Final Exam Flashcards
what are characteristics of AD inheritance
Vertical Transmission
■ 50% chance of offspring inheriting per pregancy
■ NO carriers
■ All affected individuals are heterozygous
■ Only ONE bad gene is needed to inherit
■ EX: Waardenburgs Syndrome
what is an ex of ad inheritance
waardenburgs syndrome
what is AR mode of inheritance
Horizontal transmission
■ 25% chance of offspring inheriting per pregancy
■ BOTH parents must be obligate carriers
■ Consanguinity is common
■ EX: Usher’s Syndrome
what is an ex of AR inheritance
usher’s syndrome
what are two characteristics of x linked inheritance
NO FATHER TO SON TRANSMISSION
abnormal gene is called on x chromosome
what are characteristics of x linked recessive
dad has it: 100% chance daughter is carrier, 0% son will
mom has it: 50% chance son will carry trait, 50% chance son will have trait, 50% daughter carries the trait
what are examples of x linked recessive inheritance
colorblindness, hemophilia muscular dystrophy
what are characteristics of x linked dominant
dad has it: 100% chance daughter is carrier or expresses, 0% chance son will
mom has it: 50% chancer per offspring
what is an example of x linked dominant
alport’s syndrome
what are characteristics of y linked inheritance
male to male transmission only
100% transmission to male offspring
what are characteristics of mitochondrial gene
100% risk of transmission to offspring (M&F)
only transmitted from the mother
what is another term for mitochondrial disorder
eve gene
what is an example of mitochondrial inheritance
aminoglycoside ototoxicity
what is the most common AR deafness condition
Usher’s
what is the second most common AR deafness condition
Pendred’s
what is the third most common AR deafness condition
JLNS
what are the most common autosomal dominant syndromic HL
Waardenburg
BOR
what are the most common autosomal recessive syndromic HL
Usher’s
Pendred’s
JLNS
syndromic disorders show abnormalities in
many areas
how are nonsyndromic loci named
according to their inheritance pattern
DFNA
AD
DFNB
AR
DFNX
X linked
DFNY
Y linkedj
DFNM
Modifier
AUNA
auditory neuropathy
OTSC
otosclerosis
Responsible for 50-80% of all AR HL
Connexin 26
protein found in the OHC and causes motility of them
Prestin
single gene mutations
monogenic conditions
many genes causing the same phenotype
Genetic heterogeneity
what is a characteristic/hallmark of chromosomal abnormalities?
intellectual disability
what are the branchial arch disorders
treacher collins
pierre robins
Sticklers
What are the characteristics of treacher collins
large fish mouth from poorly developed muscles
abnormal external ear (peanut ear)
small lower jaw
what are the characteristics of stickler’s syndrome
small lower jaw
cleft palate
tongue placed further back in the mouth
otitis media & CHL
why does sticklers have a conductive loss
ear canals, ossicles pinna & ME cavity form from the 1st & 2nd arches
what are the characteristics of pierre robin’s syndrome
near sightedness (myopia)
retinal detachment
CHL or mixed HL
arthritis at early age
underdevelopment of middle of face & small lower jaw
what happens in the pre embryonic period (fertilization to 3rd week)
3 germ layers form
what happens in the embryonic period (3-8th week)
organogenesis
what happens in the fetal period (9wks to birth)
maturing of tissues/organs
what is a phenocopy
environmentally caused trait that mimics a genetically determined trait
thalidomide is phenocopy of phocomelia
hair loss from chemo is phenocopy of alopecia
what is pleitropy
diverse effects of 1 gene/gene pair on several organ systems & fxns resulting in multiple phenotypic effects on the body
marfan’s syndrome
what is hemizygous
1 chromosome of the pair is present instead of the two
males due to XY
How to read 1q2_4
Chromosome 1, long arm q, band 2 region 4
what is epidemiology and why study it
Study of population health
To help understand the incidence of a certain disorder
what are modifier genes
affect phenotypic outcome of a given genotype by interacting in the same or in parallel biological pathway as the disease gene
modulate expressivity (severity), penetrance, age of onset, progression of disease, or pleiotropy
these are the common source of phenotypic variation in human populations
modifier genes
what is gene mapping
identification of approximate or exact location of a gene ona chromosome
what is gene cloning
production of exact copies of a particular gene or dna sequence
how does gene cloning happen
DNA extracted from an organism contains all of its thousands of different genes
The genetic engineer must find the one specific gene that encodes the specific protein of interest
