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General Pathology > Genetic Disease > Flashcards

Genetic Disease Flashcards

1
Q

_____% of rare diseases have a genetic cause

A

70%

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2
Q

Define hereditary disorders

A

Transmitted through gametes from parents

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3
Q

Define familial

A

Tends to occur more often in family members than is expected by chance alone

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4
Q

Define Congenital

A

Present at birth (not necessarily inherited)

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5
Q

Describe syndrome

A

A group of symptoms which consistently occur together, or a condition characterized by a set of associated symptoms (could be inherited or not)

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6
Q

List the genetic abnormalities that occur within DNA

A

-Mutation
-Amplification
-Deletion
-Translocation
-Inversion

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7
Q

What is epigenetic inheritance?

A

A genetic abnormality that happens outside of the genetic sequence

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8
Q

List the single gene mutations

A

-Point mutation
-Deletion
-Insertion

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9
Q

Describe the point mutations

A

Nucleotide substitution

-Nonsense –> truncated protein
-Missense –> mutant protein

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10
Q

Describe the types of deletion

A

-1
-Nonsense
-Missense (frameshift)

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11
Q

Describe the types of Insertion

A

+1
-Nonsense
-Missense (often frameshift)

+3x?
Trinucleotide Repeat Expansion

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12
Q

What type of mutation is Sickle Cell Anemia?

A

Missense

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13
Q

Describe repeat expansion

A

-Single gene mutation
-Nucleotide repeats are short DNA sequences that are repeated a number of times in a row
-A repeat expansion is a mutation during meiosis that increases the number of time that the short DNA sequence is repeated causing protein dysfunction and phenotypic defects

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14
Q

A trinucleotide repeat is made up of __________

A

3-base-pair sequences and is GC rich

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15
Q

List some of the larger gene alterations

A

Amplification, deletion, translocation, inversion
-can cause gain or loss of function
-common in cancers

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16
Q

What is Cytogenetics?

A

The study of inheritance in relation to the structure and function of chromosomes

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17
Q

On a centromere, if the arms of unequal length, how are they termed?

A

Short arm is call p (petite) and long arm is called q

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18
Q

Understand how they name parts of the chromosome

A

chromosome #, Arm, region, band, sub-band

**See slide 22 (page 11) of lecture

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19
Q

What is translocation?

A

Transfer of a part of one chromosome to another chromosome

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20
Q

Describe reciprocal translocation

A

Fragments are exchanged between 2 chromosomes

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21
Q

Describe balanced translocation

A

all genetic material is maintained

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22
Q

Described Robertsonian translocation

A

Translocation between acrocentric chromosomes resulting in subsequent loss of “p” arms

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23
Q

Describe other cytogenetic abnormalities

A

-Chromosomal inversion
-Isochromosome (centromere divides horizontally rather than vertically)
-Ring chromosome (ends fuse)

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24
Q

What is the term for loss of a whole chromosome? gain?

A

monosomy; trisomy

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25
Q

Explain this example of karotype nomenclature:

46, XX, t(2;5)(q31;p14)

A

46 is the total number of chromosomes

XX means female

t(2;5)(q31;p14) means balanced translocation between chromosome 2 and chromosome 5, with breaks in 2q31 and 5p14

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26
Q

What is epigenetics?

A

Changes in the regulation of gene expression that are NOT dependent on gene sequence (changes outside of the DNA)

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27
Q

Epigenetic modifications are ________

A

heritable

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28
Q

What are epigenetic changes often caused by?

