2 or more clearly different phenotypes being maintained at heterozygote frequency of >2%
Alleles that are classified as rare (<1%) or common
Combination of the allelic consitution of multiple loci on a chromsome
ie A/a and 1/2 could be A2, a2, A1, a1
What is the range of normal genetic variation at the galactosemia locus?
The product of the GALT gene (galactose 1-phosphate uridyl) converts galactose to glucose. A normal range of enzyme activity here is 120% to 50% and includes the N, L, D, and A alleles
Galactosemia results from homozygous G alleles
What is the genetic bases for ABO blood types?
Begin with a ceramide. H-transferase adds carbohydrates onto this to form H antigen. In the next step, a specific transferase adds a sugar onto the antigen to form the end product
A transferase adds N-acetylgalactosamine to form A antigen
B transferase adds galactose to form B antigen
A frameshift mutation (result of a deletion) at the allele causes there to be no functional transferase formed. H antigen remains and is called type O blood
What is the difference between the common disease-common variant model and the common disease-many rare variants model?
The CD-CV model holds that a disease stems from the additive effects of low risk common variants, of which no one is sufficient to cause the disease by itself.
The CD-MRV model holds that disease is caused by a single devastating rare variant, but that multiple different variants could mutate to cause the same disease (locus heterogeneity). This is the currently held model
What does the Holliday model refer to?
the single strand DNA breakage and bridging between ajacent strands that occurs during genetic recombination
What is the relationship between crossing over and linakge of alleles?
Linkage during crossing over depends on the physical proximity of two genes. Genes that are closer together will have a higher chance of remaining on the same chromosome after recombination.
centiMorgan=1% recombination frequency
Single nucleotide polymorphism
determine a person's genetic predisposition to develop a disease
Most disorders caused by these polymorphisms are rare, but altogether, the prevalence is ~2%
finding new drugs using expanding knowledge of the human genome
the study of heritablity in drug response
What genetic factor plays a significant role in drug metabolism?
CYP2D6; controls the clearance of 20% of drugs; part of the cytochrome p450 family; highly polymorphic; amplification and diminishing of activity leads to ultra rapid metabolizers and poor metabolizers
The majority of humans are extensive metabolizers
Why does "one does not fit all"?
Interplay of diet, environment, and polymorphisms in drug metabolizing enzymes, transporters, etc.
How are ethnicity and drug response related?
Different polymorphisms occur at different frequencies in different ethnic populations; this can affect drug metabolism and activities
How do drug-drug interactions alter the genotype-phenotype relationship?
One drug can be activated by a metabolic process that is inhibited by another drug (i.e. Terfenadine must be converted to Fexofenadine by CYP3A4 to be active. Erythromycin and other drugs compete for and inhibit this enzyme)
May also compete to be metabolized by the same enzyme
Drugs can build up to toxic levels within the body
How do drug-diet interactions alter the genotype-phenotype relationship?
Enzyme expression levels can be induced to change by diet; this alters the dose that the patient eneds to take to achieve therapeutic level (i.e. char on outside of steak increases enzymatic activity so that you will never reach maximum drug activity and the drug will wear off faster)
What is meant by Mendelian inheritance?
Single gene, usually looking at mutations that have large effects on the phenotype; follow a characteristic pattern of inheritance in families; only autosomal and x-linked conditions
Definition: Allelic Heterogeneity
mutant alleles at the same locus, each capable of producin an abnormal phenotype
Definition: Locus heterogeneity
Mutations at different loci causing the same, or very similar phenotypes (diseases)
conditions expressed in heterozygotes; only one copy of the mutant allele is sufficient to express the mutant copy; expressed in every generation of a family; males and females have equal chance of inheriting (50%) and passing on the disorder (in autosomal); no carriers; usually due to defects in non-enzyme proteins
Condition expressed in homozygous individuals; two copies of the mutant allele are required to express the disorder; can have carriers; in autosomal, males and females are equally likely to inherit (25% if 2 carrier parents) and equally likely to pass on the disorder; not usually present in more than one generation (skips); usually due to defects in enzyme proteins; disorders usually appear earlier in life
the likelihood that a characteristic will manifest itself
100% penetrance is all or none
Definition: Variable expressivity
different degrees of expression with the same genotype
Marfan syndrome, Achondroplasia, and Neurofibromatosis are all examples of what?
Autosomal dominant disorders
Mutation in gene coding for fibrillin (component of microfibrils); causes connective tissue weakness; also a carrier protein and important modulator of inflammatory reactions
Ocular-->dislocation of lens, myopia, retinal detachment
CV-->dilation of ascending aorta, dissection/rupture of aorta, mitral valve prolapse
Most patient shave an affected parent; 25-30% from new mutation; 1/10,000 people in US
Gain of function mutation in FGFR3; the increased activity inhibits normal growth plate development
80% new mutations; usually paternal when family history is there; can be associated with increased paternal age; 1/15,000 births; complete penetrance (no such thing as mild achondroplasia); if both parents have it, 50% risk of having it, 25% risk of homozygous (lethal), 25% riskk of normal stature
Short proximal extremities, normal spine length, macrocephaly with mideface hypoplasia
50% new mutations; 100% penetrance, but great variable expressivity; 1/3500 people in US
Condition of the nervous system
Cafe au lait (hyperpigmented macule), axillary freckling, neurofibroma (benign subcutaneous tumors), Lisch nodules (small pigmented lesions of the iris), learning difficulties, optic nerve glioma, CNS tumors
Cystic fibrosis and Tay-Sachs disease are examples of what?
