International Conference

Diagnosis & Treatment of Inner Ear

Disorders

Genetics of deafness

Lech Korniszewski

The Medical University of Warsaw

Institute of Physiology and Pathology of

Hearing

Hearing loss – incidence:

6-8% of population – when all

causes are combined hearing

loss – most common birth defect

1 in 1000 newborns are deaf
1 in 300 children are affected with

congenital hearing loss of a lesser

degree additional 1 in 1000 become

profoundly hearing impaired before

adulthood

Genetic hearing loss

approximately 1% of all human genes are

involved in the hearing process

inheritance: autosomal recessive
autosomal dominant
X-linked
mitochondrial



allelic mutatione in some genes can cause recessive

and dominant hearing loss



mutations in the same gene may cause syndromic or

nonsyndromic hearing loss



recessive hearing loss may be caused by a combination

of two mutations in differrent genes from the same

functional group

Syndromic hearing loss

Over 400 syndromes have been described

in which hearing loss is a component part.

There are many factors that make specific

syndrome diagnosis difficult:

*

The rarity of most of these syndromes (lack

personal experience)

*

Variability of clinical expression

*

Genetic heterogeneity (a single phenotype may

be result of different genes mutations)

*

Pleiotropy (single gene may cause many

different phenotypic effects)

Waardenburg syndromes

–

Bilateral or unilateral sensorineural

hearing loss in association with defects in
tissues derived from neural crest cells

–

pigmentary abnormalities hair, skin and

eyes

–

hearing loss is due to defective migration of

melanocytes info the intermediate layer of

the stria vascularis

–

genetically heterogeneous; inheritance AD

–

four clinical subtypes

Waardenburg syndromes

Typ
e

Gene

Protein/func
tion

Clinical features

WS1

PAX3

transcription

factor

Abnormal pigmentation of hair,

eyes and skin. Dystopia

canthorum, short philtrum,

synophrys. Deafness in 20%

(unilateral or bilateral)

WS2

MITF

transcription

factor

Abnormal pigmentation of hair,

eyes and skin. Deafness in 40%

(unilateral or bilateral). No

dysmorphic features

WS3

PAX3

transcription

factor

Features of WS1 with limb

anomalies

WS4

EDN3
EDNRB
SOX10

endothelin ligand
endothelin

receptor
transcription

factor

Abnormal pigmentation of hair,

eyes and skin with Hirschprung

disease

EDN

3

EDNRB

3

WS
1
WS
3

PAX

3

SOX

10

WS 4

transactivat

ion

WS 2

MITF

melanocyte

tyrosinase

transactivatio

n

Transcription factor hierarchy in Waardenburg syndrome:

regulation of MITF expression by SOX10 and PAX3

 

 

Branchio-oto-renal

syndrome

Hearing loss conductive, sensorineural or

mixed;
Branchial cysts and fistulae, external ear

malformations, renal dysplasia or

hypoplasia. Some patients also eye

anomalies
Gene EYA1 on 8q13.3; encoded molecule –

transcription factor.
Inheritance autosomal dominant. Genetically

heterogenous (second BOR locus on 1p31)

Treacher-Collins syndrome

Hearing loss conductive, sensorineural or

mixed;

Clinical features: down-slanting palpebral
fissures, malformation of external and middle
ears, sparse lower eyelashes and colobomata of
lower eyelids, malar hypoplasia.
Gene TCOF; encoded nuclear cytoplasmic
transport protein
Inheritance autosomal dominant

Usher syndromes

*

Syndromic association of hearing loss with retinitis
pigmentosa

*

Accounts 2-4% of all cases of profound deafness and
50% of the deaf-blind population

*

Inheritance autosomal recessive.

Genetic heterogeneity high – more than 12 loci
Clinically three main types:

TYPE

HEARING LOSS

VESTIBULAR

RESPONSE

ONSET OF

REINITIS PIGM.

I

Profound from

birth

Absent

1st decade

II

Moderate from

birth

Normal

1st or 2nd decade

III

Progressive

Variable

Variable

Usher syndrome

Type

Locus

Gene

Protein

USH1A

14q32

-

-

USH1B

11q13.5

MYO7A

myozyn VIIA

USH1C

11p15.1

USH1C

harmonin

USH1D

10q21

CDH23

cadherina 23

USH1E

21q21

-

-

USH1F

10q21-22

PCDH15

protocadherin15

USH1G

17q24-25

USH1G

SANS

USH2A

1q41

USH2A

usherin

USH2B

3p23-24.2

-

-

USH2C

5q14.3-21.3

-

-

USH3A

3q21-25

USH3A

clarin 1

Usher syndromes

Usher
syndrome
type

Gene

Molecule
encoded/function

clinical features

1B

MYO7A

myosin 7A (motor
molecule)

profound congenital deafness,
retinitis pigmentosa, vestibular
areflexia

1C

USH1C

harmonin

- " - - " -

1D

CDH23

cadherin 23

progfound congenital deafness,
variable retinitis pogmentosa and
variable vestibular function

1F

PCDH15

protocadherin 15

profound congenital deafness,
retinitis pigmentosa, vestibular
dysfunction

2A

USH2A

usherin (extracellular
matrix protein)

congenital moderate to severe
sensorineural hearing loss (normal
vestibular function) retinitis
pigmentosa

3A

USH3A

clarin 1 (trans-
membrane protein)

Progressive sensorineural hearing
loss, normal or absent vestibular
function, retinitis pigmentosa

Nonsyndromic deafness: DFNA11 (dominant) and DFNB2 (recessive) results
from other alleles of MYO7A; DFNB18 results from different harmonin mutation.

