Non-syndromic Hearing Loss and Deafness Flashcards
What percentage of genetic deafness is nonsyndromic?
75-85%
What does DFN stand for?
Deafness Neurosensory
What is the symbol for dominant conditions?
DFNA
With an associated number based on the order of discovery
What is the symbol for recessive conditions?
DFNB
For example:
DFNB1A = Connexin 26 (GJB2 gene mutation – Cx26)
DFNB1B = Connexin 26 (GJB6 gene mutation – Cx26)
What symbols are used for x-linked conditions?
DFN and numbers
DFN or DFNX1-7
What symbols are used for y-linked conditions?
DFNY
Very rare
What is a modifier gene?
Modifier genes modify severity of HL, making it worse or mild
They are identified with the primary AR or AD genes and explain intra-familial variability with identical mutations
Are most nonsyndromic deafness cases recessive or dominant?
Recessive
If the deafness is congenital, is it more likely to be recessive or dominant?
Recessive
Does recessive deafness tend to be severe to profound?
Yes
If the deafness occur late and is more mild, is it more likely recessive or dominant?
Dominant
T/F: Several forms of deafness are known to occur as a result of mutations of transcription factors
True
What are transcription factors?
Theses are proteins (excluding RNA polymerase) involved in initiating and regulating transcription of genes (DNA) to RNA
T/F: Almost all of the autosomal dominant conditions show post-lingual progressive hearing loss starting in the high frequencies
True
What are the ways that AD conditions differ from each other?
Age of onset
Rate of progression
Ultimate degree of hearing loss
Vestibular involvement
What type of inheritance does otosclerosis have?
AD
What penetrance and expressivity does otosclerosis have?
Incomplete penetrance and varying degrees or expressivity
What is incomplete penetrance?
May look like it skips generations or members of the same generation even though they may have the gene
What is varying expressivity?
Varying degrees of severity even within the same family
Does otosclerosis present as a complex genetic disorder?
Yes
With otosclerosis there is likely an interplay among multiple factors; the genetic component may not be enough to set the disease in motion
It is most likely triggered by a combination of genetic, environmental, hormonal, and/or other factors
What do the genes that are involved in otosclerosis result in?
Abnormal bone metabolism
Is otosclerosis focal?
Yes
Is otosclerosis only present in humans?
Yes
Is the etiology of otosclerosis understood?
No
What is otosclerosis?
It is a disease of abnormal bone remodeling (bone metabolism to form new bone) of the otic capsule
What is the most common age for otosclerosis to present?
Between 20 to 30 years of age
Is otosclerosis common?
Yes
Single most common cause of hearing loss in young adulthood
Does otosclerosis affect more males or females?
Females
2:1 ratio
Pregnancy and menopause can onset the condition
Is otosclerosis more common in one race over another?
Yes
Most prevalent in white (Caucasian) females
Rare in blacks; Uncommon among Asians, except Indians
What is the inheritance pattern of DFNA5?
AD
What type of hearing loss does DFNA5 present?
Nonsyndromic progressive SNHL
When does DFNA5 occur?
Hearing loss is present in childhood and becomes worse as affected individuals grow older
What severity and onset do recessive nonsyndromic hearing losses produce?
Severe to profound
Prelingual (probably congenital)
How many gene mutations of GJB2 (connexin 26) are identified that can cause nonsyndromic HL?
About 100
What percentage of autosomal recessive nonsyndromic hearing loss is caused by Connexin 26 (GJB2 gene) mutations?
Greater of equal to 50%
What is connexin 26?
It is a protein that is found in cells throughout the body
Where is connexin 26 found?
The inner ear (including utricle & saccule - nonsensory epithelia)
Skin
Liver
Bladder
Placenta
Breast
Brain
Are connexins found in cochlear hair cells?
No
They are found in the non-sensory epithelial cells and supporting cells
Is connexin associated with skin problems?
Yes
Can cause discomfort wearing CI’s or hearing aids
Can connexin be mild to severe?
Yes
Usually present from birth
What is DFNB1 and DFNB3?
First and third recessive deafness (connexin deafness)
What is GJB?
Genes for connexin deafness
What are the proteins for connexin?
Connexin 26 (Cx26) = Protein product of GJB2 gene
Connexin 30 (Cx30) = Protein product of GJB6 gene
Does GJB code for connexin?
Yes
T/F: Prior to 1996, Connexin 26 was not identified as the most common cause of nonsyndromic SNHL
True
Where is connexin 26?
13q11-q12
Assigned in 1996
Are mutations in the connexins responsible for a diversity of diseases, including deafness and skin disorders?
Yes
How many connexins are known to be expressed in the ear?
At least 4
In many populations, are mutations of the connexins the most frequent cause of AR deafness?
Yes
How are connexins arranged?
A hexagonal array of proteins in the 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 between cytoplasm of cells without entering the extracellular fluid
How many connexins are grouped together?
Groups of 6 and are organized radially around a center pore
This is called a connexon
Are connexins important for intercellular communication?
Yes
Provides a structural basis of recycling K+ back to endolymph of scala media after hair cell stimulation
Is responsible for intercellular calcium signaling
Causes electrical coupling to support cochlear amplification
What is the law of independent assortment?
