Genetics of Hearing Loss DR Nayyar

Genetics of hearing loss
By:- Dr. Supreet Singh Nayyar, AFMC For more presentations, visit www.nayyarENT.com
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7/22/2012
Overview
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
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
Over 400 syndromes
Two syndromes by different mutations of same
gene Mutations of more than one gene can cause the same clinical phenotype Mode of inheritance
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Autosomal Dominant Syndromic Hearing Impairment

Waardenburg Syndrome
Branchio-oto-renal Syndrome
Stickler Syndrome Neurofibromatosis II
Treacher Collins Syndrome

Goldenhar 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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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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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
Melnick - 1975
Penetrance is nearly 100%

Prevalence 1 in 40, 000
2% of profoundly deaf children

EYA1 , 1q31
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Otologic findings
External ear Middle ear Inner ear
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PTA Branchial anomalies
Renal anomalies
Less common phenotypic anomalies
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Branchio-oto-renal syndrome
Major and Minor Diagnostic Criteria for Branchiootorenal Syndrome
Major Criteria Second branchial arch anomalies Deafness Preauricular pits Auricular deformity Renal anomalies Minor Criteria External auditory canal anomalies Middle ear anomalies Inner ear anomalies Preauricular tags Other: 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 Mutat 2004;23:582-9
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Stickler Syndrome
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

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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
SS type I

COL2A1 Classical ocular findings with a "membranous" vitreous Normal hearing or only a mild impairment COL11A2 Minimal ocular abnormalities Mild to moderate hearing loss COL11A1 Vitreous - irregularly thickened fiber Moderate-to-severe hearing loss
SS type II

SS type III

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
Neurofibromatosis II
Hallmark hearing loss secondary to bilateral
vestibular 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,
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astrocytomas, ependymomas, and www.nayyarENT.com meningioangiomatosis
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Neurofibromatosis II
Diagnostic criteria Bilateral CN VIII schwannomas on MRI or CT scan (no biopsy necessary) (age <20y) First-degree relative with NF2 and either unilateral early-onset CN VIII schwannoma (age <30 y) or any 2 of the following:
Meningioma
Glioma Schwannoma Juvenile posterior subcapsular lenticular opacity
Molecular genetic testing of the NF2 gene is available
Causative gene merlin on chromosome 22q12

Hearing loss is usually high frequency and sensorineural Vertigo, tinnitus, and facial nerve paralysis may be
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associated findings www.nayyarENT.com
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Treacher Collins Syndrome

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
Goldenhar syndrome

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
Goldenhar syndrome
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
Autosomal Recessive Syndromic Hearing Impairment

Usher Syndrome Pendred Syndrome Jervell and Lange-Nielsen Syndrome Biotinidase Deficiency Refsum Disease
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Usher Syndrome
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
Type 1
Hearing loss Profound since birth Absent First decade of life
Type 2
Moderate-tosevere , sloping curve Normal First or second decade of life
Type 3
Progressive
Vestibular response Onset of retinitis pigmentosa
Variable Variable onset
Timing of cochlear implantation in Usher Syndrome

Pendred Syndrome
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
Pendred Syndrome
Mondini dysplasia
Enlargement of
Vestibular aqueducts Endolymphatic sac
Normal
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Dilated endolymphatic sac

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Pendred Syndrome
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

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
Biotinidase Deficiency
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
With biotin treatment
Neurologic and cutaneous manifestations resolve Hearing loss and optic atrophy usually irreversible
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Refsum Disease

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

Alport Syndrome
Mohr-Tranebjaerg Syndrome
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Alport Syndrome
Progressive sensorineural hearing
loss of varying severity Progressive glomerulonephritis leading 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
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
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

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 www.nayyarENT.com mutation 7/22/2012
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If music be the food of love, Play on, give me excess of it

William Shakespeare
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But are all children actually gifted to taste this food of love !!
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Non-syndromic deafness (NSHL)

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
Autosomal dominant Percentage Loci identified Genes identified Hearing loss onset Progression Severity Frequencies
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Autosomal recessive 80% 39 loci (DFNB) 21 genes Prelingual Nonprogressive Severe to profound All frequencies
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15% 41 loci (DFNA) 20 genes Postlingual Progressive Moderate to severe SNHL Middle & high frequencies
Autosomal Recessive
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
Vertebrate gap junction proteins
connexin
connexon
gap junction
Connexin 26 Inner ear

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
Mutations in the GJB2
Loss of function of the Cx26 protein
Recycling K+ interfered
Normal process of hearing hampered

