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HESP 632 - Medical Audiology > Lecture 13/14- Genetics > Flashcards

Lecture 13/14- Genetics Flashcards

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USMLE® Step 1 flashcards
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
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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
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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)
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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

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5
Q

What is non-coding DNA?

A

o Intron- non-coding sections of a gene

o Important biologic functions

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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

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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
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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

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9
Q

What are antibodies?

A

Bind to foreign particles- protective function

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10
Q

What are enzymes?

A

Carry out almost all of the chemical reactions in cells

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11
Q

What are messengers?

A

Transmit signals to coordinate biological processes between cells, tissues, organs

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12
Q

What are structural components?

A

Provide structure and support for cells, allow movement

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13
Q

What are transport and storage?

A

Bind and carry atoms and small molecules within cells and throughout the body

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14
Q

What is a mutation?

A

Change in a gene’s biochemical makeup, change at the DNA level

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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.

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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

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17
Q

What is a spontaneous mutation?

A

A genetic change resulting from the mispairing of bases during replications

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18
Q

What is a mutational hot spot?

A

Most likely to happen when the nearby DNA is repetitive

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19
Q

What is a point mutation?

A

Involving a single nucleotide in the DNA molecule

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20
Q

What is a missense mutation?

A

Change in a codon so that it codes for a different amino acid

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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

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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

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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

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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

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25
Q

What are the number of chromosomes?

A

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

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26
Q

What is aneuploidy?

A

One or more extra or missing chromosomes

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27
Q

What is a translocation?

A

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
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28
Q

What is a deletion?

A

Loss of genetic material, ranging from a single nucleotide to an entire pice of chromosome

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29
Q

What is an inversion?

A

Same genetic material, but it is flipped

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30
Q

What are characteristics of autosomal dominant traits?

A
  • 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
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31
Q

What is autosomal dominant inheritance?

A 
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)

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32
Q

What is penetrance?

A

o The percentage of individuals who possess a dominant gene and express it

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33
Q

What is incomplete penetrance?

A

Not every individual who has the genotype displays the phenotype

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34
Q

What is variable expressivity?

A

A genotype producing a phenotype that varies among individuals

35
Q

What are the characteristics of autosomal recessive traits?

A
  • Double dose of gene required
  • Chance of occurrence ¼
  • Carrier (heterozygous) parents
  • Horizontal family pattern
  • Male: Female 1:1
36
Q

What is recessive inheritance?

A 
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
Q

What are X-linked recessive or dominant inheritance?

A

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
Q

What is X-linked recessive inheritance?

A 
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
Q

What is a mitochondrial inheritance?

A

 Mitochondria: energy producers

 Contain single circular piece of DNA

40
Q

What are the characteristics of mitochondrial inheritance?

A
  • 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
Q

What is homoplasmy?

A

All mitochondria have DNA with mutation

42
Q

What is meteroplasmy?

A

Mutant and normal DNA found in mitochondria

43
Q

What are the characteristics of mitochondrial disorders?

A

Characterized by neurologic, cardiac, muscular Sx as well as deafness and blindness (high energy tissues)

44
Q

What is a genotype?

A

The specific genetic constitution of an organisms; the allele combinations in an individual that cause a particular trait or disorder

45
Q

What is a phenotype?

A

The observable properties of an organism; the expression of genes in traits or symptoms

46
Q

What is an allele?

A

One member of a pair of genes at a given location on a chromosome

47
Q

What is a wild type allele?

A

Most common or normal form

48
Q

What is a disease-causing mutation allele?

A

Alternations in DNA sequence of a gene associated with altered or absent gene function

49
Q

What is a polymorphism allele?

A

Alterations in the wild-type sequence of a gene function

50
Q

What is an allelic variance of unknown significance?

A

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
Q

What is a locus?

A

Each gene is found in a specific place on the chromosome

52
Q

What is homozygous?

A

The alleles do match each other

53
Q

What is heterozygous?

A

The alleles do not match each other

54
Q

What is heterogeneity?

A

Several different genes result in one phenotype

55
Q

What is a phenocopy?

A

An environmental factor mimics a genetic conditions and results in the same phenotype

56
Q

What is pleiotrophy?

A

One gene (or a pair of genes) causes multiple phenotypic effects in the body

57
Q

What does DFNA stand for?

A

Autosomal dominant

58
Q

What does DFNB stand for?

A

Autosomal recessive

59
Q

What does DFNX stand for?

A

X-linked

60
Q

What does DFNY stand for?

A

Y-linked

61
Q

What does DFNM stand for?

A

Modifier gene

62
Q

What are the characteristics of nonsyndromic DFNA hearing loss?

A

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
Q

What are the characteristics of nonsyndromic autosomal recessive hearing loss?

A

~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
Q

What are the characteristics of nonsyndromic X-linked recessive or dominant hearing loss?

A

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
Q

What are the characteristics of Connexin Deafness?

A
  • Most recessive, 6 dominant
  • Some syndromic
  • Most cases of genetic deafness caused by mutations in this gene
66
Q

What are connexins?

A

Family of genes that code for subunits of gap junction proteins

67
Q

What are jap junction proteins?

A
  • Docking channels between cells

- Allow flow of ions and small molecules between cells

68
Q

What are the clinical features of Alport Syndrome?

A

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
Q

What is the inheritance pattern of Alport syndrome?

A

X-linked, autosomal recessive, autosomal dominant

70
Q

What are the major and minor criteria for diagnosing CHARGE syndrome?

A

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
Q

How is a diagnosis of CHARGE syndrome made?

A

Requires 3 major or 2 major and any number of minor criteria

72
Q

What is the inheritance pattern for CHARGE syndrome?

A

Heterozygous mutations

73
Q

What are the clinical features of Branchio-oto-renal syndrome?

A 
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
Q

What is the inheritance pattern for Branchio-oto-renal syndrome?

A

Autosomal dominant

75
Q

What is Type I of Stickler syndrome?

A 
	SNHL
	Occasionally conductive hearing loss
	Progressive myopia (Near sightedness)
	Midface hypoplasia
	Retinal detachment
	Mitral valve prolapse
	Degenerative joint disease
	Membranous vitreous phenotype
76
Q

What is Type II of Stickler Syndrome?

A

Similar to Type I, except vitreous phenotype is “beaded”

77
Q

What is Type III of Stickler syndrome?

A

Similar to Type I, except no ocular signs

78
Q

What is the inheritance pattern of Stickler Syndrome?

A

Autosomal dominant

79
Q

What are the clinical features of Treacher Collins Syndrome?

A 
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
Q

What is the inheritance pattern of Treacher Collins Syndrome?

A

Autosomal dominant

81
Q

Why should genetic testing be recommended?

A
  • 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
Q

What are the ACMG guidelines for all newborns and infants with confirmed HL?

A

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
Q

What are the ACMG guidelines for individuals with findings that suggest a syndromic etiology?

A

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
Q

What are the ACMG guidelines for individuals lacking physical findings suggestive of a known syndrome and having histories negative for environmental causes of HL?

A

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

HESP 632 - Medical Audiology (7 decks)

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