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DEAFNESS and GENETIC COUNSELLING Kim Frumar Genetic Counsellor BACKGROUND Hearing loss is the most common birth defect and the most prevalent sensorineural disorder in developed countries 1 in 500 newborns have bilateral permanent sensorineural hearing loss and by adolescence it increases to 3.5 per 1000 More than 50% pre-lingual deafness is genetic Hearing loss increases with age- impact of both genetics and environment and interactions between environment and genetic predisposition Causes of pre-lingual deafness Single gene disorders SYNDROMIC Associated with malformations external ear or other organs Medical probs involving other organ systems NON-SYNDROMIC No visible abnormalities external ear May have abnormalities middle and/or inner ear No associated medical probs. Syndromic hearing loss Accounts for up to 30% of prelingual deafness or deafness can occur later Abnormalities in other organ systems: • can be obvious or subtle • may be congenital • may develop later Syndromic Over 400 syndromic causes of hearing loss Autosomal dominant Autosomal recessive X-linked Mitochondrial Autosomal dominant inheritance only one copy of altered gene needed to be deaf passed down through generations can occur as a spontaneous mutation in an offspring of unaffected parents Autosomal dominant pedigree I Deaf Dd dd II Dd Dd Dd Dd III ãMCRI Education Unit and Gene CRC Autosomal recessive inheritance Need 2 faulty genes to be deaf (one from each parent) Deaf offspring can arise from hearing parents 2x AR Deaf parents have 100% chance of Deaf child Autosomal recessive pedigree I Dd Dd 1 2 Deaf II 1 2 3 Dd dd DD ãMCRI Education Unit and Gene CRC X-Linked Inheritance Gene fault on X chromosome condition occurs more frequently in males than females • males only have one X- chromosome- no backup copy • females have two X- chromosomessome backup X-Linked Recessive Pedigree X-linked Deafness XY XX XY X cY XY X cX X cX X cX X cY XY X cY Mitochondrial inheritance Mitochondria• small structures within cells • provide energy for the cell • own set of 37 genes separate from 3040,000 genes in nucleus of the cell • only the egg (not the sperm) contributes mitochondria to the developing embryo • Only females will pass mitochondrial traits to their children cytoplasm mitochondrion ribosomes nucleus chromosome Autosomal dominant syndromes Waardenburg syndrome: • most common AD syndromic hearing loss • variable degrees of sensorineural hearing loss • pigmentary abnorms. of skin, hair (white forelock) and eyes (since people dye their hair, need to ask about white forelock specifically). • 4 types- WSI, WS II, WS III, WS IV • several mutations identified and some molecular genetic testing available Autosomal dominant pedigree I Deaf Dd dd II Dd Dd Dd Dd III ãMCRI Education Unit and Gene CRC Autosomal dominant syndromes Autosomal dominant pedigree I Deaf Dd dd II Branchio-oto-renal syndrome: Dd Dd Dd Dd III ãMCRI Education Unit and Gene CRC • second most common type of AD syndromic hearing loss • Conductive, sensorineural & mixed hearing loss • branchial cleft cysts or fistulae • malformations external ear inc. preauricular pits • renal anomalies • 40% have mutations in EYA1 gene (chromosome 8q13) • Molecular testing available Autosomal dominant syndromes Autosomal dominant pedigree I Deaf Dd dd II Dd Neurofibromatosis type 2 (NF2): Dd Dd Dd III ãMCRI Education Unit and Gene CRC • associated with a rare potentially treatable type of deafness • hearing loss secondary to bilateral vestibular schwannomas • hearing loss not usually until 3rd decade • Molecular genetic testing available for presymptomatic at-risk family members to facilitate early diagnosis and treatment Autosomal dominant syndromes Autosomal dominant pedigree I Deaf Dd dd II Dd Dd Dd Dd III ãMCRI Education Unit and Gene CRC Stickler syndrome: • • • • progressive sensorineural hearing loss cleft palate spondylo-epiphyseal dysplasia and osteoarthritis 3 types recognized- 2 types include severe myopia and predisposition to retinal detachment. • molecular genetic testing available Autosomal recessive syndromes Autosomal recessive pedigree I Dd Dd 1 2 Deaf II Usher syndrome: • • • • • • 1 2 3 Dd dd DD ãMCRI Education Unit and Gene CRC