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 TypeGeneProtein/funct ion Clinical features WS1 PAX3transcription factor Abnormal pigmentation of hair, eyes and skin. Dystopia canthorum, short philtrum, synophrys. Deafness in 20% (unilateral or bilateral) WS2 MITFtranscription factor Abnormal pigmentation of hair, eyes and skin. Deafness in 40% (unilateral or bilateral). No dysmorphic features WS3 PAX3transcription 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

EDN3EDNRB3 WS 1 WS 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 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: TYPEHEARING LOSSVESTIBULAR RESPONSE ONSET OF REINITIS PIGM. IProfound from birthAbsent1st decade IIModerate from birthNormal1st or 2nd decade IIIProgressiveVariable

Usher syndrome TypeLocusGeneProtein USH1A14q32-- USH1B11q13.5MYO7Amyozyn VIIA USH1C11p15.1USH1Charmonin USH1D10q21CDH23cadherina 23 USH1E21q21-- USH1F10q21-22PCDH15protocadherin15 USH1G17q24-25USH1GSANS USH2A1q41USH2Ausherin USH2B3p USH2C5q USH3A3q21-25USH3Aclarin 1

Usher syndromes Usher syndrome type GeneMolecule encoded/function clinical features 1BMYO7Amyosin 7A (motor molecule) profound congenital deafness, retinitis pigmentosa, vestibular areflexia 1CUSH1Charmonin - " - - " - 1DCDH23cadherin 23progfound congenital deafness, variable retinitis pogmentosa and variable vestibular function 1FPCDH15protocadherin 15profound congenital deafness, retinitis pigmentosa, vestibular dysfunction 2AUSH2Ausherin (extracellular matrix protein) congenital moderate to severe sensorineural hearing loss (normal vestibular function) retinitis pigmentosa 3AUSH3Aclarin 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 Chromosomal location Locus /mutation Gene symbol InheritanceProteinFunction 13q11-12DFNB1/DFNA 3 GJB 2 AR/ADConexin 26Gap junction GJB 6 AR/ADConexin 30Gap junction 7q31DFNB 4 SLC26A4ARpendrinAnion transporter 14q12-13DFNA9COCHADcochlinExtracellular matrix protein mitochondriu m 1555A>GMTRNR1Mitoch.12SrRNA 7445A>GMTTs1tRNA serine 7472insC 7511T>C Xq21.1DFN3POU3F4XLdomain class 3 Pou Transcription factor 4p16.1DFNA6/14/38WFS1ADwolframinER 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.