Lecture 13/14- Genetics Flashcards
(84 cards)
1
Q
What is Konigsmark’s Classification of genetic hearing loss?
A
- No associated abnormalities
- External ear abnormalities
- Eye disease
- Musculoskeletal disease
- Integumentary system disease (Skin, hair, and nails)
- Renal disease (Kidney)
- Nervous system disease
- Metabolic and other abnormalities
2
Q
What are the 2 universal principles of human genetics?
A
- Virtually all diseases (except some cases of trauma) have a genetic component
- There are no perfect human specimens – all of us carry a significant number of DNA glitches
3
Q
What is a genome?
A
Complete set of genetic information o Contains all of the biological information needed to build and maintain the organism o Comprised of all of the organisms’ DNA o Nuclear DNA o Mitochondrial DNA (mtDNA)
4
Q
What is an exome?
A
Protein coding portion of DNA
Proteins are the output of the DNA
o Corresponds to mature RNA
o ~1% of total genome
o Composed of ~180,000 exons
o Mutations in exome harbor ~85% disease causing mutations
5
Q
What is non-coding DNA?
A
o Intron- non-coding sections of a gene
o Important biologic functions
6
Q
What are nucleotides?
A
Nitrogen containing base
A and G are purines
T and C are prymidines
Bound together through sugars and phosphate
7
Q
How is DNA structured?
A
- Nucleotides
- DNA bases form pairs (A and T, C and G)
- Nucleotides strand forms a spiral (double helix)
- Sequence AACGTAATTTC
8
Q
What are amino acids?
A
Building blocks of proteins
o Amino acids are sequenced- linked to form proteins
o Order of amino acids dictates protein shape and function
o Proteins- critical roles in the body
9
Q
What are antibodies?
A
Bind to foreign particles- protective function
10
Q
What are enzymes?
A
Carry out almost all of the chemical reactions in cells
11
Q
What are messengers?
A
Transmit signals to coordinate biological processes between cells, tissues, organs
12
Q
What are structural components?
A
Provide structure and support for cells, allow movement
13
Q
What are transport and storage?
A
Bind and carry atoms and small molecules within cells and throughout the body
14
Q
What is a mutation?
A
Change in a gene’s biochemical makeup, change at the DNA level
15
Q
What is a mutagen?
A
A substance that causes a mutation
o Examples: radiation, aflatoxin B (fungus on peanuts), cola, tea, coffee, food additives, cigarette smoke, etc.
16
Q
What is a mutant?
A
An allele that differs from the wild type allele, altering the phenotype
o Wild type: normal variant of a gene
17
Q
What is a spontaneous mutation?
A
A genetic change resulting from the mispairing of bases during replications
18
Q
What is a mutational hot spot?
A
Most likely to happen when the nearby DNA is repetitive
19
Q
What is a point mutation?
A
Involving a single nucleotide in the DNA molecule
20
Q
What is a missense mutation?
A
Change in a codon so that it codes for a different amino acid
21
Q
What is a nonsense mutation?
A
Changes a codon specifying an amino acid into a “stop” codon (UAA, UAG, UGA)- results in a shortened protein produce
22
Q
What is a deletion and insertion?
A
Involving >1 nucleotide
o Codon deletions and inserts involving bases which are a multiple of 3 resulting in a “frame” mutation
o Expansion of a tri-nucleotide repeat
23
Q
What is a frameshift mutation?
A
Additional or deletion of bases that are not a multiple of 3 with disruption of the reading frame of the protein
24
Q
What are structural chromosomal abnormalities?
A
Telomeres: protects chromosome
• Will shorten with aging process
• Dysfunction is associated with some diseases
Centromere: involved in cell division and replication of cells
P arm (short arm)
Q arm (long arm)
Bands: specific address of a gene
25
What are the number of chromosomes?
46 chromosomes, 23 homologous pairs
• 22 pairs are autosomes (the same regardless of sex)
• 1 pair of sex chromosomes
Biologically female: XX
Biologically male: XY
26
What is aneuploidy?
One or more extra or missing chromosomes
27
What is a translocation?
Change of location.
- In genetics this typically refers to transfer of a segment of a chromosome to a new position, most often on another chromosome
28
What is a deletion?
Loss of genetic material, ranging from a single nucleotide to an entire pice of chromosome
29
What is an inversion?
Same genetic material, but it is flipped
30
What are characteristics of autosomal dominant traits?
* Only one copy of gene to product phenotype
* Chance of recurrence is ½
* Vertical family pattern
* Persons with the trait have a parent with the trait, unless they represent a new mutation
* If line broken, stays broken
* Male: female= 1:1
31
What is autosomal dominant inheritance?
```
D= dominant allele for deafness
d= allele for hearing
```
One of three possible patterns:
o DD= homozygote (Phenotype: deaf)
o Dd= heterozygote (Phenotype: deaf)
o dd= homozygote (Phenotype= hearing)
32
What is penetrance?
o The percentage of individuals who possess a dominant gene and express it
33
What is incomplete penetrance?