most common type of AR syndromic deafness dual sensory losses congenital sensorineural hearing loss later development of retinitis pigmentosa affects over 50% of people who are deaf-blind 3 types- molecular testing only available for some types Autosomal recessive syndromes Autosomal recessive pedigree I Dd Dd 1 2 Deaf II 1 2 3 Dd dd DD ãMCRI Education Unit and Gene CRC Pendred syndrome: • second most common type AR hearing loss • congenital severe to profound sensorineural hearing loss • abnormality of bony labyrinth • euthyroid goitre develops in early puberty • Molecular genetic testing available Autosomal recessive syndromes Autosomal recessive pedigree I Dd Dd 1 2 Deaf II 1 2 3 Dd dd DD ãMCRI Education Unit and Gene CRC Jervell-and Lange-Nielson syndrome: • • • • • third most common type AR hearing loss Congenital deafness ECG abnorms- Prolonged QT interval Syncopal episodes and may have sudden death High risk children-those with F/H of sudden death, SIDS, syncope, long QT syndrome- should have thorough cardiac evaluation • Genetic testing available for high risk individuals Autosomal recessive syndromes Autosomal recessive pedigree I Dd Dd 1 2 Deaf II Biotinidase deficiency: 1 2 3 Dd dd DD ãMCRI Education Unit and Gene CRC • caused by deficiency in biotin , a water-soluble Bcomplex vitamin essential for gluconeogenesis, fatty acid synthesis and breakdown of some amino-acids • Mammals cannot synthesise biotin so rely on diet and endogenous turnover of free biotin • Deficiency leads to neurological problems, visual problems and sensorineural hearing loss • Diet and treatment should be initiated as soon as possible X-linked Syndromes X-Linked Recessive Pedigree X-linked Deafness XY XX Alport syndrome: XY X cY XY X cX X cX X cX X cY XY X cY • progressive sensorineural hearing loss after age 10yr • progressive glomerulonephritis leading to endstage renal disease • variable opthalmologic findings • X-linked = 85% cases • Also AR =15% Mitochondrial syndromes Mutation in MTRNT1 gene found in 2-6% of patients with diabetes mellitus in Japan 61% of people with diabetes and this mutation have hearing loss Sensorineural develops only after onset of diabetes Non-syndromic Hearing loss At least 70% of hereditary deafness No associated visible abnormalities of the external ear nor any related medical problems 66 genes known to cause NSHL Can be associated with abnormalities of middle and/or inner ear Again AD (70-80%), AR (20-25%), XL (1-5%) and Mitochondrial Non-syndromic Hearing loss Gene loci for NSHL are designated DFN (for DeaFNess) • DFNA= Autosomal dominant • DFNB= Autosomal recessive • DFNX= X-linked • The number after these designations reflects the order they were mapped or discovered Autosomal dominant NSHL Unlike AR NSHL, AD NSHL does not have an identifiable single gene responsible for the majority of cases Audioprofiling can be distinctive in AD NSHL and is useful in developing an evaluation strategy for genetic testing Autosomal recessive NSHL DFNB1 is caused by mutations in the GJB2 gene which codes for the protein ‘connexin 26’ and the GJB6 GENE which codes for ‘connexin 30’ account for 50% of autosomal recessive NSHL Approx 1 in 33 of general population are carriers for GJB2 the other 50% are attributed to numerous other gene mutations ( up to DFNB84!) X-linked NSHL DFNX3 characterised by mixed conductive-sensorineural hearing loss DFNX2 & DFNX4 cause profound prelingual HL DFNX6- high-frequency loss from 5-7 yrs progressing to severe to profound HL by adulthood over all frequencies. Mitochondrial NSHL Hearing loss can be induced in some people who have mitochondrial mutations by aminoglycoside use. Molecular genetic testing Guided by presentation (phenotype) For example, testing for GJB2 and GJB6 is usual for congenital NSHL in the first instance then move to others if negative If CT scan shows dilated vestibular aqueduct pendrin gene testing requested (University Iowa) Until recently required multiple tests to determine cause Some centres now using multigene screening panels –currently involves sending DNA overseas University of Iowa offers OtoScope- tests for 66 genes Genetic Evaluation and Counselling The goal of genetic evaluation and counselling is to provide information and support that can