A

chemical modifications of the DNA or chromosomal proteins:
-DNA methylation (typically causes silencing)
-Histone modifications (acetylation, methylation, phosphorylation or other modifications can silence or enhance gene expression)

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29
Q

Describe non-coding RNAs in regards to epigenetic changes

A

Micro-RNAs (miRNA) and long non-coding RNAs (lncRNAs) have important regulatory functions to alter gene expression

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30
Q

Describe genomic imprinting in regards to epigenetic changes

A

DNA or histone methylation silences one chromosome’s allele while the non-imprinted allele on the other chromosome is expressed

(Imprinted genes are at greater risk to express mutational events)

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31
Q

List the major categories of genetic disorders

A

-Single gene disorders (routine mendelian inheritance and atypical inheritance disorders)
-Complex multigenic disorders
-Cytogenetic disorders (can be single gene or polyhenic)

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32
Q

List the mendelian inheritance patterns

A

-Autosomal dominant
-Autosomal recessive
-X-linked dominant
-X-linked recessive
-Codominant

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33
Q

What is Pleiotropy

A

Single gene mutation having many phenotypic effects

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34
Q

What is genetic heterogeneity

A

A mutation at several different loci causing the same trait

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35
Q

What are modifier genes?

A

Affect the severity or extent of the phenotype caused by a mutation

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36
Q

List the target groups for autosomal dominant gene defects

A

-Structural proteins
-Receptor proteins or channels
-Growth protein

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37
Q

List the target groups for autosomal recessive gene defects

A

-Enzyme proteins
-Lysosomal storage diseases

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38
Q

Describe Marfan Syndrome

A

-Autosomal dominant
-Mutation of fibrillin (ECM component of elastic fibers)
-Example of pleiotropy: elastic fibers are present in many tissues throughout the body, so the disease has wide-ranging effects

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39
Q

List the clinical defects of Marfan syndrome

A

-Elongated habitus: slender, long legs, arms and fingers
-Hyperextensible joints
-Oral: high arched palate
-Ocular: dislocation of lens
-Cardiovascular: elastic fiber fragmentation of the tunica media –> aortic dilation and dissection

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40
Q

Describe Ehlers-Danlos Syndrome

A

-Group of diseases with structural or functional defects in collagen
-Dominant or recessive

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41
Q

Describe the clinical features of Ehlers-Danlos Syndrome

A

-Very stretchable and fragile skin
-Hypermobile joints
-Internal complications: colon rupture, ocular fragility and diaphragmatic hernia

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42
Q

Describe Muscular Dystrophy (MD)

A

-Duchenne MD (severe form), Becker MD (milder form)
-X-linked recessive
-Mutation in dystrophin gene, whose protein protects muscle (skeletal and cardiac) cells during contraction, link internal cytoskeleton to the extracellular matrix
-Progressive damage, inability to repair leads to muscle cell death and replacement by scar tissue and fat
-Muscle weakness in childhood leading to death in early adulthood

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43
Q

Describe Familial Hypercholesterolemia (FH)

A

-Autosomal dominant; one of the most common Mendelian disorders
-Loss of function mutation of the low-density lipoprotein (LDL) receptor leads to:
1. elevated LDL (bad cholesterol) in the plasma
2. lack of LDL uptake into the liver cells induces hydroxymethylglutaryl-coenzyme A (HMG-CoA) to activate cholesterol synthesis

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44
Q

What are the clinical features of Familial Hypercholesterolemia (FH)

A

-High blood LDL and cholesterol cause premature atherosclerosis and coronary artery disease
-Cholesterol deposits in skin

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45
Q

Describe Cystic Fibrosis

A

-Most common autosomal recessive disorder
-Mutation in CFTR gene causes protein misfolding and degradation in the endoplasmic reticulum
-Defect in Cl- ion transport causes very thick, mucous secretion from EXOCRINE glands

46
Q

What are the clinical features of cystic fibrosis

A

-Chronic pulmonary infections
-Pancreatic exocrine insufficiency due to progressive fibrosis lead to protein, fat malabsorption, and potentially fat-solube vitamin deficiency (A,D,K), diarrhea
-Fatty liver is common –> cirrhosis
-Salty sweat gland secretion

47
Q

Describe Neurofibromatosis

A

-Von Recklinghausen disease of skin
-Autosomal dominant
-Highly variable expressivity
-Mutation in the NF1 (neurofibromin) gene leads to increased cell growth

