Genetic Testing for Hearing Loss

Transcription

1 Genetic Testing for Hearing Loss S H O B A N A K U B E N D R A N, M B B S, M S, C G C G E N E T I C C O U N S E L O R A S S T P R O F E S S O R D E P T O F P E D I A T R I C S K U S M - W

2 Objectives Indications for a genetic evaluation for hearing loss Common genetic syndromes associated with hearing loss Benefits and limitations of genetic testing for hearing loss Genetic counseling for hearing loss

3 Why have a genetic evaluation? Why did it happen? Can it happen again? Will the hearing loss be stable or get worse? Syndromic or Non syndromic?

4 Etiology of Hearing Loss ACMG 2002 Genetic Evaluation Guidelines

5 Genes interact with the environment Completely genetic Mix of genetic And environmental Completely environmental Connexin 26 Usher syndrome Aminoglycoside Induced HL Noise Induced HL Meningitis Alcohol exposure TORCH CMV

6 40% of deafness is non-genetic BUT Teratogens known genetic susceptibility Congenital/perinatal infections not all that are exposed have effects; genetic variation? Prematurity hyperbilirubinemia low birthweight NICU, ventilation what is the underlying cause of LBW, neonatal distress? Ototoxic medications known genetic susceptibility Meningitis may be predisposed by anatomical abnormality

7 Terminology DFN (for DeaFNess) DFNA - autosomal dominant DFNB - autosomal recessive DFN - X-linked (e.g. DFNB1 = recessive hearing loss gene #1)

8 Genetic Causes of HL Genetic Syndromic 30% Nonsyndromic 70% Autosomal Recessive 75-80% Autosomal Dominant 20-25% X-linked or Mitochondrial 1-2% DFNB1/Connexin 26 50% Other DFNB 50%

9 Autosomal Recessive Nonsyndromic Hearing Loss Congenital severe to profound type is most common Genetic studies have identified >60 different loci, with genes identified for only some of the loci 90% born to parents with normal hearing

11 DFNB1 GJB2 gene codes for Connexin 26 protein GJB6 gene codes for Connexin 30 protein Most common cause of nonsyndromic, autosomal recessive, congenital hearing loss (50%) Overall Connexin 26 mutations accounts for 20% of patients with nonsyndromic sensorineural hearing loss 98% of individuals with DFNB1 have two GJB2 mutations 2% have one GJB2 mutation and one GJB6 mutation

12 Compound Heterozygosity (Digeneic Inheritance) CX 26 CX 26 CX 30 CX 30 Hearing loss Hearing loss Hearing loss

13 Connexin 26 (DFNB1 / GJB2) Phenotype non-syndromic normal vision and vestibular function non-progressive (2/3) hearing loss = mild to profound with intra- and inter- familial variability few kindreds are progressive and asymmetric 2 common mutations : 35delG (85% N. Europeans) 167delT (Jewish) 235delC mutation (Chinese) Carrier rate ~3% of Caucasians 1 in % of Ashkenazi Jewish Epidemiology 1/2500-1/5000

14 DFNB1 testing strategy First screen for 35delG deletion in Connexin 26 If negative or find only one mutation DNA sequencing of Connexin 26 DFNB1 is not complete unless screening for the splice site mutation (exon 1 of GJB2) and the large GJB6-containing deletions is included If DNA sequencing of Connexin 26 is normal Targeted mutation analysis of Connexin 30 Two large deletions GJB6-D13S1830 and GJB6-D13S1854 GJB6-D13S1830 is the most common GJB6 mutation associated with DFNB1