what is inner ear homeostasis
process which chemical equilibrium of inner ear fluids & tissues is maintained
causes 50-80% of all AR genetic HL
connexin
Increased K+ transport in the endolymph or increased endolymph production
endolymphatic hydrops
what is an example of endolymphatic hydrops
meniere’s disease
Decreased K+ transport in the endolymph or decreased endolymph production
endolymphatic xerosis
what is an example of endolymphatic xerosis
connexin 26
what is connexin 26
gene mutation results in abnormal connexin gap junction proteins
protein found in the OHC and causes motility of them
prestin
what is heterogeneity
many genes causing the same phenotype
ex: hl
prelingual
Born w/ deafness, before learning language
Congenital HL
postlingual
Deaf after learning language
Hallmark of chromosomal disorders is
intellectual disability
Multiple genes involved, multiple systems affected, whole ____ abnormalities
chromosomal disorders
Branch of genetics that studies structure and function of the cell, especially the chromosomes
cytogenetics
worldwide disease
pandemic
one area that has a particular condition more than other areas in the world
endemic
caused by a mutation of a single gene and broadly classified by mode of inheritance
mendelian/monogenic
what is multifactorial disorder
traits that result from a combination of multiple environmental factors with multiple genes
OAV
what is polygenic disorder
traits/diseases caused by the impact of different genes & each gene has a small impact on the phenotype
spina bifida, cleft lip/palate, HL
what is a spontaneous mutation
genetic change resulting from mis pairing of bases during replication (not inherited)
can be due to environmental influences
Genetic changes that result from normal cell processes
what are missense mutations
conservative & non conservativew
what are point mutations
silent, nonsense, missense (conservative 7 nonconservative)
what is a conservative mutation
mutation that ends w/ different protein product but no phenotypic change
what is non conservative mutation
mutation & ends w/ different protein product that is too different that cannot have the same fxn the protein was supposed to do
what is a silent mutation
mutation but ends with the same protein that was originally coded
what is a nonsense mutation
causes a stop protein and truncated proteins
what is anticipation
worsening of symptoms of genetic disease from 1 generation to the next
what is allelic expansion
increase in bases that increases gene size
what is an example of anticipation & allelic expansion
Huntingdon’s disease
what is huntingdon’s disease and inheritance
AD
adult onset
loss of muscle coordination & control
deterioration of intellectual fxn
early death
Seen in Ash jews most
what are chromosomal abnormalities
WHOLE chromosomal disorder
have adverse affects on many systems/structures
How many chromosomal abnormalities can make it to term?
Only 3 autosomal, 1 sex linked monosomy (Turner Syndrome)
monosomy
missing a chromosome of the two
lethal
trisomy
addition of a chromosome
21
18
13
X
what is trisomy 21
downs
what is trisomy 18
edwards
what is trisomy 13
patau
what is trisomy x
Klinefelter’s
Nullisomy
no chromosome pair
lethal
aneuploidy
in somatic cells
abnormal # of chromosomes
mono, tri, & nullisomy
21, 18, 13 are most common
how does aneuploidy occur
during cell division when chromosomes do not separate equally between two daughter cells
what is genomic imprinting and examples
process in which the phenotype differs depending upon which parent transmits a particular allele or chromosome
prader willi
angelman
prader willi syndrome
Paternal origin
deletion of 15 hromosome
uncontrollable eating, intellectual disability, infertility
angelman syndrome
maternal origin
deletion of 15 chromosome
uncontrollable laughing, gait ataxia, intellectual disability
Subcentric or submetacentric
The chromosome’s p & q arms’ lengths are unequal
Metacentric
The two arms of chromosome are roughly equal in length
telocentric
Centromere is located at the terminal end of the chromosome
Not present in humans
holocentric
Entire length of the chromosome acts as the centromere
Found in worms (nematodes); not present in humans
homologous
same chromosomes
heterozygous
different genes
homozygous
same identical gene
What is the general phenotype of people with chromosomal abnormalities
more than 2 systems involved and intellectual disabilities and abnormal growth patterns
where do we see ring chromosomes
acrocentric chromosomes
what is a ring chromosome
both arms of a chromosome break and the broken ‘sticky’ ends fuse at the breakage points. The broken fragments are lost and with them any genes they may contain
