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
Why have a genetic evaluation ?
Why did it happen ? Can it happen again ?
Etiology
of Hearing Loss
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
Terminology
DFN (for DeaFNess)
DFNA - autosomal dominant DFNB - autosomal recessive DFN - X-linked
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
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
CX 26 CX 30 CX 26 CX 30
Compound Heterozygosity
(Digeneic Inheritance)
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)
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
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 —
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
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
Syndromic Hearing Loss
Is more than one organ system involved?
Are there similar issues in family members?
Genetic Syndromes with Hearing Loss as a
Major Feature
Alport
Branchial-Oto-Renal
Jervell and Lange-Nielsen Neurofibromatosis type 2 Pendred
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
Stickler Syndrome
Characterized by cleftpalate, 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
3
34 27 16
Accident Seizures
Vision prob Deaf in one ear
Thick glasses,
hearing aids, joint prob
Waardenburg Syndrome
Accounts for 3% of childhoodhearing 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
(people may dye their hair –
therefore ask specifically about white forelock)
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
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
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
Pendred Syndrome
~1/7500 Congenital severe-profound 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
Jervell and Lange-Nielsen Syndrome
3
6
fainting sudden death
long QT JLN
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
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
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:
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 3o Perchlorate discharge (if CT abnormal) o DNA
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,
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. 1998 Sep-Oct;31(5):371-88; quiz 388-9. 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. 2002 May-Jun;4(3):162-71. 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. 2009 Jun;149A(6):1169-82.
Genetic counseling of the deaf. Medical and cultural considerations.Arnos KS, Israel J, Cunningham M. Ann N Y Acad Sci. 1991;630:212-22.
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. 2010 Summer;15(3):209-27. Epub 2010 May 20.
Attitudes of deaf adults toward genetic testing for hereditary deafness. Middleton A, Hewison J, Mueller RF. Am J Hum Genet. 1998 Oct;63(4):1175-80.
Slide acknowledgementt
1. Dr.Bradley Schaefer, Geneticist, UAMS, KUSM-W