Academic Journal
Προβολή σε EDS

Genetic Landscape of Hearing Loss in Brazilian Patients Reveals Population-Specific Variants and Clinical Correlations.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Genetic Landscape of Hearing Loss in Brazilian Patients Reveals Population-Specific Variants and Clinical Correlations.
Συγγραφείς: Diogo-Cavassana S; Laboratório de Otorrinolaringologia Genética Molecular, Celular e Translacional/LIM32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.; Otorhinolaryngology Department, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil., Alencar-Coutinho D; Laboratório de Otorrinolaringologia Genética Molecular, Celular e Translacional/LIM32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.; Otorhinolaryngology Department, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil., Abreu-Oberhuber R; Laboratório de Otorrinolaringologia Genética Molecular, Celular e Translacional/LIM32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.; Otorhinolaryngology Department, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil., Paramo-Neto ME; Laboratório de Otorrinolaringologia Genética Molecular, Celular e Translacional/LIM32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.; Otorhinolaryngology Department, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil., Oiticica J; Laboratório de Otorrinolaringologia Genética Molecular, Celular e Translacional/LIM32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.; Otorhinolaryngology Department, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil., Bento RF; Laboratório de Otorrinolaringologia Genética Molecular, Celular e Translacional/LIM32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.; Otorhinolaryngology Department, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil., Batissoco AC; Laboratório de Otorrinolaringologia Genética Molecular, Celular e Translacional/LIM32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.; Otorhinolaryngology Department, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil., Lezirovitz K; Laboratório de Otorrinolaringologia Genética Molecular, Celular e Translacional/LIM32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.; Otorhinolaryngology Department, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Πηγή: Clinical genetics [Clin Genet] 2026 Aug; Vol. 110 (2), pp. 210-226. Date of Electronic Publication: 2026 Jun 03.
Τύπος έκδοσης: Journal Article; Research Support, Non-U.S. Gov't
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Munksgaard Country of Publication: Denmark NLM ID: 0253664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1399-0004 (Electronic) Linking ISSN: 00099163 NLM ISO Abbreviation: Clin Genet Subsets: MEDLINE
Imprint Name(s): Original Publication: Copenhagen, Munksgaard.
Ιατρικοί όροι (MeSH): Hearing Loss*/genetics , Hearing Loss*/epidemiology , Hearing Loss*/diagnosis , Genetic Predisposition to Disease*, Brazil/epidemiology ; Myosins/genetics ; Connexins/genetics ; Humans ; Female ; Myosin VIIa ; Male ; Mutation ; Connexin 26 ; Phenotype ; High-Throughput Nucleotide Sequencing ; Gene Frequency ; Genetic Association Studies ; Child ; Genetic Testing ; Child, Preschool ; Adolescent
Περίληψη: Hearing loss (HL) is the most prevalent sensory disorder globally and a major public health challenge in Brazil, affecting over 1.5 million individuals. While over 150 HL-associated genes have been identified, the genetic architecture in underrepresented populations remains poorly defined, often limiting diagnostic yield and precision medicine. We assessed the diagnostic performance of a comprehensive 218-gene HL panel in 99 Brazilian probands (78 non-syndromic; 21 syndromic) who had previously tested negative for GJB2/GJB6 (DFNB1) and MT-RNR1 (m.1555A>G) and did not have ear malformations. Targeted next-generation sequencing was followed by variant interpretation according to ACMG/AMP guidelines, segregation analysis, and longitudinal phenotypic re-evaluation. Integration of Brazil-specific allele-frequency data was used to refine variant classification. A molecular diagnosis or a candidate variant was identified in 61 probands, yielding an overall diagnostic yield of 43%-62%, depending on classification stringency. We identified 19 novel variants across 15 genes, with MYO7A and MYO15A as the most frequently implicated. Notably, 10.4% of patients initially diagnosed with non-syndromic HL carried pathogenic or likely pathogenic variants in syndromic genes (PEX6, BSND, USH1C, and WFS1), necessitating clinical reclassification. Segregation analysis and phenotypic reassessment further enabled the reclassification of three variants of uncertain significance (VUS). In syndromic cases, a molecular diagnosis was established in 41% of cases, including Usher, Waardenburg, Branchio-oto-renal, and Bartter syndromes. This first large-scale clinical genetic evaluation of hearing loss in Brazil demonstrates that comprehensive gene panels incorporating population-specific data significantly improve diagnostic accuracy. Our findings broaden the mutational landscape of HL-associated genes, reinforce the value of integrated genetic approaches for underrepresented populations, and underscore their direct impact on patient care and clinical management.
(© 2026 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.)
References: World Health Organization, World Report on Hearing (World Health Organization, 2021).
