genetics of hearing loss dr nayyar
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By:- Dr. Supreet Singh Nayyar, AFMC
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Genetics of hearing loss
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Overview
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Introduction
Types of genetic hearing impairment
Common types of syndromic deafness
Common types of non-syndromic deafness Genetic evaluation
Genetic counseling
Recent advances in genetic treatment
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Introduction
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Gregor Mendel - father of modern genetics
Human genome project
Otolaryngologist role in genetic hearing loss
Hearing impairment possibilities
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HEARING LOSS
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Syndromic Deafness
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Over 400 syndromes
Two syndromes by different mutations of same
gene
Mutations of more than one gene can cause thesame clinical phenotype
Mode of inheritance
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Autosomal Dominant Syndromic
Hearing Impairment
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Waardenburg Syndrome
Branchio-oto-renal Syndrome
Stickler Syndrome
Neurofibromatosis II
Treacher Collins Syndrome
Goldenhar Syndrome
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Waardenburg Syndrome
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Petrus J. Waardenburg - 1951
Aggregate prevalence 1:10,000 to 20,000
Usually autosomal dominant
Sensorineural hearing loss Pigmentary abnormalities
Hair
Iris Skin
4 clinical subtypes
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Waardenburg Syndrome
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Type 1: With dystopia canthorum
Penetrance 36% to 58%
PAX3
Type 2:
Like type 1 but without dystopia canthorum Hearing loss penetrance as high as 87%
MITF
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Waardenburg Syndrome
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Type 3 (Klein-Waardenburg syndrome): Type 1 clinical features + hypoplastic muscles
and contractures of the upper limbs
PAX3
Type 4 ( Shah-Waardenburg syndrome): Type 2 clinical features + Hirschsprungs
disease EDN3 , EDNRB , SOX10
Autosomal recessive
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Branchio-oto-renal syndrome
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Melnick - 1975
Penetrance is nearly 100%
Prevalence 1 in 40, 000
2% of profoundly deaf children
EYA1 , 1q31
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Branchio-oto-renal Syndrome
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Otologic findings
External ear
Middle ear
Inner ear
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Branchio-oto-renal Syndrome
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PTA
Branchial anomalies
Renal anomalies
Less common phenotypic anomalies
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Major and Minor Diagnostic Criteria for Branchiootorenal Syndrome
Major Criteria Minor Criteria
Second branchial arch anomalies External auditory canal anomalies
Deafness Middle ear anomaliesPreauricular pits Inner ear anomalies
Auricular deformity Preauricular tags
Renal anomaliesOther: facial asymmetry, palate
abnormalities
Chang EH, Menezes M, Meyer NC, Cucci RA, Vervoort VS, Schwartz CE, Smith RJ. Branchio-oto-renal
syndrome: the mutation spectrum in EYA1 and its phenotypic consequences. Hum Mutat2004;23:582-9
Branchio-oto-renal syndrome
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Stickler Syndrome
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Dr. Gunner Stickler - 1965
Prevalence 1:10,000
Mutations - type II and type XI collagen
Snead and Yates criteria (1) Congenital vitreous anomaly (2) Any three of
Sensorineural hearing loss Myopia with onset before age 6 years Midline clefting Joint hypermobility with abnormal beighton score Rhegmatogenous retinal detachment
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Stickler Syndrome
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SS type I COL2A1
Classical ocular findings with a "membranous" vitreous
Normal hearing or only a mild impairment
SS type II
COL11A2
Minimal ocular abnormalities
Mild to moderate hearing loss
SS type III
COL11A1
Vitreous - irregularly thickened fiber
Moderate-to-severe hearing loss
Hearing loss Conductive- eustachian tube dysfunction that commonly occurs
with palatal clefts
Sensorineural Alterations in the pigmented epithelium of the inner ear
Abnormalities of inner ear collagen
Mixed
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Neurofibromatosis II
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Hallmark hearing loss secondary to bilateralvestibular schwannomas
Incidence 1:40,000 to 1:90,000
Hearing loss usually begins in the third decade
Generally unilateral and gradual
Risk of other tumors including meningiomas,astrocytomas, ependymomas, and
meningioangiomatosis
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Neurofibromatosis II
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Diagnostic criteria
Bilateral CN VIII schwannomas on MRI or CT scan (no biopsynecessary) (age
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Treacher Collins Syndrome
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Incidence - 1/50,000 live births
Gene TCOF
Clinical features
Maldevelopment of the maxilla and mandible Downward slanting palpebral fissures
(anti mongoloid fissure)
Lower lid colobomas
Choanal atresia
Cleft palate
Conductive hearing loss Ossicular fixation
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Goldenhar syndrome
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Maurice Goldenhar 1952 OAV - Gorlin 1990
Incidence 1/3500 to 1/26000
Etiology
Possible vascular insult to 1st and 2nd branchial arches Mostly sporadic & multifactorial