It states that separate genes for separate traits are passed from parents to offspring independently of one another
More precisely, the law states that alleles of different genes assort independently of one another during gamete formation
Does the law of independent assortment hold true for connexin deafness?
No
The genes GJB2 and GJB6, which code for the protein Connexin 26 and Connexin 30 respectively, are closely link to each other on chromosome 13
They influence each other and often present together
individuals can have hearing loss when they have two mutations in the GJB2 gene or two mutations in the GJB6 gene, or one mutation in each of these genes
Do many individuals with connexin have no family history of deafness?
Yes
Because it is recessive
Although some can be dominant
How many connexin proteins are there?
At least 15
What does the number on the connexin mean?
It refers to their molecular size
What are some connexins that are involved in human deafness?
Cx26 (DFNB1/DFNA3) (most common)
CX36 (also called GJD2 - also common)
Cx30 (GJB6-DFNA3; also common)
Cx31 (DFNA2)
Cx32 (DFN or DFNX, X-linked Charcot-Marie-Tooth Disease)
What type of mutation is connexin caused from?
Deletion
Are there different connexin mutations for different ethnicities?
Yes
What ethnicities is connexin 26 less common in?
Hispanics and African-Americans
Is connexin 26 usually congenital?
Yes
Normal hearing reported consistently in 4 to 8% who passed the newborn hearing screening and normal ABR but then develop HL
Can some babies with connexin 26 pass their newborn hearing screening?
Yes they can pass it after birth and then develop hearing loss
Can the severity of hearing loss in connexin 26 be dependent on genotype?
Yes
Initially Cx26 loss was always considered severe to profound but as new genes/mutations have been found, it can vary in severity
Is the hearing loss for connexin 26 usually bilateral?
Yes
But it can be unilateral (rarely)
Often asymmetric if bilateral
Is there a wide variability between family members with connexin 26?
Yes
Is continual monitoring of connexin 26 required?
Yes
Has sudden hearing loss been reported for connexin 26?
Yes
Are some vestibular symptoms reported in cases of connexin 26?
Yes
Are connexins also present in the skin too?
Yes
Some connexin deafness patients may not make good candidates for CIs because of the fragility of the skin
Does connexin 26 typically show comorbidity with other abnormalities, such as intellectual disability or blindness?
No
Unless there is coexisting CMV or other problems
Are CIs typically used for people with connexin deafness?
Yes
It is a good option for them because there is nothing else going on
The reasons for this finding are yet unclear
Some reasons cited include the fact that most children with Cx do not have other developmental or neurological abnormalities and, therefore, do well with CIs and SLP intervention
Is gene therapy available for connexin deafness?
No, not yet
What is an example of x-linked nonsyndromic hearing loss?
X-linked Congenital Stapes Fixation with Perilymph Gusher
What is X-linked Congenital Stapes Fixation with Perilymph Gusher?
Mixed hearing loss
May be progressive
Increased hearing loss if middle ear surgery is performed to correct stapes fixation (mistaken for otosclerosis)
May result in massive & sudden loss of inner ear fluid (perilymph)
Females may have milder symptoms
What is an example of mitochondrial nonsyndromic hearing loss?
Aminoglycoside-induced ototoxicity
What is aminoglycoside-induced ototoxicity?
Irreversible but preventable hearing loss
Avoid aminoglycoside use in patients with +ve mutation
Medic Alert bracelet provided to those individuals with mutation
Mechanism of ototoxicity of aminoglycosides is due to the interference with the production of ATP in the mitochondria of cochlear hair cells
Patients may have sudden onset severe/profound SNHL when exposed to aminoglycosides, which is generally not progressive
It is not dose dependent
What are the three categories of genetic disease?
Complex genetic disorders
Monogenic diseases
Environmental diseases
What is the difference between the three categories of diseases?
Etiology
What are complex diseases caused by?
In part by the environment and in part by genes as well as by an interaction between the two
What are monogenetic diseases caused by?
Primarily by genes
Environment only plays a small role
What are environmental diseases caused by?
Primarily by the environment
Genes can play a minor role such as to determine a person’s susceptibility to being infected by certain infectious agents
How are mendelian diseases and complex genetics different from each other?
In Mendelian diseases there is a single genetic variance that results in increased risk
In complex genetics, a lot of variants are needed and the additive effect of a lot of variants cause the disorder
Is there a clear inheritance pattern for complex genetics?
No
Because there are several different variants that are responsible for the disease
Is there ever a clear autosomal dominant pedigree or autosomal recessive pedigree for complex genetics?
No
Is there family clustering of the disease in complex genetics?
There might be
But the inheritance pattern is never clear
Is there usually just one gene per family involved in complex genetics?
No
Many genes are involved
Genes and the environment are involved
What are many complex genetic diseases due to?
Single nucleotide polymorphisms (SNPs)
How many SNPs are currently known in the human genome?
10 million
Are there other variations in our genome besides SNPs?
Yes
But SNPs are the most important variation
Is age related hearing loss considered a complex disease?
Yes
Most 20-year-olds do not have a hearing loss but at least 50% of 70-year-olds do
There also is a difference between the best and worst hearing 70-year-olds
The difference between these two 70-year-old groups is partly environmental factors, but also partly genes
~ 50% of the variance is caused by genes and ~50% is caused by the environment
Has genetic analysis identified major genes for age-related hearing loss?
No
Which means its a complex trait with many loci involved