C. C. Morton and W. E. Nance , “Newborn Hearing Screening‐A Silent Revolution,” New England Journal of Medicine 354, no. 20 (2006): 2151–2164, https://doi.org/10.1056/NEJMra050700.
K. Lezirovitz and R. C. Mingroni‐Netto , “Genetic Etiology of Non‐Syndromic Hearing Loss in Latin America,” Human Genetics 141, no. 3–4 (2022): 539–581, https://doi.org/10.1007/s00439‐021‐02354‐4. Epub 2021 Oct 15. Erratum in: Hum Genet. 2022 Apr;141(3–4):997.
A. E. Shearer , M. S. Hildebrand , A. M. Odell , and R. J. H. Smith , “Genetic Hearing Loss Overview,” in GeneReviews [Internet], ed. M. P. Adam , S. Bick , G. M. Mirzaa , R. A. Pagon , S. E. Wallace , and A. Amemiya (University of Washington, Seattle, 1999), 1993–2026.
W. D. Walls , H. Azaiez , and R. J. H. Smith , “Hereditary Hearing Loss Homepage,” https://hereditaryhearingloss.org.
C. M. Sloan‐Heggen , A. O. Bierer , A. E. Shearer , et al., “Comprehensive Genetic Testing in the Clinical Evaluation of 1119 Patients With Hearing Loss,” Human Genetics 135, no. 4 (2016): 441–450, https://doi.org/10.1007/s00439‐016‐1648‐8.
A. E. Shearer and R. J. Smith , “Massively Parallel Sequencing for Genetic Diagnosis of Hearing Loss: The New Standard of Care,” Otolaryngology‐Head and Neck Surgery 153, no. 2 (2015): 175–182, https://doi.org/10.1177/0194599815591156.
A. E. Shearer , A. P. DeLuca , M. S. Hildebrand , et al., “Comprehensive Genetic Testing for Hereditary Hearing Loss Using Massively Parallel Sequencing,” Proceedings of the National Academy of Sciences of the United States of America 107, no. 49 (2010): 21104–21109, https://doi.org/10.1073/pnas.1012989107.
K. L. Seligman , A. E. Shearer , K. Frees , et al., “Genetic Causes of Hearing Loss in a Large Cohort of Cochlear Implant Recipients,” Otolaryngology‐Head and Neck Surgery 166, no. 4 (2022): 734–737, https://doi.org/10.1177/01945998211021308.
D. Yan , D. Tekin , G. Bademci , et al., “Spectrum of DNA Variants for Non‐Syndromic Deafness in a Large Cohort From Multiple Continents,” Human Genetics 135, no. 8 (2016): 953–961, https://doi.org/10.1007/s00439‐016‐1697‐z.
C. S. Reis , S. Quental , S. Fernandes , S. Castedo , and C. P. Moura , “Whole‐Exome Sequencing Targeting a Gene Panel for Sensorineural Hearing Loss: The First Portuguese Cohort Study,” Cytogenetic and Genome Research 162, no. 1–2 (2022): 1–9, https://doi.org/10.1159/000523840.
A. B. Popejoy and S. M. Fullerton , “Genomics Is Failing on Diversity,” Nature 538, no. 7624 (2016): 161–164, https://doi.org/10.1038/538161a.
G. Sirugo , S. M. Williams , and S. A. Tishkoff , “The Missing Diversity in Human Genetic Studies,” Cell 177, no. 1 (2019): 26–31, https://doi.org/10.1016/j.cell.2019.02.048. Erratum in: Cell 2019 May 2;177(4):1080.
L. A. Hindorff , V. L. Bonham , L. C. Brody , et al., “Prioritizing Diversity in Human Genomics Research,” Nature Reviews. Genetics 19, no. 3 (2018): 175–185, https://doi.org/10.1038/nrg.2017.89.
A. C. Batissoco , V. Pedroso‐Campos , E. Pardono , et al., “Molecular and Genetic Characterization of a Large Brazilian Cohort Presenting Hearing Loss,” Human Genetics 141, no. 3–4 (2022): 519–538, https://doi.org/10.1007/s00439‐021‐02372‐2.
S. Fatumo , T. Chikowore , A. Choudhury , M. Ayub , A. R. Martin , and K. Kuchenbaecker , “A Roadmap to Increase Diversity in Genomic Studies,” Nature Medicine 28, no. 2 (2022): 243–250, https://doi.org/10.1038/s41591‐021‐01672‐4.
M. M. Florentine , S. L. Rouse , J. Stephans , et al., “Racial and Ethnic Disparities in Diagnostic Efficacy of Comprehensive Genetic Testing for Sensorineural Hearing Loss,” Human Genetics 141, no. 3–4 (2022): 495–504, https://doi.org/10.1007/s00439‐021‐02338‐4.
