Global Journal of Otolaryngology ISSN 2474-7556 Powerpoint presentation Glob J Otolaryngol - Special Issue March 2017 Copyright © All rights are reserved by Lalsa Shilpa Perepa DOI: 10.19080/GJO.2017.05.555662 Genetic Hearing Loss Introduction I. One of the major cause of hearing loss is gene mutations. Procedure a. Genetic tests are performed on a sample of blood, hair, II. Inherited from parents to the offspring III. Transferred to future generations during pregnancy), or other tissue. skin, amniotic fluid (the fluid that surrounds a fetus IV. Can be syndromic or non syndromic b. For example, a medical procedure called a buckle smear uses a small brush or cotton swab to collect a sample of Need for knowing cells from the inside surface of the cheek. a) New era in audiology c. The sample is sent to a laboratory where technicians b) Knowledge about etiology of HL proteins, depending on the suspected disorder. To meet the requirements look for specific changes in chromosomes, DNA, or d. The laboratory reports the test results in writing to a i. Deeper knowledge of pathophysiological changes person’s doctor or genetic counselor. ii. Need for developing new tools. Results Genetic testing a. Not straight forward. a. 20,000 - 25,000 genes present in humans. b. Should consider family, medical histories and type of genetic test. disorder. b. Biochemical tests - indentifies the gene for genetic c. Positive - chromosome or gene with abnormality c. Identifies changes from chromosomes, genes or proteins. identified.d. Do not say the course of severity. inherited disorders. d. Testing is used to find changes that are associated with e. Test results negative - no copy of dangerous gene f. Does not rule out other gene causing same phenotype. determine a person’s chance developing or passing on a e. Confirm or rule out a suspected genetic condition or help genetic disorder. f. Several hundred genetic tests are currently in use, and g. Ambiguous and inconclusive more are being developed. h.i. OtherPolymorphism test required - natural to confirm gene variation occurring in Types of Genetic Testing normal people. i. Newborn screening polymorphism ii. Diagnostic testing j. Difficulty in distinguishing from disordered gene from k. Further testing for the family. iii. Carrier testing Cost and time iv. Prenatal testing i. Cost ranges from 3000 Rs to 50000 Rs. v. Predictive and presymptamatic testing ii. Increases if more testing done vi. Forensic testing iii. Can take several days to months for results vii. Research testing iv. Prenatal testing results - available quickly Glob J Otolaryngol 5(3): GJO.MS.ID.555662 (2017) 0065 Global Journal of Otolaryngology Risks and limitations testing a. Physical risk - very small II. Avoiding the need for more expensive and invasive III. Providing the basis for prognostic information about b. Miscarriage - prenatal testing future hearing c. Emotional problems with test results. IV. Giving direction and improving genetic counseling d. Can say the possibilities in other members in the family. e. Genetic information nondiscrimination act - amended on may 21,2008 in US V. Defining new guidelines for treatment (Figure 1). Why to perform genetic testing in hearing impairment? alone is not possible. i. Accurate genetic diagnosis based on clinical features ii.iii. DNA Syndromal analysis conditions makes it possible.with typical clinical features not seen - genetic testing can identify. iv. In future the critical decision to go for genetic testing Figure 1: Classification of Genetic Hearing Loss. will be taken by the audiologist. Congenital Hearing Loss v. So it is necessary to know the available molecular testing that are available and also the various conditions i. Hearing loss present by birth. that occur due to genes. ii. Genetically, it can be acquired due to various factors. vi. Similar to new born hearing screening genetic Causes testing can also become a routine clinical evaluation and audiologist should know the possible outcomes. a) Consanguinity vii. Genetic testing is minimally invasive. b) Paternal / maternal deafness viii. Since genetic hearing loss is more widely accepted and testing is available, genetic - phenotype correlations c)d) EarSingle-Gene anomalies Disorders (may occur with or without syndromes) can be made more reliable. Consanguinity ix. The physical effect of individual mutation or combination of mutation hearing loss can be predicted a. Common feature across many parts of the globe b. Marriage within relations with greater confidence. c. Legal system in many cultures x. An evaluation of the pedigree to assess which other test. family members may potentially benefit from the same d. Known to be a significant cause of genetic hearing loss( Turane. Causes & Apaydin,2002) Congenital SNHL xi. In some cases, the DNA diagnosis may affect the type to the patient. and timing of treatment, with potentially major benefits xii. Knowing the precise cause of the hearing loss will helps formation of polarized structure A. Disruption in planar cell polarity pathway (PCP). PCP- help to determine the most effective management and B. Regulates