assist families in making choices that are appropriate for them Genetic Evaluation and Counselling Correctly diagnosing the specific cause of hearing loss can provide information on prognosis and is essential for accurate genetic counselling Many people do not know the exact cause of their or their children’s deafness and could benefit from genetic evaluation and counselling to assist with health care and /or family planning issues Genetic Evaluation and Counselling Family history • • • • • • 3-4 generations hearing status of parents and siblings consanguinity paternity ethnicity/ country of origin syndromic vs non-syndromic features Genetic Evaluation and Counselling Medical and perinatal history • • • • • Intruterine infections meningitis ototoxic drugs prenatal alcohol exposure hypoxia/ jaundice Clinical examination • • • • otologic examination airways examination documentation of any dysmorphic features neurological examination Genetic Evaluation and Counselling Audiometry testing and comparison of tests from different family members Physical examination CT scans- to detect inner ear malformations GENETIC TESTING - if indicated Genetic testing Detects changes associated with inherited conditions: • • • • direct analysis of DNA or RNA (gene testing) chromosome analysis (cytogenetics) biochemical testing for protein products of genes indirect testing of genetic markers (linkage) Types: • prenatal inc. pre-implantation genetic diagnosis (PGD) • newborn • diagnostic • predictive • carrier screening Genetic Counselling: What is it and why is it important? It is a process in which information and support are provided to families who have or are at risk for a variety of inherited or genetic conditions including deafness, in order to assist them to negotiate the difficult personal, family, cultural, social and ethical issues that may arise. Genetic Counselling Sensitive and empathic gathering and sharing of information and results of testing Working with families on issues of grief, adjustment, acceptance of diagnosis Assisting with decision making based on the information provided Emphasis on personal and family dynamics in the context of genetic testing and diagnosis“Genetics is a Family Business” Counselling issues for Deaf families Deaf Culture The use of skilled interpreters- not family members Terminology used: • probability or chance vs risk • deaf or hearing vs affected or unaffected • deaf /hard of hearing vs hearing impaired or handicapped • Avoiding “abnormal”or “ disease causing” when referring to genes Counselling issues for Deaf families Knowledge of and experience of genetic testing and genetic counselling attitudes towards newborn and prenatal genetic testing for deafness Preference for a hearing or deaf child Risks and benefits of genetic testing for deafness Counselling issues for Deaf families Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational and social services rather than just information about prevention, reproduction or family planning Followup Repeating genetic evaluation if no specific diagnosis made initially or if test results or new tests become available Evaluation of progressive hearing loss Other speciality directed examinations according to patient need ( eg neurological, cardiac, renal etc) CONCLUSIONS The role of genetic counselling and genetic testing will continue to expand New discoveries and technologies will will increase the complexity of genetic testing options Rapid developments highlight the importance of recontacting families and ensuring families maintain links with providers CONCLUSIONS There are currently limited numbers of geneticists or genetic counsellors Therefore ALL professionals involved should to familiarise themselves with current discoveries and accepted protocols for genetic testing and counselling Mid North Coast LHD & HNE- LMNC Genetic Counsellors Coffs Harbour: • Karen Robinson, • Coffs Harbour Health Campus Ph: 6656 7806 • email: [email protected] Port Macquarie: • Ph: 65 882 783 Taree: • Kim Frumar and Carol Sorensen • Port Macquarie Health Centre • email: [email protected] Bruce Hopper • Taree Community Health Centre • email: [email protected] Ph: 6592 9703 All other areas call : Centre for Genetic Education for contact details • Ph: 9906 9599