Genetic Disease Flashcards
_____% of rare diseases have a genetic cause
70%
Define hereditary disorders
Transmitted through gametes from parents
Define familial
Tends to occur more often in family members than is expected by chance alone
Define Congenital
Present at birth (not necessarily inherited)
Describe syndrome
A group of symptoms which consistently occur together, or a condition characterized by a set of associated symptoms (could be inherited or not)
List the genetic abnormalities that occur within DNA
-Mutation
-Amplification
-Deletion
-Translocation
-Inversion
What is epigenetic inheritance?
A genetic abnormality that happens outside of the genetic sequence
List the single gene mutations
-Point mutation
-Deletion
-Insertion
Describe the point mutations
Nucleotide substitution
-Nonsense –> truncated protein
-Missense –> mutant protein
Describe the types of deletion
-1
-Nonsense
-Missense (frameshift)
Describe the types of Insertion
+1
-Nonsense
-Missense (often frameshift)
+3x?
Trinucleotide Repeat Expansion
What type of mutation is Sickle Cell Anemia?
Missense
Describe repeat expansion
-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
A trinucleotide repeat is made up of __________
3-base-pair sequences and is GC rich
List some of the larger gene alterations
Amplification, deletion, translocation, inversion
-can cause gain or loss of function
-common in cancers
What is Cytogenetics?
The study of inheritance in relation to the structure and function of chromosomes
On a centromere, if the arms of unequal length, how are they termed?
Short arm is call p (petite) and long arm is called q
Understand how they name parts of the chromosome
chromosome #, Arm, region, band, sub-band
**See slide 22 (page 11) of lecture
What is translocation?
Transfer of a part of one chromosome to another chromosome
Describe reciprocal translocation
Fragments are exchanged between 2 chromosomes
Describe balanced translocation
all genetic material is maintained
Described Robertsonian translocation
Translocation between acrocentric chromosomes resulting in subsequent loss of “p” arms
Describe other cytogenetic abnormalities
-Chromosomal inversion
-Isochromosome (centromere divides horizontally rather than vertically)
-Ring chromosome (ends fuse)
What is the term for loss of a whole chromosome? gain?
monosomy; trisomy
Explain this example of karotype nomenclature:
46, XX, t(2;5)(q31;p14)
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
What is epigenetics?
Changes in the regulation of gene expression that are NOT dependent on gene sequence (changes outside of the DNA)
Epigenetic modifications are ________
heritable
What are epigenetic changes often caused by?
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)
Describe non-coding RNAs in regards to epigenetic changes
Micro-RNAs (miRNA) and long non-coding RNAs (lncRNAs) have important regulatory functions to alter gene expression
Describe genomic imprinting in regards to epigenetic changes
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)
List the major categories of genetic disorders
-Single gene disorders (routine mendelian inheritance and atypical inheritance disorders)
-Complex multigenic disorders
-Cytogenetic disorders (can be single gene or polyhenic)
List the mendelian inheritance patterns
-Autosomal dominant
-Autosomal recessive
-X-linked dominant
-X-linked recessive
-Codominant
What is Pleiotropy
Single gene mutation having many phenotypic effects
What is genetic heterogeneity
A mutation at several different loci causing the same trait
What are modifier genes?