embryonic development. Genetic disturbances therapeutic options. causes disruption in PCP xiii. For example usher syndrome - management differs. C. Genetic mutation of GJB2 Sign language may not be best option. D. Siblings have higher incidence of autosomal recessive hearing impairment. The benefitsI. The providing of genetic an testing accurate include diagnosis the following: of the etiology of the hearing impairment. E. Increased risk of polygenic inheritancest (Northerncousins- greater et al.) F. Also, more common in near relations 1 0066 How to cite this article: Lalsa Shilpa P. Genetic Hearing Loss. Glob J Oto 2017; 5(3): 555662. DOI: 10.19080/GJO.2017.05.555662. Global Journal of Otolaryngology risk. Distant cousins- lesser risk. medical problems involving other organs. Associated with malformation of the ear and other organs with Paternal or maternal deafness I. Around 400 genetic syndromes that cause hearing loss identifiedII. One of the contributing factors for pre lingual deafness A.B. SNHLEither common of the parent occurrence has hearing loss a. Deletion of genetic material on the long arm of a. a chromosomal problem, chromosome 15 A syndrome may be caused by b. a biochemical defect, b. Loss of multiple genes in that region c. a Mendelian genetic defect, c. SRTC on Chromosome 15 - cause of HL d. or an environmental agent. Single gene disorders Pattern of Inheritance i. Single mutated gene- cause ii. Passes to generations in several ways iii. Genetic protein -non functional i. Autosomal dominant inheritance iii. X-linked inheritance iv. Defect on autosome of X chromosome - affects one ii. Autosomal recessive inheritance member of the gene pair or both carrying the same gene iv. Mitochondrial inheritance pair Autosomal dominant inheritance v. Pattern of inheritance depends on the phenotype. Ear anomalies individuals in each generation are affected; i. The pattern of inheritance is Autosomal dominant if a. Congenital ii. Both males and females are equally likely to be affected b. Occurs in isolation (Figure 2). c.d. AsDue a partto defective of syndrome genes [1-10]. Late onset genetic hearing loss I. Occurs later in life II. 9 different types of genes localized III. DFNA10 on chromosome 6 - most common IV. Connexin 6 also has impact Figure 2: Autosomal Dominant Inheritance. V.VI. Mostly Can be Age triggered related by hearing environmental impairment factors normal and one deleterious copy of the gene for the disorder, iii. Affected individuals are usually heterozygote’s with one LateVII. onset No exactProgressive gene identified genetic till hearing date. loss and each offspring of an affected individual has a 50% chance of inheriting the deleterious allele. iv. There may be variable expression among affected a)b) AutosomalOccurs at any dominant age individuals, and some who must have the deleterious allele c) It may be due to some defective genes that might cause may show no phenotypic signs. deafness, but expressed later in life. Syndromic hearing loss I. Autosomal recessive inheritance recessive if the abnormal phenotype is expressed only in A. The mode of inheritance of a disorder is Autosomal in a generally consistent pattern is known as “syndrome”. individuals who have two copies of the deleterious allele. A particular set of congenital signs repeatedly occurring 0067 How to cite this article: Lalsa Shilpa P. Genetic Hearing Loss. Glob J Oto 2017; 5(3): 555662. DOI: 10.19080/GJO.2017.05.555662. Global Journal of Otolaryngology B. Heterozygotes are not affected and are often called III. Mitochondrial Conditions carriers. a) Mitochondria are structures in the cell that produce the C. The probability that a child of carrier parents will be energy that cells need to survive. affected by one quarter; b) Neither the mitochondria nor the cell can exist without D. The probability that an unaffected sibling is a carrier is the other. two third. c) Changes in the mitochondrial genes can also result in E. If a hearing impaired parents has an affected sibling syndromes involving hearing loss. or the parents are related, the etiology is most likely to d) Mutation in the mitochondrial genome can affect energy be deleterious gene with the mode of inheritance being production through adenosine triphosphase synthesis and oxidative phosphorylation. Tissues that require high levels AutosomalF. Recessive recessive. inheritance probably explains most case of of energy are particularly affected. profound sensorineural hearing loss when family history e) Typically, mitochondrial diseases involve progressive is negative, and there is no known environment factor that neuromuscular degeneration with ataxia, ophthalmoplegia, could be responsible. and progressive hearing loss [11-20]. II.X - Linked inheritance IV. Mitochondrial mutation and syndromic hearing loss i.If a disorder has an X- linked dominant pattern of a) Systemic neuromuscular syndromes such as Kearns inheritance with complete penetrance, then all daughters Sayre Syndrome, mitochondrial encephalomyopathy, of affected fathers are affected. lactic acidosis and stroke like episodes etc frequently ii.