Pendred syndrome

Sensorineural deafness, goiter and malformation of the

inner ear



Hearing loss is most frequently profound, variable in its

onset, rapidly progressive



Goiter results from a specific defect in the organification

of iodine (abnormal release of iodine trapped by thyroid

after administration of perchlorate)



Malformation of the inner ear in 86% of cases:

dilatation of the vestibular aqueduct and endolymphatic

sacs, Mondini malformation

Inheritance autosomal recessive
Mutation of SLC26A4 gene encoding pendrin – protein
primarily involved in transport of chloride and iodide
ions.
Nonsyndromic deafness DFNB4 also result from
mutation in the SLC26A4 gene.

Jervell and Lange-Nielsen

syndrome

*

Congenital sensorineural hearing loss and

prolongation of the QT interval on

electrocardiogram

*

Hearing loss initially involves the high frequencies

and progress to become a profound

*

Prolongation of QT reflect a defect in cardiac

repolarization. This can lead to recurrent attacks of

syncope, ventricular arrhythmia and possible

sudden death.

*

Mutation in genes KCNQ4, KCNE1 coding potassium

chanels (K

+

active transport in outer hair cells)

*

Inheritance autosomal recessive

Alport syndrome



Association of sensorineural high frequency
hearing loss with progressive nephritis. Anterior
lenticonus, macular flecks, cataracts



Gene mutation: COL4A5, COL4A3, COL4A4 coding
tissue specific polypeptide subunits of collagen



The subunits are expressed in the basilar
membrane, spiral ligament and basement
membranes of the stria vascularis



Genetically heterogeneous. Inheritance X-linked
dominant and autosomal recessive

Stickler syndrome

–

sensorineural hearing loss, high

frequency, progressive

–

Myopia, retinal detachment

–

Arthropathy

–

Mid-face hypoplasia, cleft palate,

micrognathia

–

Gene defect: COL2A1, COL11A1,

COL11A2

–

Inheritance autosomal dominant

Most important genes involved in non-syndromic hearing

loss

Chromosom
al location

Locus
/mutation

Gene
symbol

Inheritance Protein

Function

13q11-12

DFNB1/DFNA
3

GJB

2

AR/AD

Conexin
26

Gap junction

GJB

6

AR/AD

Conexin
30

Gap junction

7q31

DFNB

4

SLC26A
4

AR

pendrin

Anion transporter

14q12-13

DFNA9

COCH

AD

cochlin

Extracellular
matrix protein

mitochondri
um

1555A>G

MTRNR1 Mitoch.

12SrRNA

7445A>G

MTTs1

tRNA serine

7472insC

7511T>C

Xq21.1

DFN3

POU3F4

XL

domain
class 3
Pou

Transcription
factor

4p16.1

DFNA6/14/38 WFS1

AD

wolframin

ER transmembrane
protein

Hearing loss caused by mutation

in GJB2

(connexin deafness)

–

most common cause of hearing loss in many populations

–

deafness usually stable, onset is nearly always prelingual (but not

necessarily congenital); hearing may be normal at birth and

hearing loss progress rapidly during first few month of life (some

babies may pass neonatal hearing screening but become deaf

during infancy)

–

GJB2 encodes a gap junction protein – connexin 26

–

most common mutation is a deletion of single guanine – 35delG

(70% mutant alleles, carrier frequency 2-3%)

–

mutation 35delG in thought rather a founder effect not hot-spot

deletion

–

GJB2 mutations may also be a rare cause of autosomal dominant

deafness – syndromic and nonsyndromic (DFNA3).
Specific mutation:

- hyperkeratosis palmoplantaris

-

mutilating keratoderma – (Vohwinkel sy.)

- keratoderma – ichthyosis – deafness (KID sy.)

Screening GJB2 should be offering as part
of the routine work-up in the diagnosis of
all cases of non-syndromic deafness of
unknown cause.

Rationale: - common cause of hearing impairment

- phenotype unremarkable and variable
- small coding region
- common mutations in some populations
- enables accurate genetic information to

be given to families

disadvantages: counselling difficult with missense

and
heterozygous mutation

Mitochondrial hearing loss

–

Sensorineural hearing loss is present in 40-70% patients with

mitochondrial disorders and can be syndromic or non-syndromic.

–

Mitochondrial mutations are transmitted exclusively through the

maternal line and demonstrate complete (or nearly complete)

homoplasmy.

–

Up to 20% patients receiving aminoglycosides experience

hearing impairment. 50% of those carry the 12S ribosomal RNA

mutation 1555A>G.

–

Mitochondrial hearing loss may be syndromic: Kearns-Sayre sy.,

MELAS, maternally inherited diabetes and deafness, and others

–

Pathogenesis of mitochondrial hearing loss is based on high ATP

requirement in the cochlear hair cells. A reduction of available

ATP caused by dysfunction of the mitochondrial oxidative

phosphorylation results in disturbances of the ionic gradient in

the inner ear.