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| Author(s): |
Fábio Tadeu Arrojo Martins
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia |
| Defense date: | 2017-08-28 |
| Examining board members: |
Edi Lúcia Sartorato;
Cláudia Vianna Maurer Morelli;
José Andrés Yunes;
Mauricio Kurc;
Victor Evangelista de Faria Ferraz
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| Advisor: | Edi Lúcia Sartorato; Karen Avraham |
| Abstract | |
Hearing loss is the most common sensory deficit in humans, affecting approximately 5 % of the world population. In developed countries, one in every thousand individuals presents severe to profound bilateral sensorineural hearing loss. Of the congenital cases, 50-60 % are associated with genetic factors, which affect more than 100 genes involved in both syndromic and non-syndromic hearing loss. However, this number is estimated to be over 300 genes, i.e. 1 % of all genes in the human genome. Due to the genetic and clinical heterogeneity of hearing loss, as well as the limitations of conventional molecular diagnostic technologies, new strategies are constantly being developed for better understanding of the mechanisms of hearing. Among these, massive parallel sequencing has proven to be efficient, enabling the identification and association of more than 40 genes to hearing loss in seven years. In this study, massive parallel sequencing based technologies were used to identify and characterize genetic variants that could clarify the observed phenotype in individuals with hearing loss. Of the 25 families studied, 20 were from the Middle East. They were analyzed by the HEar-Seq v3 capture panel, containing 284 genes associated with hearing loss in humans and mice. The five remaining families were from Brazil and analyzed by complete exome sequencing. Novel candidate variants and their related genes causing the familial hearing loss were functionally analyzed and their pathogenic effect was characterized in silico and in vitro. With the use of the capture panel and complete exome sequencing, the molecular cause of the hearing loss in 12 of the 25 studied cases (48 % of the cases) was elucidated. Novel, as well as known variants, were identified in the SLC26A4, USH2A, GATA3, OTOF, MYO6, STRC, CEACAM16, COL11A2 and MYH9 genes, thereby clarifying the etiology of the hearing loss in the studied families. Moreover, this work identified a new gene, SLC12A6, as related to hearing loss in humans. These results demonstrate the power of massive parallel sequencing for studying genetic disorders, especially in complex and heterogeneous cases. Additionally, the analyzes aided a conclusive diagnosis of the hearing loss, which enabled adequate genetic counseling and prognosis for the affected families (AU) | |
| FAPESP's process: | 13/05823-5 - Deep sequencing for identification and characterization of deafness genes |
| Grantee: | Fábio Tadeu Arrojo Martins |
| Support Opportunities: | Scholarships in Brazil - Doctorate |