48
Q

What are the clinical features of Neurofibromatosis

A

-Neurofibromas: benign skin tumors
-Cafe-au-lait spots: light brown skin macules

49
Q

Describe Phenylketonuria (PKU)

A

-Lack of phenylalanine hydroxylase leads to elevated levels of phenylalanine (can’t convert it to tyrosine)
-Screened for at birth

50
Q

What are the clinical features of Phenylketonuria (PKU)

A

-Common in persons of Scandinavian descent
-Impaired brain development (mental retardation, seizures)
-Decreased hair/skin pigmentation (tyrosine is a precursor of melanin)

51
Q

What is the treatment for Phenylketonuria (PKU)

A

Life-long diet restriction (avoid high-protein foods); promising new therapies - long term studies needed

52
Q

What are the dental implications of Phenylketonuria (PKU)

A

-Potential higher cariogenic diet and erosive supplements
-Headaches, ADD and trouble focusing may occur

53
Q

What are lysosomes critical in?

A

-Breakdown of complex molecules from worn-out organelles (autophagy) or from outside the cell
-Immunity: fuse with phagosomes
-Membrane repair: fusion with plasma membrane

54
Q

In lysosomal storage diseases, lack of lysosomal enzyme leads to……

A

-Accumulation of partially degraded metabolites (primary storage)
-Defective degradation of organelles (secondary story) –> old mitochondria –> triggers free radical production and apoptosis

55
Q

In lysosomal storage diseases, cell dysfunction is made worse by _________

A

macrophage activation and cytokine release

56
Q

What are the general features of lysosomal storage diseases?

A

-Autosomal recessive
-Some are common in Ashkenazi Jews
-Typically fatal in childhood
-Frequent CNS involvement

57
Q

What are some examples of lysosomal storage diseases

A

-Glycogenoses
-Tay-Sachs disease
-Niemann-Pick Disease
-Gaucher Disease
-Mucopolysaccharidoses

58
Q

Describe Glycogen storage disease

A

Deficiency of enzymes involved in glycogen metabolism leading to storage of normal and abnormal forms of glycogen mostly in the liver or muscles

59
Q

What are the clinical features of glycogen storage disease?

A

-Liver enlargement
-Muscle weakness

60
Q

What is Mucopolysaccharidoses? What are some examples?

A

-Defective breakdown and storage of mucopolysaccharides (same as glycosaminoglycans) causing increase in tissues
-Cardiac problems, mental retardation
-Ex: Hunter Sx, Hurler Sx

61
Q

Describe disorders with Atypical inheritance

A

-Trinucleotide repeats
-Mutations in mitochondrial genes
-Genomic imprinting and uniparental disomy

62
Q

In regard to triplet repeat mutations, what is Anticipation?

A

The timing of the onset of disease, and the severity of disease, relate to the number of repeats, and therefore become more severe from generation to generation

63
Q

Both ________ and _______ are variable, and relate to the number of triplet repeats

A

Penetrance; Expressivity

(The more repeats, the more penetrance and the more expressivity)

64
Q

What is penetrnce?

A

The proportion (%) of individuals with the mutation who exhibit clinical symptoms. Quantitative evaluation.

65
Q

What is Expressivity?

A

Severity or pattern by which a disease is manifested. Qualitative evaluation.

66
Q

What is Huntington Disease?

A

-Triplet repeat mutation disease
-Autosomal dominant
-Misfolded proteins in brain
-Uncontrolled movement
-Decreased cognition

67
Q

What is Fragile X Syndrome?

A

-Triplet repeat mutation disease
-X-linked train (mostly males)
-Moderate to severe retardation, post-pubertal macroorchidism (large testicles)

68
Q

Describe Mitochondrial inheritance

A

Maternal inheritance: mitochondrial DNA (mtDNA) inherited only from mother, can pass to son or daughters

69
Q

Most proteins in the mitochondria are _____ encoded and transported into the mitochondria, while the rest are encoded by _____

A

nuclear; mtDNA

70
Q

Mitochondrial diseases can be due to mutations in _________

A

nuclear DNA or mtDNA

71
Q

What is Genomic Imprinting?

