Lecture 13/14- Genetics Flashcards
What is Konigsmark’s Classification of genetic hearing loss?
- 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
What are the 2 universal principles of human genetics?
- 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
What is a genome?
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)
What is an exome?
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
What is non-coding DNA?
o Intron- non-coding sections of a gene
o Important biologic functions
What are nucleotides?
Nitrogen containing base
A and G are purines
T and C are prymidines
Bound together through sugars and phosphate
How is DNA structured?
- Nucleotides
- DNA bases form pairs (A and T, C and G)
- Nucleotides strand forms a spiral (double helix)
- Sequence AACGTAATTTC
What are amino acids?
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
What are antibodies?
Bind to foreign particles- protective function
What are enzymes?
Carry out almost all of the chemical reactions in cells
What are messengers?
Transmit signals to coordinate biological processes between cells, tissues, organs
What are structural components?
Provide structure and support for cells, allow movement
What are transport and storage?
Bind and carry atoms and small molecules within cells and throughout the body
What is a mutation?
Change in a gene’s biochemical makeup, change at the DNA level
What is a mutagen?
A substance that causes a mutation
o Examples: radiation, aflatoxin B (fungus on peanuts), cola, tea, coffee, food additives, cigarette smoke, etc.
What is a mutant?
An allele that differs from the wild type allele, altering the phenotype
o Wild type: normal variant of a gene
What is a spontaneous mutation?
A genetic change resulting from the mispairing of bases during replications
What is a mutational hot spot?
Most likely to happen when the nearby DNA is repetitive
What is a point mutation?
Involving a single nucleotide in the DNA molecule
What is a missense mutation?
Change in a codon so that it codes for a different amino acid
What is a nonsense mutation?
Changes a codon specifying an amino acid into a “stop” codon (UAA, UAG, UGA)- results in a shortened protein produce
What is a deletion and insertion?
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
What is a frameshift mutation?
Additional or deletion of bases that are not a multiple of 3 with disruption of the reading frame of the protein
What are structural chromosomal abnormalities?
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
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
What is aneuploidy?
One or more extra or missing chromosomes
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
What is a deletion?
Loss of genetic material, ranging from a single nucleotide to an entire pice of chromosome
What is an inversion?
Same genetic material, but it is flipped
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
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)
What is penetrance?
o The percentage of individuals who possess a dominant gene and express it
What is incomplete penetrance?
Not every individual who has the genotype displays the phenotype
What is variable expressivity?
A genotype producing a phenotype that varies among individuals
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
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)
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
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)
What is a mitochondrial inheritance?
Mitochondria: energy producers
Contain single circular piece of DNA
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
What is homoplasmy?
All mitochondria have DNA with mutation
What is meteroplasmy?
Mutant and normal DNA found in mitochondria
What are the characteristics of mitochondrial disorders?
Characterized by neurologic, cardiac, muscular Sx as well as deafness and blindness (high energy tissues)
What is a genotype?
The specific genetic constitution of an organisms; the allele combinations in an individual that cause a particular trait or disorder
What is a phenotype?
The observable properties of an organism; the expression of genes in traits or symptoms
What is an allele?
One member of a pair of genes at a given location on a chromosome
What is a wild type allele?
Most common or normal form
What is a disease-causing mutation allele?
Alternations in DNA sequence of a gene associated with altered or absent gene function
What is a polymorphism allele?
Alterations in the wild-type sequence of a gene function
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
What is a locus?
Each gene is found in a specific place on the chromosome
What is homozygous?
The alleles do match each other
What is heterozygous?
The alleles do not match each other
What is heterogeneity?
Several different genes result in one phenotype
What is a phenocopy?
An environmental factor mimics a genetic conditions and results in the same phenotype
What is pleiotrophy?
One gene (or a pair of genes) causes multiple phenotypic effects in the body
What does DFNA stand for?
Autosomal dominant
What does DFNB stand for?
Autosomal recessive
What does DFNX stand for?
X-linked
What does DFNY stand for?
Y-linked
What does DFNM stand for?
Modifier gene
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
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
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
What are the characteristics of Connexin Deafness?
- Most recessive, 6 dominant
- Some syndromic
- Most cases of genetic deafness caused by mutations in this gene
What are connexins?
Family of genes that code for subunits of gap junction proteins
What are jap junction proteins?
- Docking channels between cells
- Allow flow of ions and small molecules between cells
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
What is the inheritance pattern of Alport syndrome?
X-linked, autosomal recessive, autosomal dominant
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
How is a diagnosis of CHARGE syndrome made?
Requires 3 major or 2 major and any number of minor criteria
What is the inheritance pattern for CHARGE syndrome?
Heterozygous mutations
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
What is the inheritance pattern for Branchio-oto-renal syndrome?
Autosomal dominant
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
What is Type II of Stickler Syndrome?
Similar to Type I, except vitreous phenotype is “beaded”
What is Type III of Stickler syndrome?
Similar to Type I, except no ocular signs
What is the inheritance pattern of Stickler Syndrome?
Autosomal dominant
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
What is the inheritance pattern of Treacher Collins Syndrome?
Autosomal dominant
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
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
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
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