J. Shan , J. Chobot‐Rodd , R. Castellanos , et al., “GJB2 Mutation Spectrum in 209 Hearing Impaired Individuals of Predominantly Caribbean Hispanic and African Descent,” International Journal of Pediatric Otorhinolaryngology 74, no. 6 (2010): 611–618, https://doi.org/10.1016/j.ijporl.2010.03.004.
G. Bademci , F. B. Cengiz , J. Foster Ii , et al., “Variations in Multiple Syndromic Deafness Genes Mimic Non‐Syndromic Hearing Loss,” Scientific Reports 6 (2016): 31622, https://doi.org/10.1038/srep31622.
A. Koparir , P. B. Carbajal , M. Zamini , et al., “Clinical and Genetic Heterogeneity of Syndromic Hearing Loss and Its Non‐Syndromic Hearing Loss Mimics,” Molecular Medicine 32, no. 1 (2026): 50, https://doi.org/10.1186/s10020‐026‐01431‐6.
A. M. Oza , D. S. MT , S. E. Hemphill , et al., “Expert Specification of the ACMG/AMP Variant Interpretation Guidelines for Genetic Hearing Loss,” Human Mutation 39, no. 11 (2018): 1593–1613, https://doi.org/10.1002/humu.23630.
K. C. Tshering , D. S. MT , A. M. Oza , et al., “ClinGen Recuration of Hearing Loss‐Associated Genes Demonstrates Significant Changes in Gene‐Disease Validity Over Time,” Genetics in Medicine 27, no. 10 (2025): 101500, https://doi.org/10.1016/j.gim.2025.101500.
P. Lei , Q. Zhu , W. Dong , et al., “Mutation Analysis of the GSDME Gene in a Chinese Family With Non‐Syndromic Hearing Loss,” PLoS One 17, no. 11 (2022): e0276233, https://doi.org/10.1371/journal.pone.0276233.
L. N. Antunes , A. M. M. Dias , B. C. Schiavo , et al., “Genetic Heterogeneity in Autosomal Recessive Hearing Loss: A Survey of Brazilian Families,” Frontiers in Genetics 15 (2024): 1409306, https://doi.org/10.3389/fgene.2024.1409306.
D. Baux , C. Vaché , C. Blanchet , et al., “Combined Genetic Approaches Yield a 48% Diagnostic Rate in a Large Cohort of French Hearing‐Impaired Patients,” Scientific Reports 7, no. 1 (2017): 16783, https://doi.org/10.1038/s41598‐017‐16846‐9.
S. Delmaghani and A. El‐Amraoui , “The Genetic and Phenotypic Landscapes of Usher Syndrome: From Disease Mechanisms to a New Classification,” Human Genetics 141, no. 3–4 (2022): 709–735, https://doi.org/10.1007/s00439‐022‐02448‐7.
C. Fuster‐García , B. García‐Bohórquez , A. Rodríguez‐Muñoz , et al., “Usher Syndrome: Genetics of a Human Ciliopathy,” International Journal of Molecular Sciences 22, no. 13 (2021): 6723, https://doi.org/10.3390/ijms22136723.
G. García‐García , M. J. Aparisi , R. Rodrigo , et al., “Two Novel Disease‐Causing Mutations in the CLRN1 Gene in Patients With Usher Syndrome Type 3,” Molecular Vision 18 (2012): 3070–3078.
E. Nisenbaum , S. Prentiss , D. Yan , et al., “Screening Strategies for Deafness Genes and Functional Outcomes in Cochlear Implant Patients,” Otology & Neurotology 42, no. 1 (2021): 180–187, https://doi.org/10.1097/MAO.0000000000002969.
C. C. Wu , Y. H. Lin , T. C. Liu , et al., “Identifying Children With Poor Cochlear Implantation Outcomes Using Massively Parallel Sequencing,” Medicine (Baltimore) 94, no. 27 (2015): e1073, https://doi.org/10.1097/MD.0000000000001073.
V. G. Dantas , E. L. Freitas , V. A. Della‐Rosa , et al., “Novel Partial Duplication of EYA1 Causes Branchiootic Syndrome in a Large Brazilian Family,” International Journal of Audiology 54, no. 9 (2015): 593–598, https://doi.org/10.3109/14992027.2015.1030511.
W. Bertani‐Torres , K. Lezirovitz , D. Alencar‐Coutinho , et al., “Waardenburg Syndrome: The Contribution of Next‐Generation Sequencing to the Identification of Novel Causative Variants,” Audiology Research 14, no. 1 (2023): 9–25, https://doi.org/10.3390/audiolres14010002.
I. Ratbi , K. D. Falkenberg , M. Sommen , et al., “Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome‐Biogenesis Genes PEX1 and PEX6,” American Journal of Human Genetics 97, no. 4 (2015): 535–545, https://doi.org/10.1016/j.ajhg.2015.08.011.