Connexin 26
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
2-3% of Non syndromic hearing loss
5 loci (DFN) and 2 genes identified

Either high or all frequencies affected
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X-Linked Congenital Stapes Fixation with Perilymph Gusher

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
Mitochondrial Non Syndromic Hearing Impairment

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 !!
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Mitochondrial Syndromic Hearing Impairment
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Molecular Genetic Testing

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
Goal: Cause of deafness Other medical implication Chance of recurrence in future children Implications for other family members Assist family in making choices that are appropriate for them Team approach including clinical/medical
geneticist, genetic counselor, social worker, psychologist

Recent Advances in Genetic Manipulation

Therapeutic insertion of genetic material into
inner 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

Potential of twin technologies of stem cell and
gene 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
To exploit alternative pathways to carry out the task
that is affected by mutation

E.g. connexin 26 mutation Another connexin may be capable of substituting in
gap junction, but its gene may not normally be expressed in the cochlea
A drug might therefore be developed to activate
expression of the alternative connexin gene in cells needing to form gap junction
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Conclusion
Know the roots May be the future Researches required
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References
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 by Xavier Estivill et al
GJB2 Gene Mutations in Cochlear Implant Recipients -
Prevalence and Impact on Outcome Lawrence et al. ,ARCH

OTOLARYNGOL HEAD NECK SURG/VOL 130, MAY 2004
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Various Journal Articles from internet www.nayyarENT.com
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Thank You For more ENT PG presentations, visit www.nayyarENT.com
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Genetics of Hearing Loss DR Nayyar

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Genetics of hearing loss

Types of genetic hearing impairment

Hearing impairment possibilities

Two syndromes by different mutations of same

Autosomal Dominant Syndromic Hearing Impairment

Treacher Collins Syndrome

Usually autosomal dominant Sensorineural hearing loss

Pigmentary abnormalities Hair Iris Skin

Type 3 (Klein-Waardenburg syndrome):

Type 4 ( Shah-Waardenburg syndrome):

Penetrance is nearly 100%

2% of profoundly deaf children

Hearing loss Conductive- eustachian tube dysfunction that commonly occurs

with palatal clefts

astrocytomas, ependymomas, and www.nayyarENT.com meningioangiomatosis

Molecular genetic testing of the NF2 gene is available

Causative gene merlin on chromosome 22q12

associated findings www.nayyarENT.com

Treacher Collins Syndrome

Cardiac, renal, pulmonary, CNS, skeletal

Autosomal Recessive Syndromic Hearing Impairment

3% to 6% of congenitally deaf persons

11 loci and 6 genes have been identified

Vestibular response Onset of retinitis pigmentosa

Variable Variable onset

Timing of cochlear implantation in Usher Syndrome

Prevalence 7.5 to 10 per 100,000

Expressed in inner ear, thyroid, and kidney

Dilated endolymphatic sac

Jervell and Lange-Nielsen Syndrome

0.21% Syndrome characterized by

KVLQT1 , KCNE1 Encode for K+ channel expressed in the heart and

inner ear Hearing impairment

Visual problems and conjunctivitis Mild to moderate SNHL Cutaneous features

Refsum 1946 Faulty phytanic acid metabolism

High serum concentration of phytanic acid

Dietary modification Plasmapharesis

X-Linked Syndromic Hearing Impairment

autosomal recessive and x-linked X-linked 85%

Loss of integrity due to defective collagen

TIMM8A Involved in translocation of proteins across inner mitochondrial

Mitochondrial Syndromic Hearing Impairment

If music be the food of love, Play on, give me excess of it

Non-syndromic deafness (NSHL)

mapping and/or discovery

connexin30 (Cx30, GJB6).

Connexin 26 Inner ear

basement membrane, limbus, and spiral prominence of the cochlea

Loss of function of the Cx26 protein

Normal process of hearing hampered

Specific ethnic groups

5 loci (DFN) and 2 genes identified

X-Linked Congenital Stapes Fixation with Perilymph Gusher

Progressive mixed hearing loss

Mitochondrial Non Syndromic Hearing Impairment

Susceptibility to aminoglycoside ototoxicity

Presbycusis and genes !!

Mitochondrial Syndromic Hearing Impairment

Molecular Genetic Testing

SLC26A4 (Pendred syndrome)

TECTA, COCH, POU4F3)

geneticist, genetic counselor, social worker, psychologist

Recent Advances in Genetic Manipulation

Number of vectors studied in vivo

Cochlear gene therapy