Genetic Hearing Loss | PPT Download

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Genetic Hearing Loss | PPT Download

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Genetic Hearing Loss

Jing Shen M.D.

Ronald Deskin M.D.

UTMB Dept of Otolaryngology

March 2004


Hearing loss occurs in 1 out 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



Linkage mapping

Mouse model


Families too small for linkage analysis

Assortive mating introducing various genes into one single pedigree

Incomplete penetrance


Syndromic deafness

Has other abnormalities

About 20-30% of genetic hearing loss

Two syndromes can be caused by different mutations of the same gene

Mutations of more than one gene can cause the same clinical phenotype


Alport syndrome

At least 1% of congenital hearing loss

X-linked inheritance (80%), autosomal recessive as well as dominant

Sensorineural hearing loss: mostly affect high tone

Renal dysfunction

Microscopic hematuria

Man are more severely affected than woman

Onset in early childhood and progress to renal failure in adulthood

increased risk of developing anti-GBM nephritis after renal transplantation

Alport syndrome

Ocular abnormalities


Retina flecks

Defective collagen type 4 causes abnormalities in the 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

Branchio-oto-renal syndrome

2% of profoundly deaf children

Autosomal dominant disorder

Otologic anomalies:

variable hearing loss (sensorineural, conductive or mixed)

malformed pinna, preauricular pits

Branchial derived abnormalities: cyst, cleft, fistula

Renal malformation: renal dysplasia with anomalies of the collecting system, renal agenesis

Sometimes with lacrimal duct abnormalities: aplasia, stenosis

EYA1 gene mutation – knockout-mice showed no ears and kidneys because apoptotic regression of the organ primordia

Jervell and Lange-Nielsen syndrome

Autosomal recessive

0.25% of profound congenital hearing loss

Prolonged QT interval, sudden syncopal attacks

Severe to profound sensorineural hearing loss

2 genes identified:

KVLQT1: expressed in the stria vascularis of mouse inner ear


Both gene products form subunits of a potassium channel involved in endolymph homeostasis

Norrie syndrome

X-linked inheritance

Ocular symptoms with congenital blindness: pseudotumor of the retina, retinal hyperplasia, hypoplasia and necrosis of the inner layer of the retina, cataracts, phthisis bulbi

Progressive sensorineural hearing loss

Mental deficiency

Norrin gene: encodes a protein related to mucins

Pendred Syndrome

Most common form of syndromal deafness- 4-10 %

Autosomal recessive disorder

Sensorineural hearing loss

bilateral, severe to profound, and sloping in the higher frequencies

incomplete partition of the cochlear

Pendred syndrome

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

PDS gene mutations:

on chromosome 7q31

encodes pendrin: an anion transporter in inner ear, thyroid, kidney

PDS knockout mouse:

complete deaf

endolymph-containing spaces enlargement

inner and outer hair cell degeneration

no thyroid abnormality


Stickler syndrome

Autosomal dominant

Variable sensorineural hearing loss

Ocular symptoms: progressive myopia, resulting in retina detachment and blindness

Arthropathy: premature degenerative changes in various joints

Orofacial features: midface hypoplasia

Three genes: COL2A1, COL11A1, COL11A2

Associated with defective collagen protein

Each gene mutation corresponding to a phenotype

Treacher-collins syndrome

Autosomal dominant with variable expression

Conductive hearing loss

Craniofacial abnormalities:

Coloboma of the lower lids, micrognathia, microtia, hypoplasia of zygomatic arches, macrostomia, slanting of the lateral canthi

TCOF1 gene:

Involved in nucleolar-cytoplasmic transport

mutation results in premature termination of the protein product

Usher syndrome

Autosomal recessive disorder

Sensorineural hearing loss

Progressive loss of sight due to retinitis 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

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

MYO7A: encodes for myosin 7A, molecular motor for hair cells

USH1C: encodes for harmonin, bundling protein in stereocilia

CDH23: encodes cadherin 23, an adhesion molecule may be important for crosslinking of stereocilia, also may be involved in maintaining the ionic composition of the endolymph

Myosin 7A, harmonin, and cadherin 23 form a transient functional complex in stereocilia



Waardenburg syndrome

About 2% of congenital hearing loss

Usually autosomal dominant

Dystonia canthorum

Pigmentary abnormalities of hair, iris and skin

Sensorineural hearing loss

4 clinical subtypes

Waardenburg syndrome

Type 1:

With dystopia canthorum

Penetrance for hearing loss 36% to 58%

Wide confluent eyebrow, high broad nasal root, heterochromia irides, brilliant blue eyes, premature gray of hair, eyelashes, or eyebrows, white forelock, vestibular dysfunction

Type 2:

like type 1 but without dystopia canthorum

Hearing loss penetrance as high as 87%


Waardenburg syndrome

Type 3 (Klein-Waardenburg syndrome):

Type 1 clinical features + hypoplastic muscles and contractures of the upper limbs

Type 4 ( Shah-Waardenburg syndrome):