what are the ring chromosomes
r13, r14, r15, r21, r22 (acrocentrics)
what are the 3 ways down’s can occur
nondisjunction
RT
mosaicism
what is nondisjunction
95% of down’s
As the embryo develops, the extra chromosome is replicated in every cell of the body and accounts for an extra chromosome 21
the failure of the chromosomes to separate, which produces daughter cells with abnormal numbers of chromosomes
what is robertsonian translocation
4% of down’s
chromosomes break at their centromeres and the long arms fuse to form a single chromosome with a single centromere
The short arms also join to form a reciprocal product, which typically contains nonessential genes and is usually lost within a few cell divisions
Centromeres break and the long arms fuse → short arms fuse to form a new chromosome → new small chromosomes go away after few cell cycles → end result has new balanced chromosome with all the genetic information needed
what chromosomes are usually seen with RT
acrocentric
13, 14, 15, 21, 22
When long arm of 21 translocates with chromosome 14 (or 15)
Heterozygous carrier is phenotypically normal/balanced
If mother is RT carrier, risk of 2nd trisomy 21 pregnancy is
10-15%
what is mosaicism
1% down’s
Presence of two or more cell lines (cell populations) that differ genetically in an individual or tissue but that are derived from a single zygote
some cells have a genetic change
individual composed of cells of 2 genetically different types
how does mosaic down’s occur
Occurs in nondisjunction of chromosome 21 takes place in one but NOT ALL of the initial cell divisions after fertilization
Some cells contain 46 chromosomes and others contain 47, which contain an extra chromosome 21
How does down’s mosaicism differ from nondisjunction?
nondisjunction is when the the 21 chromosome is replicated in every cell division but mosaicism occurs when nondisjunction of chromosome 21 takes place in only one of the initial cell divisions instead of all.
all males are mosaics
FALSE
all females
How does x inactivation occur
because females are mosaics and inherit 2 Xs they have to inactivate one
the inactivated one is called a Barr Body
lyonization
x inactivation
form of germ cell mosaicism
x inactivation
once an x is inactivated, will it ever reactivate?
NO
stays inactive throughout lifetime of the cell
what could be an explanation of why more females are affected with autoimmune disorders?
some of inactivated x genes are still expressing and this only happens in women
genes create proteins that should not be there
the paternal x is always inactivated
FASLE it is random
darkened condensed chromosomal region in a cell
Barr body
what is a normal female
random x inactivated (barr body)
active x
mix of Xm & Xp
what is chimerism
presence of 2 sets of DNA or organs that do not match the DNA of the rest of the organism
result of mosaicism
chimerism
what is assortative mating
Mating of people with the same phenotype resulting in more expected phenotype
The Deaf community
what is linguistic homogamy
Mating b/w individuals that have the same language such as “native” signers
what is the founder effect
Population derived from small group or are socially isolated; common in AR
As carriers of the disease have children & the new population starts to grow, the mutated gene becomes more prevalent
population bottleneck
Reduction in population size
gene draft
seen in bottleneck
random fluctuations in numbers of gene variants in population
balanced polymorphism
process of natural selection
An acronym for group of diseases that cause severe fetal anomalies, HL, & death if exposed in utero
TORCH
what is torch
toxoplasmosis
other (HIV, syphalis, etc.)
rubella
cmv
herpes
what is a karyotype
all the chromosomes laid out
disorders w/ external ear changes
treacher collins
BOR
disorders w/ eye disease
ushers, norrie
disorders w/ musculoskeletal
crouzon & stickler
disorders w/ renal disease
alport
disorders with cardiac
JLNS
disorders w/ neurolgic/neuromuscular
friedreich ataxia
disorders w/ endocrine
pendred
disorders w/ metabolic
biotindase deficiency, muccopolusacharidoses (MPS)
disorders w/ integumentary system
waardenburg
disorders w/ no associated physical/mental characteristics
connexin & deafness
Trisomy 13
Mode of transmission
other systems affected
major signs/symptoms
differential diagnosis? why?
patau syndrome
chromosomal disorder
brain defects, cleft palate/lip, blindness, severe intellectual disabilities, severe to profound SNHL/deafness, abnormal cochlea & vestib system
Trisomy 18
Mode of transmission
other systems affected
major signs/symptoms
differential diagnosis? why?
