PREVALENCE OF STRC AND OTOA GENE PATHOGENIC DELETIONS AND VARIANTS IN BRAZILIAN PATIENTS.

• Grant number: 25/05677-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: June 01, 2025
• End date: May 31, 2026
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Karina Lezirovitz Mandelbaum
• Grantee: Maria Eduarda Paramo Neto
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 23/07188-7 - Investigation of new hereditary forms of hearing loss and its pathophysiological mechanism, AP.R

Abstract

Hearing loss (HL) affects around 70 million people worldwide, and in 50% to 60% of cases, its origin is genetic. More than 150 genes have been associated with non-syndromic HL, including **STRC** and OTOA, both with an autosomal recessive inheritance pattern and often involved in large deletions (CNVs). The STRC gene, located on chromosome 15, encodes the stereocilin protein. A significant challenge is the presence of a pseudogene with 99.6% sequence identity, which complicates accurate identification. Additionally, deletions involving **STRC** and CATSPER2 are associated with Deafness-Infertility Syndrome. HL linked to STRC is mild to moderate, congenital, bilateral, and symmetrical. The OTOA gene, located on chromosome 16, encodes otoancorin, which is necessary for the fixation of the tectorial membrane in the inner ear, essential for hearing. Variations in OTOA include large deletions, duplications, and mutations that can result in pre-lingual hearing loss of moderate to severe degrees. Studies show that conventional sequencing methods, such as Sanger sequencing, do not differentiate the STRC gene from its pseudogene. Techniques such as MLPA, qPCR, and long-range PCR have demonstrated greater efficiency. Since 2013, the Genetic Deafness Clinic at Hospital das Clínicas has treated over 600 patients, with 80% still without a defined genetic cause. In a pilot study involving 78 patients with mild to moderate HL, five homozygous deletions in STRC and five heterozygous deletions were identified. However, qPCR analysis covers only part of the gene, possibly missing deletions in other regions. This finding suggests a significant contribution of STRC to these HL cases. The current study aims to identify deletions in the STRC, OTOA, and CATSPER2 genes using MLPA and investigate variants through long-range PCR to determine their role in non-syndromic hearing loss. (AU)