Philippines.
⁹ MED-EL, 6020 Innsbruck, Austria.
¹⁰ Institute of Human Genetics, UP Manila-NIH, Manila 1000, Philippines.
¹¹ Philippine Genome Center, UP Diliman Campus, Quezon City 1101, Philippines.
¹² UP Manila College of Medicine, Manila 1000, Philippines.

PMID: 33924653
PMCID: PMC8069784
DOI: 10.3390/genes12040566

Abstract

Background: Hearing loss remains an important global health problem that is potentially addressed through early identification of a genetic etiology, which helps to predict outcomes of hearing rehabilitation such as cochlear implantation and also to mitigate the long-term effects of comorbidities. The identification of variants for hearing loss and detailed descriptions of clinical phenotypes in patients from various populations are needed to improve the utility of clinical genetic screening for hearing loss. Methods: Clinical and exome data from 15 children with hearing loss were reviewed. Standard tools for annotating variants were used and rare, putatively deleterious variants were selected from the exome data. Results: In 15 children, 21 rare damaging variants in 17 genes were identified, including: 14 known hearing loss or neurodevelopmental genes, 11 of which had novel variants; and three candidate genes IST1, CBLN3 and GDPD5, two of which were identified in children with both hearing loss and enlarged vestibular aqueducts. Patients with variants within IST1 and MYO18B had poorer outcomes after cochlear implantation. Conclusion: Our findings highlight the importance of identifying novel variants and genes in ethnic groups that are understudied for hearing loss.

Keywords: CBLN3; GDPD5; IST1; anomalies; cochlear implant; enlarged vestibular aqueduct; genetic testing; hearing loss; inner ear; malformations; temporal bone.

PubMed Disclaimer

Conflict of interest statement

C.T. is an employee of MED-EL, but MED-EL had no role in the study design, data analysis and manuscript preparation. All authors declare no conflict of interest.

Figures

**Figure 1**
Temporal bone images in six patients with hearing loss. (A) ID1 with the heterozygous *DSPP* c.730G>A (p.(Gly244Arg)) variant has enlarged vestibular aqueduct (EVA, arrow) on the left. (B,C) ID3 with the heterozygous *LMX1A* and *COL2A1* variants has bilaterally malformed cochleae with incomplete cochlear turns (plus signs) and left-sided EVA (arrow). (D) ID5 with the heterozygous *DMXL2* variant has a high jugular bulb (HJB, asterisk) on the left. (E) ID7 with the heterozygous *MYO7A* variant plus potentially compound heterozygous *PCDH15* and *CDH23* variants has HJB (asterisk) on the left. There is also fluid in the middle ear space (marked by X), indicating otitis media. (F,G) ID8 with the heterozygous *COL11A1* and *TECTA* variants has left-sided superior semicircular canal dehiscence (SSCD, hash sign). (H,I) ID19 with the heterozygous *MYO18B* c.2555C>T (p.(Ala852)) variant has multiple congenital inner ear anomalies with bilaterally malformed cochleae, vestibules and semicircular canals (plus signs), as well as absence of the right cochlear and inferior vestibular nerves.

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References

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1. Dai P., Huang L.H., Wang G.J., Gao X., Qu C.Y., Chen X.W., Ma F.R., Zhang J., Xing W.L., Xi S.Y., et al. Concurrent hearing and genetic screening of 180,469 neonates with follow-up in Beijing, China. Am. J. Hum. Genet. 2019;105:803–812. doi: 10.1016/j.ajhg.2019.09.003. - DOI - PMC - PubMed
1. Omichi R., Shibata S.B., Morton C.C., Smith R.J.H. Gene therapy for hearing loss. Hum. Mol. Genet. 2019;29:R65–R79. doi: 10.1093/hmg/ddz129. - DOI - PMC - PubMed
1. Azaiez H., Booth K.T., Ephraim S.S., Crone B., Black-Ziegelbein E.A., Marini R.J., Shearer A.E., Sloan-Heggen C.M., Kolbe D., Casavant T., et al. Genomic landscape and mutational signatures of deafness-associated genes. Am. J. Hum. Genet. 2018;103:484–497. doi: 10.1016/j.ajhg.2018.08.006. - DOI - PMC - PubMed
1. Girotto G., Morgan A., Krishnamoorthy N., Cocca M., Brumat M., Bassani S., La Bianca M., Di Stazio M., Gasparini P. Next generation sequencing and animal models reveal SLC9A3R1 as a new gene involved in human age-related hearing loss. Front. Genet. 2020;10:142. doi: 10.3389/fgene.2019.00142. - DOI - PMC - PubMed