A

-Atypical Inheritance
-Epigenetic alteration (methylation) that transcriptionally silences a gene on one chromosome such that only one allele is expressed. If that functional allele is deleted, disease occurs

72
Q

What is Uniparental disomy?

A

-Atypical inheritance
-2 chromosomes from one parent and none from the other. If retained copy is imprinted –> loss of gene function

73
Q

What are two examples of syndromes caused by atypical inheritance

A

Prader-Willi Sx, Angelman Sx

74
Q

Describe complex multigenic disorders?

A

-“multifactorial” or “polygenic” disorders
-Not caused by single mutated inherited gene, rather by multiple inherited genetic polymorphisms (“normal” alleles) that predispose to disease
-Each polymorphism varies in its significance
-Environmental and lifestyle factors significantly influence whether the inherited traits will be expressed phenotypically

75
Q

Give some disease examples of multigenic disorders

A

-Type 1 and 2 diabetes
-Hypertension
-Gout
-Cancer
-Glaucoma
-Epilepsy
-Schizophrenia

76
Q

What happens if the total number of “effector alleles” and environmental influences exceeds a certain threshold in complex multigenic inheritance?

A

A phenotypic expression occurs

(Before this point there will be no manifestation of the condition)

77
Q

Describe the general features of Cytogenic disorders

A

-Change in chromosome # (not inherited) or change in chromosome structure (potentially inherited)
-Loss of chromosomal material is worse than gain
-Usually chromosomal disorders occur de novo (parents are normal, recurrence in siblings is low)
-Sex chromosomal disorders often are subtle at birth. Infertility, which is common is diagnosed in adolescence.

78
Q

In regards to Cytogenic disorders, imbalance if sex chromosomes is tolerated better than with autosomes. Why?

A

-Lyonization (only one X chromosome is mostly active)
-Only small amount of genetic information carried by Y chromosome

79
Q

Describe Down Syndrome; Trisomy 21

A

-Most common cytogenetic disorder
-Trisomy 21 caused by non-disjunction at first meiotic division
-Maternal age increases the chance of non-disjunction

80
Q

What are the clinical features of Down Syndrome?

A

Epicanthic folds + flat facial profile, mental retardation, hypothyroid, cardiac malformations; increased risk for leukemia, increased infections including periodontal disease

81
Q

Describe Klinefelter Syndrome

A

Male with at least two X chromosomes and one or more Y chromosomes (XXY typically)

82
Q

What are the clinical features of Klinefelter Syndrome?

A

-Decreased male traits (reduced facial/body hair, smell testes) can be improved with testosterone replacement therapy
-Infertility
-Gynecomastia- male breast development
-Mild intellectual impairment

83
Q

Describe Turner Syndrome

A

Phenotypic female with loss of one X chromosome (XO)

84
Q

What are the clinical features of Turner Syndrome? Dental findings?

A

-Slowed growth- short stature
-Webbing of the neck
-Low posterior hairline
-Primary amenorrhea and infertility
-Decreased female secondary sex characteristics
-Cardiovascular problems: most common cause of death in childhood
-Hypothyroidism
-Usually intellectually normal

Dental Findings:
May have increased caries rate, hypoplasia of crowns and roots

85
Q

Describe Prenatal genetic testing

A

-Targets at-risk patients (maternal age >34, confirmed carrier status, fetal abnormalities on ultrasound, other sibling affected, ect.)
-Sample: amniocentesis, placental biopsy or maternal blood

86
Q

Describe Postnatal genetic testing

A

-Congenital abnormalities, mental/developmental delays, suspected chromosomal problems
-Sample: use peripheral blood lymphocytes

87
Q

When should a dentist suspect a rare, possibly genetic, disease?