Not every individual who has the genotype displays the phenotype
34
What is variable expressivity?
A genotype producing a phenotype that varies among individuals
35
What are the characteristics of autosomal recessive traits?
* Double dose of gene required
* Chance of occurrence ¼
* Carrier (heterozygous) parents
* Horizontal family pattern
* Male: Female 1:1
36
What is recessive inheritance?
```
R= allele for hearing
r= allele for deafness
```
One of three patterns:
o RR= homozygous (Phenotype: hearing)
o Rr= heterozygous (Phenotype: hearing)
o rr= homozygous (Phenotype: deaf)
37
What are X-linked recessive or dominant inheritance?
o Males> females
o No father to son transmission
o All the daughters of a male with the trait will be carriers
o Carrier females; 50% chance to have sons with the trait, 50% chance to have carrier daughters
o Trait may be transmitted through a series of carrier females
38
What is X-linked recessive inheritance?
```
X= allele for hearing
x= allele for deafness
```
One of four patterns:
• XX= homozygote (Phenotype: hearing female)
• Xx= heterozygote (Phenotype: hearing female)
• XY= hemizygote (Phenotype: hearing male)
• xY= hemizygote (Phenotype: deaf male)
39
What is a mitochondrial inheritance?
Mitochondria: energy producers
| Contain single circular piece of DNA
40
What are the characteristics of mitochondrial inheritance?
* Trail is passed through maternal line only
* All offspring of a mother with the disorder will inherit the trait
* No children of a father with the disorder will inherit the trait
* Both sexes are affected
* Reduce penetrance, variable expressivity and pleiotropy
41
What is homoplasmy?
All mitochondria have DNA with mutation
42
What is meteroplasmy?
Mutant and normal DNA found in mitochondria
43
What are the characteristics of mitochondrial disorders?
Characterized by neurologic, cardiac, muscular Sx as well as deafness and blindness (high energy tissues)
44
What is a genotype?
The specific genetic constitution of an organisms; the allele combinations in an individual that cause a particular trait or disorder
45
What is a phenotype?
The observable properties of an organism; the expression of genes in traits or symptoms
46
What is an allele?
One member of a pair of genes at a given location on a chromosome
47
What is a wild type allele?
Most common or normal form
48
What is a disease-causing mutation allele?
Alternations in DNA sequence of a gene associated with altered or absent gene function
49
What is a polymorphism allele?
Alterations in the wild-type sequence of a gene function
50
What is an allelic variance of unknown significance?
Alteration in the sequence of a gene, the significance of which is unclear until further study of the genotype and corresponding phenotype in a sufficient large population
51
What is a locus?
Each gene is found in a specific place on the chromosome
52
What is homozygous?
The alleles do match each other
53
What is heterozygous?
The alleles do not match each other
54
What is heterogeneity?
Several different genes result in one phenotype
55
What is a phenocopy?
An environmental factor mimics a genetic conditions and results in the same phenotype
56
What is pleiotrophy?
One gene (or a pair of genes) causes multiple phenotypic effects in the body
57
What does DFNA stand for?
Autosomal dominant
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What does DFNB stand for?
Autosomal recessive
59
What does DFNX stand for?
X-linked
60
What does DFNY stand for?
Y-linked
61
What does DFNM stand for?
Modifier gene
62
What are the characteristics of nonsyndromic DFNA hearing loss?
12-15% of prelingual hereditary hearing loss
Less severe than DFNB
Postlingual more common than prelingual
Sometimes hard to differentiate from environmental factors and aging
Genetically heterogeneous
All SNHL except in a single family linked to DFNA23
5 loci have congenital or prelingual age of onset
- Remaining loci are Postlingual and progressive
- Some start at HF and eventually progress to middle and low frequencies
- 2 loci start in the low frequencies
- Others- all frequencies or greater in middle frequencies
63
What are the characteristics of nonsyndromic autosomal recessive hearing loss?
~56% of prelingual hereditary hearing loss
```
Predominately:
o Prelingual SNHL
o Bilateral
o Severe-to-profound
o Stable
o All frequencies
```
Tendency to partner with another deaf person
64
What are the characteristics of nonsyndromic X-linked recessive or dominant hearing loss?
Congenital Stapes Fixation with Perilymphatic Gusher (Nance Syndrome)
- Hearing loss is SN or mixed
- When mixed, congenital fixation of stapes footplate
- CT scan: dilation of IAC with abnormal communication between the subarachnoid space and endolymph
65
What are the characteristics of Connexin Deafness?
- Most recessive, 6 dominant
- Some syndromic
- Most cases of genetic deafness caused by mutations in this gene
66
What are connexins?
Family of genes that code for subunits of gap junction proteins
67
What are jap junction proteins?