Edwards syndrome
chromosomal disorder
usually female, males have high abortion
intellectual disability w/ seizures, small mouth, high arched palate, heart defects, ossification of ossicles & severe HL/deaf based on temporal bone studies
Trisomy 21
Mode of transmission
other systems affected
major signs/symptoms
differential diagnosis? why?
down’s
chromosomal disorder: nondisjucntion, RT, mosaicism
intellectual & developmental disabilities, large tongue, stenotic ear canals, CHL, SNHL or mixed, infertility
Turner syndrome
Mode of transmission
other systems affected
major signs/symptoms
differential diagnosis? why?
45 X0
99% fetuses abort
spontaneous mutations
short w/ thick neck, look like females, missing an x, streak gonads, infertile, narrow ear canals
Long term consequences of ear infections?
S/L development
How do babies learn language?
incidental learning
Klinefelter’s syndrome
Mode of transmission
other systems affected
major signs/symptoms
differential diagnosis? why?
47 XXY
spontaneous - higher risk w/ increased maternal age
single most common cause of male infertility
man boobs at puberty, infertility, males, SNHL, tall and thin w/ long legs
treacher collins syndrome
Mode of transmission
other systems affected
major signs/symptoms
differential diagnosis? why?
first arch syndrome
AD
coloboma, fish like mouth, cleft palate, atresia, absent/malformed ossicles, mild-moderate bilateral CHL
OAV - unilateral vision & skeletal abnormalities
BOR
Mode of transmission
other systems affected
major signs/symptoms
differential diagnosis? why?
second most common cause of AD HL
variable expressivity and high incomplete penetrance
renal abnormalities (polycystic kidneys), CHL SNHL or mixed that is delayed but not progressive, uni/bilateral preauricular pits or branchial fistulas, not enough urine/amniotic fluid during pregnancy
alports: usually has ocular abnormalities
oculo-auriculo-vertebral
Mode of transmission
other systems affected
major signs/symptoms
differential diagnosis? why?
multifactorial inheritance
unilateral malformation from arches
facial asymmetry, vision loss, skeletal issues, CHL, pinna abnormalities
what are the differences bw treacher and OAV
OAV is unilateral, skeletal abnormalities & visual impairments
TC has no skeletal abnormalities or visual issues & bilateral facial structures
CHARGE association
Mode of transmission
other systems affected
major signs/symptoms
differential diagnosis? why?
coloboma
heart defects
atresia of nasal choanae
retarded growth/development
genital/urinary abnormalities
ear anomalies/deafness
behavior issues mistaken for ADHD/autism, external ear anomalies, balance issues, ossicular malformations, mondini malformation, deaf/blind
Ushers syndrome
Mode of transmission
other systems affected
major signs/symptoms
differential diagnosis? why?
most common AR syndromic HL
progressive SNHL first & vision loss later in life from retinitis pigmentosa
most common in finnish decent
Norrie syndrome
what are the types of ushers
1: more severe, abnormal vestib & congenital severe-profound SNHL
2: milder HL, no vestib
3: rare, progressive snhl w/ vestibular dysfunction
retinitis pigmentosa
AR
HL SNHL
intellectual disability common
norrie syndrome
Mode of transmission
other systems affected
major signs/symptoms
differential diagnosis? why?
x linked recessivve
male
visual problems (retinal detachment), SNHL, dementia, sunken & hazy eyes
Ushers: no CNS involvement, due to RP
crouzon syndrome
Mode of transmission
other systems affected
major signs/symptoms
differential diagnosis? why?
AD
early fusion of cranial bones (looks like down’s)
bulging eyes/vision problems, abnormal head shape, atresia of EAC w/ ossicular deformity, CHL but also mixed, absent or narrowed oval and/or round window
stickler syndrome
Mode of transmission
other systems affected
major signs/symptoms
differential diagnosis? why?
AD
Collagen disorder
eye abnormalities, mixed or progressive high frequency SNHL, joint problems
achondroplasia
Mode of transmission
other systems affected
major signs/symptoms
differential diagnosis? why?
sporadic mutations
both parents carry dominant gene
dwarfism
average trunk w/ short arms & legs, CHL, otosclerosis, frontal bossing
osteogenesis imperfecta
Mode of transmission
other systems affected
major signs/symptoms
differential diagnosis? why?