Affect the severity or extent of the phenotype caused by a mutation
List the target groups for autosomal dominant gene defects
-Structural proteins
-Receptor proteins or channels
-Growth protein
List the target groups for autosomal recessive gene defects
-Enzyme proteins
-Lysosomal storage diseases
Describe Marfan Syndrome
-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
List the clinical defects of Marfan syndrome
-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
Describe Ehlers-Danlos Syndrome
-Group of diseases with structural or functional defects in collagen
-Dominant or recessive
Describe the clinical features of Ehlers-Danlos Syndrome
-Very stretchable and fragile skin
-Hypermobile joints
-Internal complications: colon rupture, ocular fragility and diaphragmatic hernia
Describe Muscular Dystrophy (MD)
-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
Describe Familial Hypercholesterolemia (FH)
-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
What are the clinical features of Familial Hypercholesterolemia (FH)
-High blood LDL and cholesterol cause premature atherosclerosis and coronary artery disease
-Cholesterol deposits in skin
Describe Cystic Fibrosis
-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
What are the clinical features of cystic fibrosis
-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
Describe Neurofibromatosis
-Von Recklinghausen disease of skin
-Autosomal dominant
-Highly variable expressivity
-Mutation in the NF1 (neurofibromin) gene leads to increased cell growth
What are the clinical features of Neurofibromatosis
-Neurofibromas: benign skin tumors
-Cafe-au-lait spots: light brown skin macules
Describe Phenylketonuria (PKU)
-Lack of phenylalanine hydroxylase leads to elevated levels of phenylalanine (can’t convert it to tyrosine)
-Screened for at birth
What are the clinical features of Phenylketonuria (PKU)
-Common in persons of Scandinavian descent
-Impaired brain development (mental retardation, seizures)
-Decreased hair/skin pigmentation (tyrosine is a precursor of melanin)
What is the treatment for Phenylketonuria (PKU)
Life-long diet restriction (avoid high-protein foods); promising new therapies - long term studies needed
What are the dental implications of Phenylketonuria (PKU)
-Potential higher cariogenic diet and erosive supplements
-Headaches, ADD and trouble focusing may occur
What are lysosomes critical in?
-Breakdown of complex molecules from worn-out organelles (autophagy) or from outside the cell
-Immunity: fuse with phagosomes
-Membrane repair: fusion with plasma membrane
In lysosomal storage diseases, lack of lysosomal enzyme leads to……
-Accumulation of partially degraded metabolites (primary storage)
-Defective degradation of organelles (secondary story) –> old mitochondria –> triggers free radical production and apoptosis
In lysosomal storage diseases, cell dysfunction is made worse by _________
macrophage activation and cytokine release
What are the general features of lysosomal storage diseases?
-Autosomal recessive
-Some are common in Ashkenazi Jews
-Typically fatal in childhood
-Frequent CNS involvement
What are some examples of lysosomal storage diseases
-Glycogenoses
-Tay-Sachs disease
-Niemann-Pick Disease
-Gaucher Disease
-Mucopolysaccharidoses
Describe Glycogen storage disease
Deficiency of enzymes involved in glycogen metabolism leading to storage of normal and abnormal forms of glycogen mostly in the liver or muscles
What are the clinical features of glycogen storage disease?
-Liver enlargement
-Muscle weakness
What is Mucopolysaccharidoses? What are some examples?
-Defective breakdown and storage of mucopolysaccharides (same as glycosaminoglycans) causing increase in tissues
-Cardiac problems, mental retardation
-Ex: Hunter Sx, Hurler Sx
Describe disorders with Atypical inheritance
-Trinucleotide repeats
-Mutations in mitochondrial genes
-Genomic imprinting and uniparental disomy
In regard to triplet repeat mutations, what is Anticipation?
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
Both ________ and _______ are variable, and relate to the number of triplet repeats
Penetrance; Expressivity
(The more repeats, the more penetrance and the more expressivity)
What is penetrnce?
The proportion (%) of individuals with the mutation who exhibit clinical symptoms. Quantitative evaluation.
What is Expressivity?
Severity or pattern by which a disease is manifested. Qualitative evaluation.
What is Huntington Disease?
-Triplet repeat mutation disease
-Autosomal dominant
-Misfolded proteins in brain
-Uncontrolled movement
-Decreased cognition
What is Fragile X Syndrome?
-Triplet repeat mutation disease
-X-linked train (mostly males)
-Moderate to severe retardation, post-pubertal macroorchidism (large testicles)
Describe Mitochondrial inheritance
Maternal inheritance: mitochondrial DNA (mtDNA) inherited only from mother, can pass to son or daughters
Most proteins in the mitochondria are _____ encoded and transported into the mitochondria, while the rest are encoded by _____
nuclear; mtDNA
Mitochondrial diseases can be due to mutations in _________
nuclear DNA or mtDNA
What is Genomic Imprinting?