Type 2 clinical features + Hirschsprung’s disease

Five genes on five chromosomes have been identified

Waardenburg syndrome

Type 1 and type 3:

all associated with PAX3 gene mutation

Type 2:

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 4:

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


Non-syndromic deafness

About 70-80% of hereditary hearing loss

Autosomal dominant (15%):

41 loci (DFNA) and 20 genes identified

Usually postlingual onset, progressive

Severity from moderate to severe

Majority of the hearing loss in middle, high or all frequencies

Autosomal recessive (80%):

33 loci (DFNB) and 21 genes identified

Usually prelingual onset, non-progressive

Severity from severe to profound

All frequencies affected

X-linked (2-3%):

4 loci (DFN) and 1 gene identified

Either high or all frequencies affected

Non-syndromic deafness

Identified genes encode:

Unconventional myosin and cytoskeleton proteins

Extracellular matrix proteins

Channel and gap junction components

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

Ion homeostasis

Potassium recycling to maintain high potassium concentration in endolymph

KCNQ4: encodes a potassium channel

SLC26A4: encodes an anion transporter, pendrin

4 gap junction genes: GJB2, GJB3, DJB6, GJA1

Encode connexin proteins

Function of gap junctions: molecular pores connecting two adjacent cells allowing small molecules and metabolites exchange


GJB2 (Gap Junction Beta 2)

The first non-syndromic sensorineural deafness gene to be discovered

On chromosome 13q11

50% of recessive non-syndromic hearing loss

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

Transcription factors


X-linked mixed hearing loss

Stapes fixation causing conductive hearing loss

Increased perilymphatic pressure

Causing the typical “gusher” during stapes footplate surgery – stapes-gusher syndrome


Autosomal dominant hearing loss

Knockout mice fail to develop hair cells with subsequent loss of spiral and vestibular ganglia




Cytoskeleton proteins

Associated with actin-rich stereocilia of hair cells

Myosin: actin-dependent molecular motor proteins


MYO3A, MYO6, MYO7A, MYO15 – all have vestibular dysfunction

Otoferlin: calcium triggered synaptic vesicle trafficking


one particular mutation accounts for 4.4% of recessive prelingual hearing loss negative for GJB2  mutation

Actin-polymerization protein: HDIA1

Harmonin: organize multiprotein complexes in specific domains (tight junction, synaptic junction)

USH1C (also in Usher type 1c)

Cadherin:  important for stereocilia organization

CDH23 ( also in Usher type 1d)

Extracellular matrix components


Encodes alpha tectorin- component of the tectorial membrane

Knockout mice with detachment of tectorial membrane from the cochlear epithelium


Encodes collage type XI polypeptide subunit 2

Knockout mice with atypical and disorganized collagen fibrils of the tectorial membrane


Encodes COCH (coagulation factor C homologue) protein

Expressed in cochlear and vestibular organs

Associated with vestibular problems

Unknown function genes


Dominant sensorineural hearing loss

Responsible for 75% of low frequency nonsyndromic progressive hearing

Responsible for up to 90% of cases of Wolfram syndrome, a recessive disorder with diabetes mellitus, diabetes insipidus, optic atrophy, and deafness


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 syndrome, MELAS, MERRF

Also in families with diabetes and sensorineural hearing loss

Associated with skin condition: palmoplantar keratoderma

With non-syndromic hearing loss

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



Prenatal: infection, medication

Perinatal: risk factors

Postnatal: infection, speech and language milestones


hearing loss in first and second degree relatives

Hearing loss occurred before age 30

Consanguinity or common origin from ethnically isolated areas


Physical exam: features of syndromic hearing loss

Hair color: white forelock, premature graying

Facial shape

Skull shape

Eye: color, position, intercanthal distance, cataracts, retinal findings

Ear: preauricular pit, skin tags, shape and size of pinna, abnormality of EAC and TM

Oral cavity: cleft

Neck: brachial anomalies, thyroid enlargement

Skin: hyper/ hypopigmentation, café-au-lait spots

Digits: number, size, shape

Neurological exam: gait, balance


Audiologic evaluation

Lab testing: based on history and physical exam

Torch titers

CBC and electrolytes


thyroid function test (perchlorate discharge test)


Radiological study:

CT temporal bone is the test of choice

Dilated vestibular aqueduct (>1.5mm at middle third or >2mm anywhere along its length)

Mondini malformation

Semicircular canal absence or dysplasia

Internal auditory canal narrowing or dilation

Renal ultrasound

Genetic screening


most common cause of severe to profound nonsyndromic recessive deafness

High prevalence of 35delG mutation

Small size of GJB2 gene

SLC26A4- most common cause of Mondini dysplasia or dilated vestibular aqueduct syndrome

EYA1- 30-40% of families with a branchio-oto-renal phenotype


Genetic counseling


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, psychologists

Consent need to be obtained for genetic testing

Cochlear gene therapy

Adenoid associated virus as vector

Routes of delivery

Safety concern

Hearing loss

Regional and distal dissemination



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