AD
connective tissue disorder
blue sclera, bone fragility, CHL or mixed beginning in late teens and gradually progressing to profound deafness, tinnitus & vertigo
alport syndrome
Mode of transmission
other systems affected
major signs/symptoms
differential diagnosis? why?
x linked (dom or rec)
progressive kidney inflammation to renal failure, hematuria, nephritis, bilateral variable progressive SNHL, variable eye defects
BOR: has polycystic kidneys &B.A. abnormalities
what are the 3/4 criteria that must be met for a diagnosis of alports
family Hx of hematuria
renal disease from biopsy
high frequency SNHL progressive during childhood
opthalmologic signs
Auditory neuropathy spectrum disorder ANSD
other systems affected
major signs/symptoms
differential diagnosis? why?
AR or mitochondrial
severe impairment of speech perception especially in noise due to disruption of synchronous VIII N firing
CI’s are treatment
only condition that audio is not used for condition determination
what are the 3 ways ANSD is inherited
ar or mitochondrial
genetic nonsyndromic - abnormal OTOF gene (can be replaced in gene therapy & regain normal hearing)
genetic syndromic - associated w/ peripheral neuropathies (charcot-marie-tooth & Friedreich’s ataxia)
environmental - viral involvement (Guillen Barre syndrome)
Charcot Marie Tooth
other systems affected
major signs/symptoms
differential diagnosis? why?
AR
Progressive neurodegenerative disease, affects motor & sensory nerves, absent limb reflexes, muscle atrophy, slowly progressive SNHL onset in child/adulthood (could be due to auditory neuropathy)
Friedreich’s Ataxia
other systems affected
major signs/symptoms
differential diagnosis? why?
AR
inability to coordinate voluntary muscular movements
nystagmus, dysarthria, scoliosis, high foot arch
what are the triad manifestations for FA diagnosis
hypoactive knee & ankle reflex
progressive cerebellar dysfunction
preadolescent onset
hereditary sensory & autonomic neuropathy Type 1 (HSAN1)
other systems affected
major signs/symptoms
differential diagnosis? why?
AD
neurodegenerative disorder
early onset dementia
lack of feeling in toes & ulceration (leading to amputation)
adult onset progressive SNHL to deafness
neurofibromatosis (NF)
other systems affected
major signs/symptoms
differential diagnosis? why?
AD
NF1- peripheral form, >6 cafe au lait spots, tumors on and under skin, Lisch nodules, 5% w/ VIII N tumors (vestibular schwannoma)
NF2 - central form, benign tumors, progressive vision loss, < 6 cafe au lait spots, bilateral acoustic neuromas
management for NF2
ABI
What are the parts of an ABI
bypassess AN & connects to the bs directly
microphone & sound processor, decoding chip under the skin, & electrodes on the B.S.
Jervell & Lange-Nielsen Syndrome (ALNS)
other systems affected
major signs/symptoms
differential diagnosis? why?
AR
Long AT interval, sudden death, associated w/ SIDS, bilateral severe to profound SNHL
loss of sensory cells
Ward-Romano syndrome - long QT w/ NORMAL hearing (AD)
why do we see heart and ears affected in JLNS
because the K+ genes are affected and K+ is important for the ears & heart
Pendred Syndrome
other systems affected
major signs/symptoms
differential diagnosis? why?
AR
thyroid goiters, delayed onset, hypothyroidism, EVA, profound & rapidly progressive SNHL
DFNB4 - no thyroid defects, prelingual profound nonsyndromic SNHL, temporal bone abnormalities
DIDMOAD
other systems affected
major signs/symptoms
differential diagnosis? why?
DI - diabetes insipidus (thirsty & excessive urination)
DM - diabetes millitus (thirst, excessive urination, & high blood sugar)
Optic atrophy
bilateral slowly progressing SNHL
stria vascularis atrophy in 2nd decade
what is EVA
enlarged vestibular aqueduct
bony canal that begins in the temporal bone & travels from inner ear to deep in the skull
inside is a fluid filled tube (endolymphatic duct) that has the endolymphatic sac (balloon shaped structure)
MOST COMMON ANATOMIC ABNORMALITIY IN PERMANENT HL IN KIDS
unilateral/bilateral SNHL, moderate to profound, BPPV can occur
what are the fxns of the endolymphatic duct & sac
help ensure homeostasis of inner ear fluid
how to avoid progression of HL in eva kids
avoid contact sports that can lead to head injury
wear head protection
avoid barotrauma (rapid changes in air pressure)
muccopolysaccharidosis
other systems affected
major signs/symptoms
differential diagnosis? why?