AD and AR variants reported
Incomplete development Ear Nose Soft palate,lip, and mandible
Usually one side of the body
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Goldenhar syndrome
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Clinical features Epibulbar dermoids
Upper eyelid colobomas
Mandibular hypoplasia
Microtia, preauricular appendages FN involvementfacial muscle hypoplasia
Hemifacial microsomia 90% unilateral
Lateral facial clefts/Macrosomia
Hemi vertebrae anomalies
Cardiac, renal, pulmonary, CNS, skeletal
OMENS ocular, mandibular, ear, FN, soft tissue
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Autosomal Recessive Syndromic
Hearing Impairment
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Usher Syndrome
Pendred Syndrome
Jervell and Lange-Nielsen Syndrome
Biotinidase Deficiency
Refsum Disease
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Usher Syndrome
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Prevalence 4.4 per 100,000
3% to 6% of congenitally deaf persons
Cause of 50% of deaf-blindness
Characterized by Sensorineural hearing loss
Retinitis pigmentosa
Vestibular dysfunction
11 loci and 6 genes have been identified
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Usher Syndrome
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Type 1 Type 2 Type 3Hearing loss Profound since
birth
Moderate-to-
severe ,
sloping curve
Progressive
Vestibularresponse
Absent Normal Variable
Onset ofretinitispigmentosa
First decade of
life
First or second
decade of life
Variable onset
Timing of cochlear implantation in Usher Syndrome
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Pendred Syndrome
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Vaughan Pendred - 1896
Prevalence 7.5 to 10 per 100,000
SLC26A4, encodes pendrin
Functions as a chloride/iodide transporter
Expressed in inner ear, thyroid, and kidney
Hearing loss
SNHL
Prelingual
Bilateral
Profound
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Pendred Syndrome
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Mondini dysplasia
Enlargement of Vestibular aqueducts
Endolymphatic sac
NormalDilated
endolymphatic sac
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Pendred Syndrome
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Thyroid goiter
Second decade
Euthyroid
Perchlorate discharge test >10% radioactivity +ve test
Sensitivity low
Genetic testing
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Jervell and Lange-Nielsen Syndrome
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Jervell and Lange-Nielsen - 1957 Prevalence 0.21%
Syndrome characterized by Congenital deafness
Prolonged QT interval Syncopal attacks
KVLQT1 , KCNE1
Encode for K+ channel expressed in the heart and
inner ear Hearing impairment
Due to changes in endolymph homeostasis
Congenital, bilateral, and severe to profound
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Biotinidase Deficiency
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Leads to deficiency in biotin Neurologic features
Seizures, hypertonia
Developmental delay,ataxia
Visual problems and conjunctivitis
Mild to moderate SNHL
Cutaneous features
Alopecia Skin rash
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Biotinidase Deficiency
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With biotin treatment Neurologic and cutaneous manifestations resolve
Hearing loss and optic atrophy usually irreversible
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Refsum Disease
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Refsum 1946
Faulty phytanic acid metabolism
Phytanoyl-CoA hydroxylase
Clinical features Severe progressive SNHL
Scaly skin (icthyosis)
Neurologic damage, cerebellar ataxia
Peripheral neuropathy
Night blindness
Cataracts
Retinitis pigmentosa
Diagnosis High serum concentration of phytanic acid
Treatment Dietary modification
Plasmapharesis
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X-Linked Syndromic Hearing
Impairment
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Alport Syndrome Mohr-Tranebjaerg Syndrome
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Alport Syndrome
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Progressive sensorineural hearingloss of varying severity
Progressive glomerulonephritisleading to end-stage renal disease
Variable ophthalmologic findings(e.g. anterior lenticonus)
Autosomal dominant,autosomal recessive and x-linked
X-linked 85%
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Alport Syndrome
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COL4A5, COL4A3, COL4A4
Type IV collagen
Found in Basilar membrane
Parts of the spiral ligament
Stria vascularis
Loss of integrity due to defective collagen
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Mohr-Tranebjaerg Syndrome
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Deafness-dystonia-optic atrophy syndrome
Progressive, post-lingual SNHL
Other findings
Visual disability
Dystonia
Multiple fractures
Mental retardation
TIMM8A
Involved in translocation of proteins across inner mitochondrial
membrane
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Mitochondrial Syndromic Hearing
Impairment
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2-10 mitochondrial chromosomes in each mitochondrion
Transmitted only through mothers
Affect tissues with high energy demands
Syndromic mitochondrial diseases MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke
like episodes) syndrome
MERRF (myoclonic epilepsy and red ragged fibers) syndrome
Kearns-Sayre syndrome (KS)
Maternally inherited diabetes and deafness
0.5% to 2.8% of diabetic patients
Hearing loss occurs late and is progressive, bilateral, and high frequency;
Presence is correlated with the level of heteroplasmy for 3243 a-to-g mt dna
mutation
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But are all children actually gifted totaste this food of love !!