A

-Often occurs during development/growth
-Multiple lesions, bilateral lesions, multiple organs (bones/teeth or skin/mucosal surfaces)
-Visual abnormalities/asymmetry pf the head, face, jaws
-Abnormalities in teeth, hair, nails, digits, sweat glands or salivary glands
-Correlate these findings with the medical history: developmental abnormalities of any other organ system
-Ask about family members having similar changes

88
Q

How is a molecular diagnosis of genetic disease made?

A

-Can look for germline or somatic changes of genes or proteins
-High-resolution microarrays (gene chips or protein chips) that can scan for DNA and protein defects genome-wide
-Next-Generation sequencing- high-throughput, automated approach

89
Q

What is a single nucleotide polymorphism (SNP)?

A

-Mostly bialletic (only 2 choices, such as A or T)
-They are a physical landmark within the genome
-While effect on disease is weak, can alter gene expression
-“Neutral” SNPs have no effect on gene function but may be coinherited with a disease-associated gene it could be useful
-Evaluated using comparative array-based genomic hybridization

90
Q

Describe the steps of Illumnia Sequencing

A
  1. Prepare genomic DNA
  2. Attach DNA to surface
  3. Bridge amplification
  4. Fragments become double-stranded
  5. Denature the double stranded molecules
  6. Complete amplification

The complementary strand of DNA in each cluster is synthesized with flourescent-tagged nucleotides, and lasers identify each base for each cluster for each cycle

91
Q

Definition of Gene

A

A segment of DNA that codes for synthesis of a polypeptide; determines a trait or component of a trait

92
Q

Definition of Chromosome

A

A thread of DNA composed of multiple aligned genes. Each chromosome has a mate composed of similarly functioning genes, one derived from each parent. There are 23 pairs.

93
Q

Definition of Alleles

A

Term describing a pair of like genes

94
Q

Definition of Sex Chromosomes

A

The one pair of chromosomes that determines gender. X chromosome, derived from the mother, is large and carries many other genes; Y chromosome, derived from father, is small and determines only male gender

95
Q

Definition of Autosomes

A

The 22 pairs of chromosomes (all except the sex chromosomes)

96
Q

Definition of Dominant

A

Among alleles, typically only 1 determines the attribute. That gene is dominant

97
Q

Definition of Recessive

A

The allele of the pair that doesn’t have influence on the attribute

98
Q

Definition of Codominant

A

When both alleles have equal influence on an attribute and the attribute represents a blend

99
Q

Definition of Genotype.

-Heterozygous
-Homozygous
-Hemizygous

A

Genotype: the makeup of your alleles

Heterozygous: both genes are different (hybrid)

Homozygous: Both gene are the same

Hemizygous: possessing only one gene (without the allele) as occurs with the X chromosome because the Y chromosome has no corresponding allele

100
Q

Definition of Phenotype

A

The outward expression of the gene makeup

101
Q

Definition of Penetrance

A

The ability of a dominant gene to express itself in a phenotype. Listed as %

102
Q

Definition of Expressivity

A

The degree to which a dominant gene expresses itself in a phenotype

103
Q

Definition of Forme Fruste

A

A minimum expression of a dominant gene in the phenotype

104
Q

Definition of Proband

A

The original person that presents a genetic disease to your attention

105
Q

Definition of Kindred

A

The probands whole family

106
Q

Definition of Mutation, Germline, and Somatic

A

Mutation: change in a gene that alters its function

Germline: Occurs in all body cells and germ cells and is thus passed on to children

Somatic: Occurs in an isolated group of cells and is not heritable

107
Q

Definition of Inherited

A

Derived from your parent’s genes

108
Q

Definition of Genetic disease

A

Caused by a germline mutation but not necessarily passed on to children

109
Q

Definition of Familial

A

Runs in families - often but not necessarily inherited

110
Q

Definition of Carrier

A

One who silently carries a mutated recessive gene in the germline

General Pathology (32 decks)

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