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 deaf1 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 lossapproximately 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 Type

Gene Protein/function

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 EDN3EDNRBSOX10

endothelin ligandendothelin receptortranscription factor

Abnormal pigmentation of hair, eyes and skin with Hirschprung disease

      

EDN3 EDNRB3

WS 1WS 3

PAX 3 SOX 10 WS 4

transactivation

WS 2 MITF

melanocyte tyrosinase

transactivation

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 anomaliesGene EYA1 on 8q13.3; encoded molecule – transcription factor. Inheritance autosomal dominant. Genetically heterogenous (second BOR locus on 1p31)

Treacher-Collins syndromeHearing loss conductive, sensorineural or

mixed;Clinical features: down-slanting palpebralfissures, malformation of external and middleears, sparse lower eyelashes and colobomata

oflower eyelids, malar hypoplasia.Gene TCOF; encoded nuclear cytoplasmic transport proteinInheritance 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 lociClinically 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 syndromesUsher 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 malformationInheritance autosomal recessiveMutation of SLC26A4 gene encoding pendrin – proteinprimarily involved in transport of chloride and iodideions. 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

Chromosomal location

Locus/mutation

Gene symbol

Inheritance Protein Function

13q11-12 DFNB1/DFNA3

GJB2 AR/AD Conexin 26

Gap junction

GJB6 AR/AD Conexin 30

Gap junction

7q31 DFNB4 SLC26A4

AR pendrin Anion transporter

14q12-13 DFNA9 COCH AD cochlin Extracellular matrix protein

mitochondrium

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.