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If music be the food of love,Play on, give me excess of it
William
Shakespeare
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Non-syndromic deafness (NSHL)
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70-80% of hereditary hearing loss Specific nomenclature
Different gene loci - DFN
Autosomal dominant - DFNA
Autosomal recessive - DFNB
X-linked - DFN
Number following these reflects order of gene
mapping and/or discovery
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Non-syndromic deafness
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Autosomal dominant Autosomal recessive
Percentage 15% 80%
Loci identified 41 loci (DFNA) 39 loci (DFNB)
Genes identified 20 genes 21 genes
Hearing loss onset Postlingual Prelingual
Progression ProgressiveNon-
progressive
SeverityModerate tosevere SNHL
Severe to
profound
FrequenciesMiddle & high
frequenciesAll frequencies
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Autosomal Recessive
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DFNB1 locus on chromosome 13q11
50% of AR NSHL
connexin26 (Cx26, gene symbol GJB2)
connexin30 (Cx30, GJB6).
Extensive genotype-phenotype studies
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Connexin 26
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Vertebrate gap junction proteins
connexin
connexon
gapjunction
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Connexin 26 Inner ear
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Supporting cells, stria vascularis,
basement membrane, limbus, and
spiral prominence of the cochlea
Mechanosensory transduction
Passage of K+
Recycling of K+ ions
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Connexin 26
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More than 90 mutations described Specific ethnic groups
35delG ,167delT, 235delC , W24X
Moderate-to-profound deafness Symmetric
Non-progressive
Genetic testing importance
Prognostic information - cochlear implant
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X-linked
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2-3% of Non syndromic hearing loss
5 loci (DFN) and 2 genes identified
Either high or all frequencies affected
X Li k d C it l St Fi ti
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X-Linked Congenital Stapes Fixation
with Perilymph Gusher
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DFN3 - POU3F4
Progressive mixed hearing loss
Reduced vestibular responses
Radiologic findings
Widening of the lateral IAM
Dilation of the vestibule
Widening of labyrinthine portion
of FN
Large cochlea
Thin separation b/w IAM &
vestibule
Stapedectomy - perilymph
Mit h d i l N S d i
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Mitochondrial Non Syndromic
Hearing Impairment
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Familial Progressive Sensorineural Deafness
Susceptibility to aminoglycoside ototoxicity
1555 A-to-G mutation
Changes the 12S ribosomal RNA gene
Altering its structure to make it more similar to bacterial rRNA Hearing loss even at normal doses
Can even be seen months after aminoglycoside exposure
Outer hair cells in the basal turn of the cochlea are affected first
Damage eventually extends to include apical outer hair cells and inner hair cells
Presbycusis and genes !!
Mit h d i l S d i H i
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Mitochondrial Syndromic Hearing
Impairment
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Molecular Genetic Testing
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GJB2, GJB6
SLC26A4(Pendred syndrome)
EYA1 (BOR syndrome)
Issues
Large size of many (MYO7A, MYO15)
Low relative contribution to deafness (DFNB9, HDIA1,
TECTA, COCH, POU4F3)
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Genetic Counseling
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Goal: Cause of deafness Other medical implication Chance of recurrence in future children Implications for other family membersAssist family in making choices that are appropriate
for them
Team approach including clinical/medical
geneticist, genetic counselor, social worker,psychologist
R t Ad i G ti
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Recent Advances in Genetic
Manipulation
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Therapeutic insertion of genetic material intoinner ear
Hope
Prevent, arrest, reverse or cure
Number of vectors studied in vivo
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Cochlear gene therapy
Adenoid associated
virus as vector
Routes of delivery Safety concern
Hearing loss
Regional and distal
dissemination
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Stem cell & Gene therapy
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Potential of twin technologies of stem cell andgene therapy.
Hair cells of cochlea very vulnerable
Once dead not naturally replaced
Trigger regeneration of cochlear hair cells
Combined dual treatment of stem cell insertion
and gene transfer
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Drug Therapy
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To exploit alternative pathways to carry out the taskthat is affected by mutation
E.g. connexin 26 mutation
Another connexin may be capable of substituting ingap junction, but its gene may not normally beexpressed in the cochlea
A drug might therefore be developed to activateexpression of the alternative connexin gene in cellsneeding to form gap junction
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Conclusion
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Know the roots
May be the future
Researches required
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References
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Scott Bown 7th
Edition Cummings 4th Edition
Article Genetics of Hearing Loss by Dr Michelle Vas, MD
(Paed), PGDDN from Hearsay July 2009
Hereditary hearing loss homepage -
http://hereditaryhearingloss.org
Connexin deafness homepage - http://davinci.crg.es/deafness/
Familial Progressive Sensorineural Deafness Is Mainly Due to
the mtDNA A1555G Mutation and Is Enhanced by Treatment with
Aminoglycosides byXavier Estivill et al
GJB2 Gene Mutations in Cochlear Implant Recipients -
Prevalence and Impact on Outcome Lawrence et al. ,ARCHOTOLARYNGOL HEAD NECK SURG/VOL 130, MAY 2004
Various Journal Articles from internet
http://hereditaryhearingloss.org/http://davinci.crg.es/deafness/http://davinci.crg.es/deafness/http://hereditaryhearingloss.org/ -
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