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[1] GBD 2017 Disease and Injury Incidence and Prevalence Collaborators Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1789–1858. doi: 10.1016/S0140-6736(18)32279-7. - DOI - PMC - PubMed

[2] GBD 2017 Disease and Injury Incidence and Prevalence Collaborators Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1789–1858. doi: 10.1016/S0140-6736(18)32279-7. - DOI - PMC - PubMed

[3] Dai P., Huang L.H., Wang G.J., Gao X., Qu C.Y., Chen X.W., Ma F.R., Zhang J., Xing W.L., Xi S.Y., et al. Concurrent hearing and genetic screening of 180,469 neonates with follow-up in Beijing, China. Am. J. Hum. Genet. 2019;105:803–812. doi: 10.1016/j.ajhg.2019.09.003. - DOI - PMC - PubMed

[4] Dai P., Huang L.H., Wang G.J., Gao X., Qu C.Y., Chen X.W., Ma F.R., Zhang J., Xing W.L., Xi S.Y., et al. Concurrent hearing and genetic screening of 180,469 neonates with follow-up in Beijing, China. Am. J. Hum. Genet. 2019;105:803–812. doi: 10.1016/j.ajhg.2019.09.003. - DOI - PMC - PubMed

[5] Omichi R., Shibata S.B., Morton C.C., Smith R.J.H. Gene therapy for hearing loss. Hum. Mol. Genet. 2019;29:R65–R79. doi: 10.1093/hmg/ddz129. - DOI - PMC - PubMed

[6] Omichi R., Shibata S.B., Morton C.C., Smith R.J.H. Gene therapy for hearing loss. Hum. Mol. Genet. 2019;29:R65–R79. doi: 10.1093/hmg/ddz129. - DOI - PMC - PubMed

[7] Azaiez H., Booth K.T., Ephraim S.S., Crone B., Black-Ziegelbein E.A., Marini R.J., Shearer A.E., Sloan-Heggen C.M., Kolbe D., Casavant T., et al. Genomic landscape and mutational signatures of deafness-associated genes. Am. J. Hum. Genet. 2018;103:484–497. doi: 10.1016/j.ajhg.2018.08.006. - DOI - PMC - PubMed

[8] Azaiez H., Booth K.T., Ephraim S.S., Crone B., Black-Ziegelbein E.A., Marini R.J., Shearer A.E., Sloan-Heggen C.M., Kolbe D., Casavant T., et al. Genomic landscape and mutational signatures of deafness-associated genes. Am. J. Hum. Genet. 2018;103:484–497. doi: 10.1016/j.ajhg.2018.08.006. - DOI - PMC - PubMed

[9] Girotto G., Morgan A., Krishnamoorthy N., Cocca M., Brumat M., Bassani S., La Bianca M., Di Stazio M., Gasparini P. Next generation sequencing and animal models reveal SLC9A3R1 as a new gene involved in human age-related hearing loss. Front. Genet. 2020;10:142. doi: 10.3389/fgene.2019.00142. - DOI - PMC - PubMed

[10] Girotto G., Morgan A., Krishnamoorthy N., Cocca M., Brumat M., Bassani S., La Bianca M., Di Stazio M., Gasparini P. Next generation sequencing and animal models reveal SLC9A3R1 as a new gene involved in human age-related hearing loss. Front. Genet. 2020;10:142. doi: 10.3389/fgene.2019.00142. - DOI - PMC - PubMed

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Identification of Novel Candidate Genes and Variants for Hearing Loss and Temporal Bone Anomalies

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Identification of Novel Candidate Genes and Variants for Hearing Loss and Temporal Bone Anomalies

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