16 List of autosomal recessive hearing loss loci Locus Name Gene Symbol Onset Type DFNB1 GJB2 Prelingual 1 Usually stable GJB6 DFNB2 MYO7A Prelingual, postlingual Unspecified DFNB3 MYO15 Prelingual Severe to profound; stable DFNB4 SLC26A4 Prelingual, postlingual Stable, progressive DFNB6 TMIE Prelinqual Severe to profound; stable DFNB7/11 TMC1 DFNB8/10 TMPRSS3 Postlingual 2, Prelingual Progressive, stable DFNB9 OTOF Prelingual Usually severe to profound; stable DFNB12 CDH23 Prelingual Severe to profound; stable DFNB16 STRC Prelingual Severe to profound; stable DFNB18 USH1C Prelingual Severe to profound; stable DFNB21 TECTA Prelingual Severe to profound; stable DFNB22 OTOA Prelingual Severe to profound; stable DFNB23 PCDH15 Prelingual Severe to profound; stable DFNB24 RDX Prelingual Severe to profound; stable DFNB25 GRXCR1 Prelingual Moderate to profound; progressive DFNB28 TRIOBP Prelingual Severe to profound; stable DFNB29 CLDN14 Prelingual Severe to profound; stable DFNB30 MYO3A Prelingual Severe to profound; stable DFNB31 DFN31 Prelingual DFNB32/82 GPSM2 Prelingual Severe to profound; stable DFNB35 ESRRB Unknown Severe to profound DFNB36 ESPN Prelingual DFNB37 MYO6 Prelingual DFNB39 HGF Prelingual Severe to profound; downsloping DFNB49 MARVELD2 Prelingual Moderate to profound; stable DFNB53 COL11A2 Prelingual Severe to profound; stable DFNB59 PJVK Prelingual Severe to profound; stable DFNB61 SLC26A5 Prelingual Severe to profound; stable DFNB63 LRTOMT Prelingual Severe to profound; stable DFNB67 LHFPL5 Prelingual Severe to profound; stable DFNB73 BSND Prelingual Severe to profound; stable DFNB77 LOXHD1 Postlingual Moderate to profound; progressive DFNB79 TPRN Prelingual Severe to Profound; stable DFNB84 PTPRQ Prelingual Moderate to profound; progressive

18 Autosomal Dominant NSHL Usually post-lingual Usually progressive (onset in 2nd or 3rd decades) Accounts for 15% of cases of nonsyndromic hearing loss In general, onset is postlingual and is progressive Some forms also include vestibular dysfunction Over 40 genes have been identified Many found in only one or two families

20 Mitochondrial gene associated with HL 12S rrna gene mutation A1555G confers a sensitivity to aminoglycosides HL within days of even a single dose 40% of those not exposed develop HL by 30 years of age Isolated sensorineural hearing loss. Variable age of onset: congenital - 7th decade. Flat, sloping or high frequency hearing loss. Progressive hearing loss. Mild-to-profound sensorineural hearing loss with or without a history of aminoglycoside exposure, or Hearing loss that appears to be consistent with maternal inheritance.

22 Syndromic Hearing Loss Is more than one organ system involved? Are there similar issues in family members? Is there a distinctive or characteristic appearance?

23 Genetic Syndromes with Hearing Loss as a Major Feature Alport Branchial-Oto-Renal Jervell and Lange-Nielsen Neurofibromatosis type 2 Pendred Stickler syndrome Waardenburg

24 Branchio-oto-renal Syndrome (BOR) Estimated to occur in 2% of children with congenital hearing loss Ear: pits/tags, abnormalities of the external, middle, or inner ear Hearing loss: can be mild to profound, sensorineural, conductive, or mixed Branchial arch: sinus or cyst in neck Renal: agenesis, hypoplasia, or dysgenesis Patient picture

25 Characterized by cleft palate, micrognathia, severe myopia, retinal detachments, cataracts, short stature, and hypermobility SNHL in about 40%, conductive can also be seen Most autosomal dominant, although can be recessive Mutations in one of four collagen genes (COL2A1) At risk for retinal detachment, arthritis Stickler Syndrome

26 4 5 Thick glasses, hearing aids, joint prob Glasses Vision prob Deaf in one ear Seizures Accident HL, vision prob Epilepsy Detached retina Deaf in one ear 2 17m HL, cataract Dev delay

27 Waardenburg Syndrome Accounts for 3% of childhood hearing impairment Incidence is 1 in 4000 live births AD PAX 3 gene mutation May have unilateral or bilateral SNHL Pigmentary features include: white forelock heterochromia irides premature graying vitiligo Craniofacial features include: dystopia canthorum (lateral displacement of inner canthus of eye) broad nasal root and synophrys Patient picture (people may dye their hair therefore ask specifically about white forelock)

28 Alport Syndrome Hearing, vision, and renal involvement Blood in urine (hematuria) often first symptom Typically progresses to renal failure HL may not become evident until the second decade of life, 80-90% by age 40 Anterior lenticonus - eye finding 85% of cases are X-linked, with some dominant and recessive families

29 Neurofibromatosis Type 2 Affects 1 in 40,000 Hallmark feature is vestibular schwannoma - tumor on 8th nerve Symptoms include tinnitis, hearing loss, balance problems, occasional facial palsy Other features include tumors on brain or spinal cord, early cataracts Autosomal dominant, 50% de novo