AR
two types
Hurler syndrome (more severe, MPS IH) - gargoylism, course facial features, large tongue, skeletal abnormalities, large babies, developmental delays, chronic progressive, shortened lifespan
hunter syndrome (x linked, MPS II) survivable to adulthood, more common, rapid intellectual deterioration, abdominal hernia, contractures of arms, death bw 10-15 yrs
biotidinase deficiency
other systems affected
major signs/symptoms
differential diagnosis? why?
AR
deficiency of biotin
ataxia, developmental delay
optic atrophy
SNHL
affects the optic and auditory nerve and cochlea
Waardenburg Syndrome
other systems affected
major signs/symptoms
differential diagnosis? why?
most common AD syndromic HL
caused by hereditary deficit of neural crest cells
white forelock hair, premature greying, vestibular abnormalities, profound w/ corner audio or moderate HL in low-mid frequencies, BM thickening
4 types
what are the 4 types of Waardenburg Syndrome
WSI - more unilateral deafness, pigment disturbances, dystopia cnathorum, heterochromiairides
WS2- less unilateral HL, pigment disturbances, heterochromiairides, no dystopia canthorum
WS3 (klein-Waardenburg)- b/l upper extremity defects, hl, pigment disturbances
WS4 (Waardenburg-Shah)- rare, more severe HL (deafness), Hirschsprung disease, pigment disturbances
what is hirschsprung disease seen in WS4
stool impaction/constipation
gut will not empty because the nerves to contract are missing due to the absence of neural crest ceels
Almost all of the autosomal dominant conditions show
post-lingual progressive HL starting in the high frequencies
almost all AD conditions with HL differ in
age of onset
rate of progression
ultimate degree of HL
vestib involvement
AD nonsyndromic HLs
otosclerosis
DFNA5
otosclerosis
other systems affected
major signs/symptoms
differential diagnosis? why?
ossification of the stapes footplate and its ossification into the oval window
AD
starts around the otic capsule; NO remodeling of otic capsule after embryologic development
what is the site of lesion for otosclerosis
around the otic capsule
who is the most vulnerable population for otosclerosis
young white females
reason unknown
menopause exacerbates this
DFNA5
other systems affected
major signs/symptoms
differential diagnosis? why?
AD
progressive SNHL
HL present in childhood & progresses as they get older
Nearly all recessive conditions are associated with
severe to profound SNHL that is prelingual
> 50% of autosomal recessive nonsyndromic hearing loss is caused by
connexin 26
what is connexin deafness
found in nonsensory epithelial & supporting cells (NOT IN COCHLEAR HAIR CELLS)
connexins associate in groups of 6
they are a hexagonal array of proteins in membrane of each cell that line up to the corresponding connexin proteins of the adjacent cell forming a channel (gap junction) that permits ion transfer bw cytoplasm of cells without entering extracellular fluid
what are the 1st & 3rd recessive connexin deafness
DFNB1 & DFNB3
what are the genes for connexin deafness
GJB
most common GJB2 & GJB6
what are the protein products of GJB2 & GJB6
Connexin 26 (Cx26)
Connexin 30 (Cx30)
GJB2, Cx26, is assigned to
13q11-q12
how are connexins important for cellular communication
provide structural basis for K+ recycling back to the endolymph of the scala media after hair stimulation
responsible for intercellular calcium signaling
causes electrical coupling to support cochlear amplification
why does Connexin not hold true of mendelians 2nd law (law of independent assortment)
Because GJB2 & GJB6 are so close together it is very common for them to be transmitted together
individuals can have 2 or 1 mutation in GJB2 & GJB6. IF there are two mutations, the risk increases from
50-100%
Connexin 32
x linked
charcot marie tooth
connexin 26
protein product of GJB2 gene mutation
DFNB1/DFNB3
13q11-q12
gene mutation that results in abnormal gap junction proteins
Responsible for 50-80% of all AR HL
connexin 26
what are the common mutations of connexin 26 and the common ethnicities it affects
35delG - caucasians & asians
167delT - Ashkenazi jews
235delC - east asian populations
where is connexin 26 found
inner ear (utricle & saccule, nonsensory epithelial), skin, liver, bladder, placenta, etc.
what is the mutation that occurs in Cx26
frameshift mutation (deletion)
causes truncated proteins
what are the auditory manifestations of Cx26
congenital bilateral (often symmetrical) mild to profound HL
vertigo/tinnitus reported
other Cx phenotypes
skin diseases
this is why CI’s may not work for these patients
what is the intervention for Cx
CI’s
connexin 30
protein product of GJB6
chromosome 13?