-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
What is Uniparental disomy?
-Atypical inheritance
-2 chromosomes from one parent and none from the other. If retained copy is imprinted –> loss of gene function
What are two examples of syndromes caused by atypical inheritance
Prader-Willi Sx, Angelman Sx
Describe complex multigenic disorders?
-“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
Give some disease examples of multigenic disorders
-Type 1 and 2 diabetes
-Hypertension
-Gout
-Cancer
-Glaucoma
-Epilepsy
-Schizophrenia
What happens if the total number of “effector alleles” and environmental influences exceeds a certain threshold in complex multigenic inheritance?
A phenotypic expression occurs
(Before this point there will be no manifestation of the condition)
Describe the general features of Cytogenic disorders
-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.
In regards to Cytogenic disorders, imbalance if sex chromosomes is tolerated better than with autosomes. Why?
-Lyonization (only one X chromosome is mostly active)
-Only small amount of genetic information carried by Y chromosome
Describe Down Syndrome; Trisomy 21
-Most common cytogenetic disorder
-Trisomy 21 caused by non-disjunction at first meiotic division
-Maternal age increases the chance of non-disjunction
What are the clinical features of Down Syndrome?
Epicanthic folds + flat facial profile, mental retardation, hypothyroid, cardiac malformations; increased risk for leukemia, increased infections including periodontal disease
Describe Klinefelter Syndrome
Male with at least two X chromosomes and one or more Y chromosomes (XXY typically)
What are the clinical features of Klinefelter Syndrome?
-Decreased male traits (reduced facial/body hair, smell testes) can be improved with testosterone replacement therapy
-Infertility
-Gynecomastia- male breast development
-Mild intellectual impairment
Describe Turner Syndrome
Phenotypic female with loss of one X chromosome (XO)
What are the clinical features of Turner Syndrome? Dental findings?
-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
Describe Prenatal genetic testing
-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
Describe Postnatal genetic testing
-Congenital abnormalities, mental/developmental delays, suspected chromosomal problems
-Sample: use peripheral blood lymphocytes
When should a dentist suspect a rare, possibly genetic, disease?
-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
How is a molecular diagnosis of genetic disease made?
-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
What is a single nucleotide polymorphism (SNP)?
-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
Describe the steps of Illumnia Sequencing
- Prepare genomic DNA
- Attach DNA to surface
- Bridge amplification
- Fragments become double-stranded
- Denature the double stranded molecules
- 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
Definition of Gene
A segment of DNA that codes for synthesis of a polypeptide; determines a trait or component of a trait
Definition of Chromosome
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.
Definition of Alleles
Term describing a pair of like genes
Definition of Sex Chromosomes
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
Definition of Autosomes
The 22 pairs of chromosomes (all except the sex chromosomes)
Definition of Dominant
Among alleles, typically only 1 determines the attribute. That gene is dominant
Definition of Recessive
The allele of the pair that doesn’t have influence on the attribute
Definition of Codominant
When both alleles have equal influence on an attribute and the attribute represents a blend
Definition of Genotype.
-Heterozygous
-Homozygous
-Hemizygous
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
Definition of Phenotype
The outward expression of the gene makeup
Definition of Penetrance
The ability of a dominant gene to express itself in a phenotype. Listed as %
Definition of Expressivity
The degree to which a dominant gene expresses itself in a phenotype
Definition of Forme Fruste
A minimum expression of a dominant gene in the phenotype
Definition of Proband
The original person that presents a genetic disease to your attention
Definition of Kindred
The probands whole family
Definition of Mutation, Germline, and Somatic
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
Definition of Inherited
Derived from your parent’s genes
Definition of Genetic disease
Caused by a germline mutation but not necessarily passed on to children
Definition of Familial
Runs in families - often but not necessarily inherited
Definition of Carrier
One who silently carries a mutated recessive gene in the germline