30 Usher Syndrome Prevalence of 3.5 per 100,000 population; 1 in 70 carrier frequency Autosomal recessive 11 loci, 2 Association of hearing loss with retinitis pigmentosa At least 11 loci 2 identified Progressive vision loss - night blindness and loss of peripheral vision noted in second decade Electroretinography can identify abnormalities in younger children - Three subtypes Type 1: congenital bilateral profound HL and abnormal vestibular function Type 2: moderate HL and normal vestibular function Type 3: progressive HL and progressive loss of vestibular function

31 Pendred Syndrome ~1/7500 Congenital severeprofound SNHL Enlarged vestibular aqueduct or Mondini dysplasia on temporal bone CT Thyroid goiter - develops in adolescence or adulthood Autosomal recessive SLC26A4 gene Mutations in this gene may cause up to 5-10% of congenital hearing loss Patient picture

32 Jervell and Lange-Nielsen Syndrome Profound SNHL and syncopal episodes resulting from cardiac conduction defect ECG reveals large T waves and prolonged QT interval Can result in sudden death ECG should be done on all children with uncertain etiology of hearing loss Autosomal recessive inheritance fainting long QT 3 6 sudden death JLN

33 Evaluation for Syndromic Hearing Loss Family history Three generation family history Age onset hearing loss Description of hearing loss Heritable / non-heritable Conductive / neurosensory / mixed Unilateral / bilateral Symmetric / asymmetric Congenital / acquired Progressive / stable / fluctuant Isolated / syndromic

34 Evaluation for Syndromic Hearing Loss Visual anomalies : heterochromia, retinitis pigmentosa, myopia, retinal detachment, early cataracts, night blindness Dysmorphology: preauricular pits, ear anomalies, cleft lip/palate, dental anomalies, pits, lumps or fistulae on the neck Endocrine work up: thyroid disorders and diabetes Cardiac work up: syncope, sudden death, prolonged QT interval, fainting spells, CHD Renal abnormalities hematuria, proteinuria, structural defects Skin abnormalities abnormal pigmentation, premature graying, white forelock, dry skin/keratoderma Bone: arthritis, loose joints, joint swelling, dislocation, frequent broken bones

35 Medical Genetic Evaluation of Hearing Loss Smith et al 1998 Stage 1 o Medical Genetics o Audiology o Otolaryngology Stage 2 o Vestibular o Ophthalmology o CT of temporal bones o Urinalysis/serum creatinine o Serology Stage 3 o Perchlorate discharge (if CT abnormal) o DNA o Electrocardiogram o Electroretinogram

36 Genetic counseling for hearing loss "In contrast to the medical model which considers deafness to be a pathologic condition, many deaf people do not consider themselves to be handicapped but define themselves as being part of a distinct cultural group with its own language, customs, and beliefs. Strategies for effective genetic counseling to deaf people include the recognition that perception of risk is very subjective and that some deaf individuals may prefer to have deaf children." [Arnos et al 1991]

37 References Medical genetic evaluation for the etiology of hearing loss in children. Smith SD, Kimberling WJ, Schaefer GB, Horton MB, Tinley ST. J Commun Disord Sep-Oct;31(5):371-88; quiz Review. Genetics Evaluation Guidelines for the Etiologic Diagnosis of Congenital Hearing Loss. Genetic Evaluation of Congenital Hearing Loss Expert Panel. ACMG statement. ACMG.Genet Med May-Jun;4(3): Genetests.org A prospective, longitudinal study of the impact of GJB2/GJB6 genetic testing on the beliefs and attitudes of parents of deaf and hard-of-hearing infants. Palmer CG, Martinez A, Fox M, Zhou J, Shapiro N, Sininger Y, Grody WW, Schimmenti LA. Am J Med Genet A Jun;149A(6): Genetic counseling of the deaf. Medical and cultural considerations.arnos KS, Israel J, Cunningham M. Ann N Y Acad Sci. 1991;630: Deaf adults' reasons for genetic testing depend on cultural affiliation: results from a prospective, longitudinal genetic counseling and testing study. Boudreault P, Baldwin EE, Fox M, Dutton L, Tullis L, Linden J, Kobayashi Y, Zhou J, Sinsheimer JS, Sininger Y, Grody WW, Palmer CG. Deaf Stud Deaf Educ Summer;15(3): Epub 2010 May 20. Attitudes of deaf adults toward genetic testing for hereditary deafness. Middleton A, Hewison J, Mueller RF. Am J Hum Genet Oct;63(4): Slide acknowledgementt 1. Dr.Bradley Schaefer, Geneticist, UAMS, KUSM-W 2. Allison Schreiber, MS, CGC, Genetic Counselor, Cleveland Clinic