HEARING LOSS AND DEAFNESS

Hearing loss is generally one of the most common diseases that occur in childhood, with a frequency of approximately 1 in 1000 births. It is divided into acquired (due to environmental factors, but also to fetal infections, e.g. toxoplasmosis, rubella, cytomegalovirus), of genetic etiology-inherited and of yet unknown etiology.

Hearing loss with a genetic etiology may be part of a syndrome (over 400 syndromes include hearing loss) and non-syndromic, following all three possible types of inheritance: recessive, dominant and X-linked.

Non-syndromic hearing loss and particularly the form that occurs before the development of language communication in children, is in >50% of cases a genetic disease and is mainly due to recessive mutations with an increased carrier frequency in the general population.

It is very important for the proper management of patients, but also for genetic counseling for future pregnancies, that we can distinguish inherited forms of deafness from acquired (non-genetic) forms.

This is achieved by combining various clinical tests recommended by the specialist otolaryngologist, but also with appropriate genetic tests.

More than 100 genes are estimated to be involved in hearing loss and deafness. However, mutations in two of these genes, GJB2 (connexin 26) and GJB6 (connexin 30), represent more than 65% of non-syndromic recessive deafness and about 35% of sporadic forms, with a carrier frequency of 1 in 33 in the general population.

In practice, this means that about 1 in 7 children with deafness harbor mutations in these two genes. Specifically for the GJB2 gene, a single mutation called 35delG constitutes ~90% of all pathogenic mutations of the gene, with a carrier frequency in the general population of about 3.5% (1 out of 28 individuals).

Especially in hearing loss occurring in childhood, early medical and educational interventions are essential for normal development of speech and language. Moreover, even severe hearing loss can be restored nowadays very effectively with hearing aids or cochlear implants.

The strategies applied to genetic testing for hearing loss are aimed at accurate and efficient identification of the genetic causes and the findings are useful for:

• for understanding the precise cause,
• predicting the acoustic parameters,
• prevention of the disease in the family,
• proper management of the symptoms, and
• for determining the most effective treatment

Understanding the molecular mechanism leading to the deterioration of cells in the inner ear through genetic testing undoubtedly facilitates the development and introduction of new and specialized treatments for different types of hearing loss.

Due to the special characteristics of the disease, genetic testing in hearing loss is of extremely high value in medical practice and is required in order to complete the diagnosis.

Furthermore, genetic diseases associated with hearing loss are expressed with all possible types of inheritance, i.e. as autosomal recessive, autosomal dominant and X-linked, making it even more complicated to diagnose the specific type.

Molecular genetic testing of the genes GJB2 and GJB6 is typically the first and basic genetic test performed in patients with non-syndromic hearing loss and with a suspected recessive inheritance.

If the above test does not reveal the genetic cause of hearing loss, we are now in a position to apply, in one step, genomic testing through Next Generation Sequencing – NGS for the detection of mutations in more than 120 genes, which have been associated with all types of syndromic and non-syndromic hearing loss and deafness, irrespective of the mode of inheritance.

Therefore, the application of NGS has become a highly effective diagnostic strategy, through the parallel analysis of a large number of genes involved in hearing loss.

InterGenetics has developed and offers an NGS panel for the genomic analysis of 129 genes (see gene list below), associated with a wide spectrum of syndromic and non-syndromic types of hearing loss and deafness, irrespective of the mode of inheritance.

DEAFNESS_129_GENES.pdf

We perform DNA sequence analysis, via Next Generation Sequencing (NGS) on a Genome Analyzer-Ion Proton platform, of all exons and intron-exon junctions/splice sites of the 129 genes, allowing us to detect >98% of all pathogenic mutations of the genes through the use of specially developed bioinformatics tools.

Where possible and/or necessary, we carry out additional MLPA analysis in order to detect deletions/duplications of the genes (please consult the final test report).

The test is highly sensitive and complex, so it is necessary that the results are assessed by a specialized team of clinical and molecular geneticists, in order to ensure safe and reliable testing.

Proper clinical genetic assessment and genetic counseling, both before and after testing, is essential in order to determine the optimum testing strategy and also to communicate properly the concepts of pathological and normal.