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Sofia Nunes1, Teresa Imízcoz2, Gorka Alkorta2, Patrícia Cueto3, Ana Coutinho4, Herédio Sousa5, Diana Antunes1

1 - Department of Medical Genetics, Hospital de Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
2 - CIMA Lab Diagnostics, Clínica Universidad de Navarra, Pamplona, Espanha
3 - Dreamgenics S. L., Oviedo, Espanha
4 - GenoMed® – Diagnósticos de Medicina Molecular SA, Instituto de Medicina Molecular, Lisboa, Portugal
5 - Department of Otorhinolaryngology, Hospital de Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal

- 26th Annual Meeting of the Portuguese Society of Human Genetics (SPGH), Coimbra, november 2022.
- Clinical Research Award to the Best Oral communication on Clinical Research of the 26th Annual Meeting of the Portuguese Society of Human Genetics (SPGH)

Introduction: Hearing loss affects around 34 million children worldwide and can contribute to language acquisition delay, thus affecting cognitive development. Genetic heterogeneity of sensorineural hearing loss (SNHL) constitutes a major challenge in the detection of disease-causing variants. Therefore, early access to a molecular genetic diagnosis is essential to optimize clinical management and to offer better genetic counselling.
Objective: We aimed to better genetically characterize the pediatric Portuguese population of hearing loss.
Methodology: We carried out a retrospective study on a cohort of 102 pediatric probands with SNHL, followed up in the deafness consultation at the Otorhinolaryngology Department of Hospital Dona Estefânia between December/2018-January/2021. Probands had no previous genetic studies and non-genetic causes were excluded. Blood samples were sent to CIMA Lab which performed a targeted NGS panel of 180 genes related to SNHL. Our team manually curated 3036 variants based on the Expert specifications of the ACMG/AMP Variant Interpretation Guidelines and ClinGen Hearing Loss Variant Curation Expert Panel.
Results: Probands were between 9 months and 16 years of age. We identified causative variants in 17 different genes (COL2A1, COL4A5, EYA4, GJB2, GJB6, HOMER2, LOXHD1, MITF, PCDH15, MYO6, MYO7A, MYO15A, PAX3, SLC26A4, STRC, TMC1 and USH2A) in 42 (41.2%) out of 102 probands. Of these variants, 11 had never been reported in the literature. No potentially causative variants were identified in 25 probands (24.5%). In the remaining 35 probands (34.3%), further studies are ongoing to clarify potential causal variants. Of these, we would like to highlight 15 cases in which presumptive causative variants were identified in CDH23, COL4A3, GJB2, MYO6, POU4F3, SLC26A4, TBC1D24, TECTA, USH1G and WFS1.
Conclusion: We present the results of the largest Portuguese cohort subjected to targeted sequencing for SNHL to date and also the first cohort in pediatric age. The application of NGS technologies in SNHL proved to be an effective tool for ensuring an appropriate diagnostic yield. Our study provides new insights into the variants related to SNHL in the Portuguese population and allowed the identification of novel variants, which may contribute to expand the knowledge of the genetics of hearing loss.

Palavras Chave: Hearing loss, genetics, pediatric age