B. Vona , “Rethinking Non‐Syndromic Hearing Loss and Its Mimics in the Genomic Era,” European Journal of Human Genetics 33, no. 2 (2025): 147–150, https://doi.org/10.1038/s41431‐024‐01579‐x.
Z. M. Ahmed , T. N. Smith , S. Riazuddin , et al., “Nonsyndromic Recessive Deafness DFNB18 and Usher Syndrome Type IC Are Allelic Mutations of USHIC,” Human Genetics 110, no. 6 (2002): 527–531, https://doi.org/10.1007/s00439‐002‐0732‐4.
S. Khateb , L. Zelinger , T. Ben‐Yosef , et al., “Exome Sequencing Identifies a Founder Frameshift Mutation in an Alternative Exon of USH1C as the Cause of Autosomal Recessive Retinitis Pigmentosa With Late‐Onset Hearing Loss,” PLoS One 7, no. 12 (2012): e51566, https://doi.org/10.1371/journal.pone.0051566.
A. M. Shajan , M. Kumar , P. Navaneethan , S. Danda , and M. M. Beck , “An Unusual Case of BSND Gene‐Related (Type IV) Bartter Syndrome Presenting as Antenatal Bartter Syndrome: A Case Report and Review of Literature,” Maternal‐Fetal Medicine 5, no. 2 (2023): 128–130, https://doi.org/10.1097/FM9.0000000000000182.
C. de Muijnck , J. B. T. Brink , A. A. Bergen , C. J. F. Boon , and M. M. van Genderen , “Delineating Wolfram‐Like Syndrome: A Systematic Review and Discussion of the WFS1‐Associated Disease Spectrum,” Survey of Ophthalmology 68, no. 4 (2023): 641–654, https://doi.org/10.1016/j.survophthal.2023.01.012.
S. Otsuka , C. Morimoto , S. Y. Nishio , et al., “The Heterozygous p.A684V Variant in the WFS1 Gene Is a Mutational Hotspot Causing a Severe Hearing Loss Phenotype,” Genes (Basel) 16, no. 1 (2025): 57, https://doi.org/10.3390/genes16010057.
M. R. Gasparin , F. Crispim , S. L. Paula , et al., “Identification of Novel Mutations of the WFS1 Gene in Brazilian Patients With Wolfram Syndrome,” European Journal of Endocrinology 160, no. 2 (2009): 309–316, https://doi.org/10.1530/EJE‐08‐0698.
X. M. Ouyang , D. Yan , L. L. Du , et al., “Characterization of Usher Syndrome Type I Gene Mutations in an Usher Syndrome Patient Population,” Human Genetics 116, no. 4 (2005): 292–299, https://doi.org/10.1007/s00439‐004‐1227‐2.
M. Toms , W. Pagarkar , and M. Moosajee , “Usher Syndrome: Clinical Features, Molecular Genetics and Advancing Therapeutics,” Therapeutic Advances in Ophthalmology 12 (2020): 2515841420952194, https://doi.org/10.1177/2515841420952194.
T. Li , R. Faridi , W. G. Newman , and T. B. Friedman , “Perrault Syndrome Overview,” in GeneReviews, ed. M. P. Adam , S. Bick , G. M. Mirzaa , R. A. Pagon , S. E. Wallace , and A. Amemiya (University of Washington, Seattle, 2014).
S. B. Pierce , K. M. Chisholm , E. D. Lynch , et al., “Mutations in Mitochondrial Histidyl tRNA Synthetase HARS2 Cause Ovarian Dysgenesis and Sensorineural Hearing Loss of Perrault Syndrome,” Proceedings of the National Academy of Sciences of the United States of America 108, no. 16 (2011): 6543–6548, https://doi.org/10.1073/pnas.1103471108.
K. Nunes , M. Araújo Castro E Silva , M. R. Rodrigues , et al., “Admixture's Impact on Brazilian Population Evolution and Health,” Science 388, no. 6748 (2025): eadl3564, https://doi.org/10.1126/science.adl3564.
Grant Information: 2023/07188-7 Fundação de Amparo à Pesquisa do Estado de São Paulo; BGI GENOMICS
Contributed Indexing: Keywords: Bartter syndrome; Heimler syndrome; NGS; Usher syndrome; Waardenburg syndrome; genetic hearing loss
Substance Nomenclature: 0 (Myosin VIIa)
0 (MYO7A protein, human)
127120-53-0 (Connexin 26)
EC 3.6.4.1 (Myosins)
0 (MYO15A protein, human)
0 (GJB2 protein, human)
0 (Connexins)
Entry Date(s): Date Created: 20260603 Date Completed: 20260702 Latest Revision: 20260726
Update Code: 20260726
PubMed Central ID: PMC13327172
DOI: 10.1111/cge.70186
PMID: 42233699
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1399-0004
DOI:10.1111/cge.70186