Abstract:
In humans, hereditary hearing loss (HL) is a frequently occurring disorder with genetic
heterogeneity. The incidence of sensorineural HL is 1 to 2 per 1000 at birth, and it is estimated
that this disorder can be linked to as many as 1000 different genes. The main aim of this thesis
is to identify novel genes and clarify clinical heterogeneity related to HL. The cohort for the thesis
was mainly collected from Iran, with some families also from Germany. Using exome sequencing,
genome sequencing, and functional in vitro tests, including splicing assays for a variety of genes,
we detected and established diagnoses in about 74% of our patients. Interestingly, I was involved
in the identification of a novel gene: CLRN2, which causes non-syndromic sensorineural HL. This
thesis also confirmed gene-disease evidence for two genes, COL11A1 and COL9A3, causing
non-syndromic HL and Stickler syndrome type 6, respectively. In another part of this thesis, the
phenotype related to MPDZ was expanded and its role was consolidated in human HL.
Additionally, I contributed to functional validation of selected variants identified in PIGS and IPO8
that are associated with variable syndromic HL. Furthermore, I was also involved in a project that
established that KARS1 causes syndromic HL with variable phenotypes, but HL is the main
phenotype in all patients. In summary, the results of this thesis added several genes to molecular
genetic diagnostic panels, as well as the literature and are highly recommended for re-analysis
in unsolved cases with HL.
Novel genes