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Research Center for Genetic Engineering and Biotechnology “Georgi D. Efremov”, MASA DEAFNESS What is deafness: Genetic testing: Partial or complete loss of hearing The level of hearing impairment is determined by the intensity of sound (measured in decibels (dB)). Depending on the level of decibels lost, hearing impairment can be divided into mild, moderate, severe and complete or profound deafness Hearing impairment is the most common sensory deficit in humans. Approximately 1 in 1000 newborns is affected by severe to profound deafness at birth. Additionally 1 in 1000 children progressively develops hearing loss during childhood. With the age hearing loss progressively increases, so that over 50% of individuals above 80 years of age are affected Types and causes of hearing loss: Deafness is influenced by both genetic and environmental factors, with inherited causes defined as the most prominent etiological factor in deafness in developed countries. When associated with other symptoms it is referred as syndromic hearing loss (SHL), while when occur as an isolated symptom it is referred as non-syndromic hearing loss (NSHL). NSHL accounts about 70% of genetic deafness and is almost exclusively monogenic and highly heterogeneous . NSHL can be transmitted as autosomal recessive (80%), autosomal dominant (20%), X-linked deafness and mitochondrial fashion (2%). The autosomalrecessive forms of deafness are generally the most severe and are almost exclusively caused by cochlear defects of hair cells (sensoryneural deafness). Autosomal-dominant forms of deafness are usually post-lingual and progressive. Genetics : Price (МКД) Detection of point mutations/small deletions/insertions in the GJB2 gene using DNA sequencing method 7.500 Aminoglycoside induces deafness (5 mtDNA mutations) 5.000 Detection of point mutations/small deletions/insertions in the SLC26A4 gene using DNA sequencing method Detection of point mutations/small deletions/insertions in the SLC26A4 gene using DNA sequencing method Benefits of Genetic Testing: Accurate determination of the etiology of the patient's hearing loss. Reduction of the need for further invasive diagnostic tests. Basis for clinical prognosis, potential medical complications. Guidance regarding treatment and long-term medical management, particularly in the young infant. Definitive information to guide genetic counseling of families. The genetic basis of hearing loss is complex. To date, 42 different genes have been found implicated in autosomal recessive NSHL. Mutations in some of these genes, such as GJB2, MYO7A, CDH23, OTOF, SLC26A4, TMC1, are quite common and can be tested in individuals with hearing loss. Mutations in many other genes are extraordinarily rare, some of which have been reported in only one or two consanguineous families. Analyses performed at RCGEB “Georgi D. Efremov” Elucidation of the genetic basis of hearing loss is crucial for management of patients and their families. Therefore, genetic testing is recommended as an integral part of the evaluation of children with permanent hearing loss. Mutations in the GJB2 gene (13q12) are the most common cause of sporadic and recessive NSHL, in many populations worldwide. More than 100 different mutations in this gene have been described with specific prevalence in different ethnic groups and geographic regions. In Caucasians the most common mutation is 35delG, while W24X is frequent among Gypsies. Pendred syndrome, the most common syndromic form of deafness, is an autosomal recessive disorder associated with developmental abnormalities of the cochlea, sensoryneural hearing loss, and diffuse thyroid enlargement (goiter) Mutations in mitochondrial DNA (mtDNA) are found to contribute to sensoryneural deafness, including both syndromic and non-syndromic forms. Hot spot regions for deafness mutations are the MTRNR1 gene and the MTTS1 gene. Nucleotide changes are observed with a variable frequency among different populations of deaf persons. OTOF-related deafness (DFNB9 nonsyndromic hearing loss) is characterized by two phenotypes: prelingual nonsyndromic hearing loss and, less frequently, temperature-sensitive nonsyndromic auditory neuropathy. The nonsyndromic hearing loss is bilateral severe-toprofound congenital deafness. 25.000 25.000 Literature: 1. Online Mendelian Inheritance in Man, http://www.ncbi.nlm.nih.gov/omim; # 121011 (GAP JUNCTION PROTEIN, BETA-2; GJB2) # 274600 (PENDRED SYNDROME; PDS, SLC26A4) # 601071 (DEAFNESS, AUTOSOMAL RECESSIVE 9; DFNB9) 2. Sukarova Stefanovska E., Momirovska A., Cakar M., Efremov G.D. GJB2 mutations in non syndromic hearing loss in the Republic of Macedonia. Balkan Journal of Medical Genetics, 2009, 12(2): 11-17 3. Sukarova Stefanovska E., Cakar M., Filipce I., Plaseska Karanfilska D. Genetics of nonsyndromic hearing loss in the Republic of Macedonia. BJMG, 15, Suppl., 2012 RCGEB, 2013