Genetic Hearing Impairment PDF

Genetics of Hearing Losses ASPA 2304 PAEDIATRICS FOR AUDIOLOGY AND SPEECH SCIENCES Epidemiology Hearing loss occurs in 1 of every 1,000 births 50 % are hereditary Syndromic vs. nonsyndromic 30% syndromic 70% nonsyndromic Autosomal dominant vs. autosomal recessive vs. x-linked vs....

Genetics of Hearing Losses ASPA 2304 PAEDIATRICS FOR AUDIOLOGY AND SPEECH SCIENCES Epidemiology Hearing loss occurs in 1 of every 1,000 births 50 % are hereditary Syndromic vs. nonsyndromic 30% syndromic 70% nonsyndromic Autosomal dominant vs. autosomal recessive vs. x-linked vs. mitochondrion Syndromic deafness Has other abnormalities 20-30% of genetic hearing loss Two syndromes can be caused by different mutations of the same gene NZ_2012 Mutations of more than one gene can cause the same clinical phenotype  NZ_2012 AUTOSOMAL DOMINANT SYNDROMIC HEARING IMPAIRMENT Waardenburg syndrome ~2% of congenital hearing loss Usually autosomal dominant Dystopia canthorum Aka telecanthus. Describes a subtle but unusual facial feature in which the inner corners of the eyes NZ_2012 (canthi) are spaced farther apart than normal, yet the eyes (pupils) themselves are normally spaced. The result is that the eyes appear to be widely spaced, even though they are not. Pigmentary abnormalities of hair, iris and skin Sensorineural hearing loss A type of hearing loss in which the cause lies in the vestibulocochlear nerve (Cranial nerve VIII), the inner ear, or central processing centers of the brain. Waardenburg syndrome Type 1: With dystopia canthorum Penetrance for hearing loss = 36% to 58% Eg: penetrance is 40%; so 40% of those with the mutation will develop the disease, while 60% will not. Wide confluent eyebrow NZ_2012 High broad nasal root Heterochromia irides Heterochromia means different-colored, and irides is the plural form of iris—the colored portion of the eye. Thus, someone with heterochromia of the irides has different-colored eyes, often one brown and one blue. Brilliant blue eyes Premature gray of hair, eyelashes, or eyebrows White forelock Vestibular dysfunction Associated with PAX3 gene mutation Waardenburg syndrome Type I Heterochromia iridis NZ_2012 A novel mutation of PAX3 in a Chinese family with Waardenburg syndrome Waardenburg syndrome Type 2: Similar as Type 1 but without dystopia canthorum Hearing loss penetrance as high as 87% NZ_2012 Associated with dominant mutations of MITF gene Associated with homozygous deletion of SLUG gene MITF was found to activate the SLUG gene Waardenburg syndrome Type 3 (Klein-Waardenburg syndrome): Type 1 clinical features + hypoplastic muscles and contractures of the upper limbs Associated with PAX3 gene mutation NZ_2012 Type 4 ( Shah-Waardenburg syndrome): Type 2 clinical features + Hirschsprung’s disease Hirschsprung's disease is a disorder of the gut that occurs when all or part of the large intestine has no nerves and therefore cannot function. EDNRB gene – encodes endothelin-b receptor, development of two neural crest derived-cell lineages, epidermal melanocytes and enteric neurons EDN3 gene – encodes endothelin-3, ligand for the endothelin-b receptor SOX10 gene – encodes transcription factor Branchio-oto-renal syndrome 2% of profoundly deaf children Otologic anomalies: Variable hearing loss (sensorineural, conductive or mixed) Malformed pinna, preauricular pits Branchial derived abnormalities: cyst, cleft, fistula NZ_2012 Renal malformation: renal dysplasia with anomalies of the collecting system, renal agenesis Renal agenesis = one (unilateral) or both (bilateral) fetal kidneys fail to develop. Sometimes with lacrimal (tears) duct abnormalities: aplasia, stenosis (abnormal narrowing) EYA1 gene mutation – knockout-mice showed no ears and kidneys because apoptotic regression of the organ primordia Branchio-oto-renal syndrome NZ_2012 Branchio-oto-renal syndrome Hearing impairment Other characteristics Estimated to be present Cup‐shaped pinnae in 70‐93% Preauricular pits/tags Variable age of onset Deep overbite and a Mild to profound long, narrow face NZ_2012 severity SNHL, CHL, or mixed Mondini’s dysplasia and stapes fixation can also be present Mondini’s dysplasia = flattened cochlea with development only of the basal Coil. Branchio-oto-renal syndrome NZ_2012 Stickler syndrome Variable