DJB6-DFNA3
x linked nonsyndromic HL
x linked congenital stapes fixation with perilymph gusher
congenital stapes fixation with perilymph gusher
other systems affected
major signs/symptoms
differential diagnosis? why?
x linked
mixed HL
can be progressive if middle ear surgery is performed & can result in sudden loss of perilymph
otosclerosis
mitochondrial nonsyndromic hl
aminoglycoside-induced ototoxicity
aminoglycoside-induced ototoxicity
other systems affected
major signs/symptoms
differential diagnosis? why?
irreversible but preventable sudden onset severe-profound SNHL when exposed to aminoglycosides
generally not progressive
otosclerosis
what are complex genetics? what is it mostly due to?
caused by environment & genes as well as the interaction bw the two
no clear inheritance pattern
due to single nucleotide polymorphisms (SNPs-snips)
age related HL
complex disease
most 20 yr olds do not have HL but at least 50% of 70 yr olds do
also variety to 70 yr old that have HL (differences due to environmental factors but also genes)
what tests would be useful for pendred symtpoms
physical exam - thyroid
radiology - EVA/mondini’s dysplasia
what tests would be useful for Usher’s
physical exam - vestib abnormalities & visual problems
what tests would be useful for Waardenburg
physical exam - hx or presence of pigment abnormalities
what tests would be usefull for Alport
lab test - urine analysis & routine blood tests
what tests would be good for BOR
Radiology - renal ultrasound
what tests would be good for JLNS
EKG - QT interval eval
family hx of syncope or SIDS
Lab, radiology, and other specific tests that may be useful for identification of various genetic disorders
factors that cause HL (low birth weight, nicu time, infections, etc.)
S/L milestones (deaf infants coo/babble up to 6 mos)
family Hx (consanguinity, family members w/ HL)
physical exam
audio exam - OAE/ABR, behavioral assessment/audio, hx of HL in family
lab tests - based on hx, physical exam & PT age
endocrine fxn
EKG
radiology
Who should undergo genetic screening/testing?
children w/ HL
If a child has a HL that is nonsyndromic, what is the first thought for a diagnosis?
GJB2 (Connexin 26 & 30) because they are the MOST COMMON
Clinical benefits of identifying genetic disorders
provides professionals the ability to make an accurate diagnosis & prognosis
provides scientific explanation for the problem & why it occurred so it prevents the blame game
to recognize if other systems will be affected (congenital heart defects, etc.)
to recognize if there is a risk for developmental delays (intellectual disability, etc.)
provides accurate recurrence risk for offsprings
what do they test for first? if that is negative what do they test for next?
Test for Connexin first, if negative, they test for EVA, +EVA = Pendred
Ethical & psychosocial issues associated with genetic testing
provides info affecting reproductive choices
misassigned paternity (dad may not be biological dad)
insurance discrimination (can use test results to deny coverage to individuals)
Deaf community negative attitudes towards genetic testing (do accept it for Ushers)
why does the deaf community accept genetic testing for Usher’s
because they want to be prepared for vision and HL since ASL will not be beneficial for these individuals later
what is involved in genetic testing
detailed clinical & family Hx
comprehensive exam of PT & other members of family if necessary
What are the steps to diagnose a child with HL
NBHS
confirmation of HL (ABR)
detailed family Hx
ENT, audiology & genetic evals
molecular testing (first GJB2&6)
if negative - cranial imaging (EVA for pendred), cardiac eval (EKG for long QT interval), ophthalmologic eval, guided molecular testing for HL genes (otoSCOPE)
what should you do and not do in diagnosing a child with HL
do - detailed family hx, consider genetic etiology, rule out syndromic HL, testing for GJB genes, temporal bone imagine
do not - call sporadic/environmental, quote negligible recurrence risk, offer molecular panel for HL at outset
what is otoSCOPE
otologic sequence capture of pathogenic exons
genetic panel for HL
what is FISH
fluorescence in situ hybridization
provides a way to visualize and map genetic material in a cell