- Docking channels between cells
| - Allow flow of ions and small molecules between cells
68
What are the clinical features of Alport Syndrome?
o Hematuira
o Nephritis with progressive renal failure
o Eye abnormalities including anterior lenticonus, cataracts, and maculopathy
o Progressive sensorineural hearing loss with onset of hearing loss in late childhood to early adulthood
69
What is the inheritance pattern of Alport syndrome?
X-linked, autosomal recessive, autosomal dominant
70
What are the major and minor criteria for diagnosing CHARGE syndrome?
Major criteria
o C: Coloboma
o A: Atresia choanae or cleft lip or palate
o E: Ear anomaly- external, middle, or inner ear or semicircular canal hypoplasia
```
Minor criteria
o H: Heart defect
o R: Retarded growth and development
o G: Genitourinary problems
o Dysphagia
o Structural brain abnormalities
o Skeletal/limb anomalies
o Arhinecephaly and/or anosmia
o Semicircular canal agnesis or hypoplasia
```
71
How is a diagnosis of CHARGE syndrome made?
Requires 3 major or 2 major and any number of minor criteria
72
What is the inheritance pattern for CHARGE syndrome?
Heterozygous mutations
73
What are the clinical features of Branchio-oto-renal syndrome?
```
o SNHL, conductive, or mixed hearing loss
o Branchial pits, cysts, and/or fistulae
o Renal dysplasia or aplasia
o Malformed pinnae
o Ear pits and/or tags
```
74
What is the inheritance pattern for Branchio-oto-renal syndrome?
Autosomal dominant
75
What is Type I of Stickler syndrome?
```
SNHL
Occasionally conductive hearing loss
Progressive myopia (Near sightedness)
Midface hypoplasia
Retinal detachment
Mitral valve prolapse
Degenerative joint disease
Membranous vitreous phenotype
```
76
What is Type II of Stickler Syndrome?
Similar to Type I, except vitreous phenotype is “beaded”
77
What is Type III of Stickler syndrome?
Similar to Type I, except no ocular signs
78
What is the inheritance pattern of Stickler Syndrome?
Autosomal dominant
79
What are the clinical features of Treacher Collins Syndrome?
```
o Malar hypoplasia
o Malformed auricles
o Conductive hearing loss
o Ear tags
o Downward slanting palpebral fissures
o Lower lid coloboma
o Mandibular hypoplasia
o Macrostomia
```
80
What is the inheritance pattern of Treacher Collins Syndrome?
Autosomal dominant
81
Why should genetic testing be recommended?
* Identify etiology, calculate recurrence risk and anticipate other features of syndromes
* Correlate prognosis from cohort of patients with same genotypes
* Current next-generation sequencing technology can identify etiology in large number of cases
* Understand the mechanism of disease in order to develop targeted therapies
* The patient should have the option
82
What are the ACMG guidelines for all newborns and infants with confirmed HL?
Medical and birth history
Prenatal: maternal infections, illnesses, drug exposures
Birth history: prematurity, low birth weight, hypoxia, hyperbilirubinemia, sepsis, ototoxic drugs
Postnatal: viral illnesses, meningitis, head trauma, noise exposure, ototoxic drugs
Audiometric assessment
```
Three-generation family pedigree
1st and 2nd degree relatives with HL, features associated with HL, or sudden cardiac death
Pattern of inheritance
Ethnicity and country of origin
Consanguity
```
83
What are the ACMG guidelines for individuals with findings that suggest a syndromic etiology?
o Pretest genetic counseling
o Genetic testing
o Appropriate studies to determine if other organs are involved
o Appropriate referrals to other specialists
o Plans for near and long-term follow-up
84
What are the ACMG guidelines for individuals lacking physical findings suggestive of a known syndrome and having histories negative for environmental causes of HL?
Tiered diagnostic appraoch
Pretest genetic counseling
Genetic testing
Single gene based on family history suggestive of a particular gene
Singleton cases and pedigrees suggestive of autosomal recessive inheritance: DFNB1 (GJB2 and adjacent GJB6)
If negative, panels targeting HL genes, WES or WGS
Genetic test results
If genetic testing is positive in a HL gene, then mutation specific genetic counseling and appropriate referrals
If genetic testing is negative, the possibility of genetic or acquired etiology remains
Temporal bone imaging
CT or MRI- depending on what is being considered
CT scan of temporal bone
• Abnormal cochlea in ~20% with congenital hearing loss > morphogenetic defect
• Normal cochlea suggests neuroepithelial defect
• What is being looked for?
o Enlarged vestibular aqueduct
o Mondini dysplasia
o Lateral canal dysplasia- CDH7
o Calcification of cochlea- CMV, meningitis
MRI
• Better at evaluating CN8- may have aplasia or hypoplasia of the nerve despite normal bony canal
• Better at detecting mild cochlear dysplasia and modiolar deficiencies
• More expensive and likely to require sedation
• Preferred for unilateral profound hearing loss
o CMV testing concurrent with genetic testing
