Sequencing of clinical exome identifies multilocus genomic variation related to three known hearing loss syndromes in one patient.

Introduction: Genetically determined hearing loss may occur in an isolated or syndromic form. There is a wide range of syndromes for which hearing loss represents one of the characteristic features, such as Stickler and Alport syndrome. One of the most frequently observed inner ear malformation identified during a radiological workup of hearing loss patients is large vestibular aqueduct syndrome (LVAS). Objective: The aim of the study was to identify genetic variants that cause hearing loss in an adult female patient who was diagnosed with bilateral hearing loss, LVAS, high myopia, osteoarthritis and microhematuria. Material and methods: Next-generation sequencing of clinical exome was performed using the TruSight One sequencing kit (Illumina) on DNA isolated from the proband's blood sample. Analysis of the results focused on variants located in the genes related to hearing loss. To test for the presence of a haplotype located in the 5' region of the SLC26A4 gene (CEVA) in the proband and to confirm the presence and segregation of the identified pathogenic variants in the proband and her family members Sanger sequencing was performed. Results: Nextgeneration sequencing revealed the presence of a known COL2A1 pathogenic variant (NM_001844.4: c.1833+1G>A) causative for Stickler syndrome and one pathogenic change in COL4A5 (NM_000495.4: p.Gly624Asp/c.1871G>A) causative for Alport syndrome. In SLC26A4 (NM_000441.1: p.Leu597Ser/c.1790T>C) only one known pathogenic variant was found and the CEVA haplotype was not detected. Conclusions: Simultaneous testing of many genes using nextgeneration sequencing followed by family analysis identified a de novo pathogenic variant in the COL2A1 gene and after clinical reanalysis, the patient was diagnosed with Stickler syndrome, which is inherited in an autosomal dominant manner. The patient was found to be a carrier of a COL4A5 variant for the X-linked Alport syndrome, which explains the occurrence of microhematuria and may account for some degree of her hearing loss. The cause of LVAS still remains unknown as only one SLC26A4 pathogenic variant and no CEVA haplotype were found, and the disorder is inherited in an autosomal recessive manner. Our study identifies the presence of three rare known hearing loss syndromes in one patient and emphasizes the important role of genetic testing in guiding clinical diagnosis. [ABSTRACT FROM AUTHOR]