sensorineural hearing loss Ocular symptoms: progressive myopia, resulting in retina detachment and blindness Arthropathy: premature degenerative changes in NZ_2012 various joints Orofacial features: midface hypoplasia Three genes: COL2A1, COL11A1, COL11A2 Associated with defective collagen protein Each gene mutation corresponding to a phenotype Stickler syndrome NZ_2012 Neurofibromatosis Type 2 (NF2) Epidemiology Prevalence of 1 in 210,000 people Etiology NF2 tumor NZ_2012 suppressor gene mutation on chromosome 22 Diagnosis Manchester criteria Audiometry MRI Neurofibromatosis Type 2 NZ_2012 Treacher-collins syndrome (TCS) Autosomal dominant with variable expression Variable expressivity occurs when a phenotype is expressed to a different degree among individuals with the same genotype. Conductive hearing loss NZ_2012 Occurs when there is a problem conducting sound waves anywhere along the route through the outer ear, tympanic membrane (eardrum), or middle ear (ossicles). May occur in conjunction with sensorineural hearing loss or alone. Craniofacial abnormalities: Coloboma of the lower lids, micrognathia, microtia, hypoplasia of zygomatic arches, macrostomia, slanting of the lateral canthi Treacher-collins syndrome Mutation in TCOF1 gene: Involved in nucleolar-cytoplasmic transport Results in premature termination of the protein product NZ_2012 Airway Upper airway narrowing a major issue Nasopharynx is 50% smaller than normal More prone to obstructive sleep apnea  sudden infant death syndrome Treacher-collins syndrome NZ_2012 Patient with TCS and mutation within the TCOF1 gene  NZ_2012 AUTOSOMAL RECESSIVE SYNDROMIC HEARING IMPAIRMENT Usher syndrome Sensorineural hearing loss Progressive loss of sight due to retinitis NZ_2012 pigmentosa Three different clinical types 11 loci and 6 genes have been identified Usher syndrome Type 1: Profound congenital deafness, absent vestibular response, onset of retinitis pigmentosa in the first decade of life NZ_2012 Type 2: Sloping congenital deafness, normal vestibular response, onset of retinitis pigmentosa in first or second decade of life Type 3: Progressive hearing loss, variable vestibular response, variable onset of retinitis pigmentosa Usher syndrome Type Locus name gene USH1A unknown USH1B MYO7A USH1C USH1C NZ_2012 I USH1D CDH23 USH1E unknown USH1F PCDH15 USH1G unknown USH2A USH2A II USH2B unknown USH2C unknown III USH3 USH3  Usher syndrome MYO7A: encodes for myosin 7A, molecular motor for hair cells USH1C: encodes for harmonin, bundling protein in stereocilia NZ_2012 CDH23: encodes cadherin 23, A: An electron microscope scan of the actin bundle, made up of an adhesion molecule may organized stereocilia, projecting from a single hair cell. B: A diiagram of these structures showing a passive mode (gray, be important for crosslinking background) and an active mode (green, foreground), in which the of stereocilia, also may be stereocilia bend in unison in response to an incoming sound wave. C. A diagram showing a magnified view of the tips of two individual involved in maintaining the stereocilia (green) tethered together by the Usher protein, Cadherin ionic composition of the 23. endolymph Myosin 7A, harmonin, and cadherin 23 form a transient functional complex in stereocilia Pendred Syndrome Most common form of syndromal deafness; 4 - 10% Sensorineural hearing loss Bilateral, severe to profound, and sloping in the higher frequencies NZ_2012 Incomplete partition of the cochlear Vestibular dysfunction: Enlargement of the vestibular aqueducts, the endolymphatic sac and duct Thyroid goiter: Usually euthyroid, can be hypothyroid Defective organic binding of iodine Positive potassium perchlorate discharge test  Pendred syndrome NZ_2012 Otologic features of Pendred syndrome in patient. (A) Enlarged vestibular aqueduct of patient compared with normal individual (white arrows). (B) Mondini defect: absence of middle turn of the cochlea and smaller cochlea in our patient compared with normal individual (narrow white arrow – apical turn, wide white arrow – middle turn, black arrow – basal turn of the cochlea). Pendred syndrome PDS gene mutations: On chromosome 7q31 Encodes pendrin: an anion transporter in inner ear, thyroid, kidney NZ_2012 PDS knockout mouse: Complete deaf Endolymph-containing spaces enlargement Inner and outer hair cell degeneration No thyroid abnormality Jervell and Lange-Nielsen syndrome 0.25% of profound congenital hearing loss Prolonged QT interval, sudden syncopal attacks Long QT syndrome = delayed repolarization of the heart following a heartbeat; increased risk of episodes of torsade de pointes (irregular NZ_2012 heartbeat that originates from the ventricles). These episodes may lead to palpitations, fainting and sudden death due to ventricular fibrillation. Severe to profound sensorineural hearing loss 2 genes identified: KVLQT1: expressed in the stria vascularis of mouse inner ear KCNE1 Both gene products form subunits of a potassium channel involved in endolymph homeostasis  NZ_2012 X-LINKED SYNDROMIC HEARING IMPAIRMENT Alport syndrome At least 1% of congenital hearing loss X-linked inheritance (85%), autosomal recessive as well as dominant Sensorineural hearing loss: mostly affect high tone NZ_2012 Renal dysfunction Microscopic hematuria Men are more severely affected than woman Onset in early childhood and progress to renal failure in adulthood Increased risk of developing anti- glomerular basement membrane (anti- GBM) nephritis after renal transplantation Alport syndrome Ocular abnormalities Lentiglobus Retina flecks Defective collagen type 4 causes abnormalities in the NZ_2012 basement membrane 3 genes: COL4A5, COL4A3, COL4A4 These collagens found in the basilar membrane, parts of the spiral ligament, and stria vascularis Exact mechanism of hearing loss is unknown Alport syndrome NZ_2012 Norrie syndrome Ocular symptoms with congenital blindness: pseudotumor of the retina, retinal hyperplasia, hypoplasia and necrosis of NZ_2012 the inner layer of the retina, cataracts, phthisis bulbi Progressive sensorineural hearing loss Leukocoria Mental deficiency Norrin gene: encodes a protein related to mucins  NZ_2012 NON-SYNDROMIC HEARING IMPAIRMENT Non-syndromic deafness Up to 80% of hereditary hearing loss Autosomal dominant (23%): 41 loci (DFNA) and 20 genes identified Usually postlingual onset, progressive Severity from moderate to severe NZ_2012 Majority of the hearing loss in middle, high or all frequencies Autosomal recessive (75-80%): 33 loci (DFNB) and 21 genes identified Usually prelingual onset, non-progressive Severity from severe to profound All frequencies affected Mutations in GJB2 account for the majority of recessive forms of prelingual hearing loss Non-syndromic deafness X-linked (2-3%): 4 loci (DFN) and 1 gene identified Either high or all frequencies affected NZ_2012 Non-syndromic deafness Identified genes encode: Unconventional myosin and cytoskeleton proteins Extracellular matrix proteins Channel and gap junction components NZ_2012 Transcription factors Proteins with unknown functions More than one gene found in the same loci (DFNA2 and DFNA3) Some genes cause autosomal dominant and autosomal recessive hearing loss Some genes cause non-syndromic and syndromic hearing loss GJB2 (Gap Junction Beta 2) The first non-syndromic sensorineural deafness gene to be discovered The only gene causing non-syndromic deafness that can be routinely tested for On chromosome 13q11 50% of recessive non-syndromic hearing loss NZ_2012 Encodes connexin 26 Expressed in stria vascularis, basement membrane, limbus, spiral prominence of cochlea Recycling of potassium back to the endolymph after stimulation of the sensory hair cell 80 recessive and 6 dominant mutations 35delG mutation One guanosine residue deletion from nucleotide position 35 Results in protein truncation High prevalence in Caucasian population Screening test available Mitochondrial disorders 2-10 mitochondrial chromosomes in each mitochondrion Transmitted only through mothers With syndromic hearing loss Associated with systemic neuromuscular syndromes: such as Kearns-Sayre NZ_2012 syndrome, MELAS, MERRF MELAS: mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes MERRF: mitochondrial encephalomyopathy with ragged red fibers Also in families with diabetes and sensorineural hearing loss Associated with skin condition: palmoplantar keratoderma With aminoglycoside ototoxic hearing loss A1555G mutation in the 12S ribosomal RNA gene Maternally transmitted predisposition to aminoglycoside ototoxicity Accounts for 15% of all aminoglycoside induced deafness NZ_2012