Autosomal recessive disorders
Cystic Fibrosis (CF)
1/2500, but carrier rate is 1/25; onset is anywhere from birth to adult
Epithelial ion transporter (CFTR) mutations; transmembrane conductance regulator gene; pancreas enzymes don't absorb food very well; over 1000 alleles lead to this, most are extremely rare; 80% caused by deletion of Phe at 508 (7q21-34)
Meconium ileus (thick fetal stools); malabsorption due to exocrine pancreatic insuficiency; epithelial inflammation and chronic infection in respiratory tract; excessive salt in perspiration (dysfuntional exocrine sweat glands); and male infertility (>95%; caused by congenital absence of vas deferences and obstructive azoospermia)
1/100,000; higher incidence in Ashkenazi-Jewish population
Hexosaminidase A deficiency leads to lysosomal storage disorder; lysosome swells, cells lose function, organ dysfunction; hexo is responsible for GM2 (present in plasma membranes) degredation; most prominent effect in neurons (brain and retina) because of GM2 accumulation
Whorled myeling figurs within lysosomes is characteristic; cherry red spots on macula of eye
Normal at birth, but increased startle response at 5-6 months; progressive weakness, loss of skills by 6-24 months; death by 2-4 years
What are the inidications for a genetic referral?
Newly diagnosed or suspected genetic condition; child with multiple congenital anomalies; family history of genetic condition; genetic testing for late-onset condtion; prenatal diagnosis for old pregnant women or loss of pregnancy; teratogen exposure; infertility; consanguinity
First person in the family brought to the physicians attention with the disease
The person ebing studied in the pedigree
How would you calculate carrier risk given the frequency of a condition?
Hardy-Weinberg says p^2 + 2pq + q^2=1 and p + q=1
Given the frequency, calculate q, then p, then 2pq
What are the assumptions of the Hardy Weinberg equation?
The population is large
Locus autosomal (M and F have similar frequencies)
No mutations, no migrations
Equal fitness of individuals
What information should be included in the pedigreee?
Name, relationship, birth date
Date of death, cause if known
Current age or age at death
Number of siblings (including those who died at birth or infancy)
Symptoms and health conditions of each individual
What is a Bayesian analysis?
A mathematical method to calculate recurrence risks combining information from genetics, pedigree, and test results
How is an X-linked trait transmitted?
Through the X chromosome
What does it mean to say there is allelic heterogeneity in Duchenne/Becker dystrophy?
Several different mutations at the same locus cause the same phenotype (disorder)
There are lots of things that can go wrong in the same spot on the chromosome to cause these disorders
What are 2 characteristics of X-linked inheritance?
No male-male transmission
All daughters of an affected man are carriers (phenotype depends on whether it's dominant or recessive and the pattern of X-inactivation in the daughter)
X-linked Recessive Conditions
Most X-linked conditions are recessive
Carried by unaffected mother (heterozygous) and expressed in sons
Affected relatives must be related through the mother of the proband
X-linked dominant conditions
All daughters of an affected man will have the condition; none of his sons
Daughters and sons of an affected female have a 50% chance of having the disorder
Typically lethal to the male
Tend to be less severe and more variable in females
Pedigrees resemble autosomal dominant, but no male-male transmission
What are some apparant exceptions to Mendelism inheritance?
Environmental modifiers, oligomeric disease (locus heterogeneity or extreme variable expressivity), sporadically lethal, and male lethality
How can females be affected with an X-linked trait?
X-linked dominant trait or
onely one X is active in a given cell; random inactivation of X leads to variable expressivity of disorders in females or
Turner Syndrome (Single X)
Duchenne, Becker, and Hemophilia A are all examples of what?
X-linked Recessive disorders
1/3500 males; XLR
No dystrophin produced; muscle degeneration and replacement with fat cells (causes the pseudohypertrophy of the calves)
Normal babies; late to walk; Gower manuever (can't get up from 4 point stance); wheelchair bound by 11 years; 20% with MR; death in late teens
Diagnose with elevated CK levels and muscle biopsy
Becker Muscular Dystrophy
1/3500 males; XLR
Some dystrophin produced
Normal babaies, able to walk into second decade; no MR; live past 21 years
Diagnosis: elevated CK levels and muscle biopsy
Describe mutations found in the gene coding for dystrophin
Huge gene (2300 kb)
Multiple different mutations associated
90% of the mutations are detectable
1/10,000 males; XLR; 50% family history (50% de novo)
Deficiency in the blood clotting factor VIII
Excessive or spontaneous bleeding; severity depends on where mutation is and whether you form any protein at all
Severe form (low factor VIII activity) leads to bleeding into joints, muscles and internal organs; spontaneous head bleeds in infants
Mild form (moderate factor VIII activity) leads to prolonged bleeding after injury or surgery
Treatment with Factor VIII infusions leads to prolonged life, but severe arthritis and deformed joints
Diagnosis: Excessive bleeding or prolonged PTT time
Vitamin D Ricketts and Fragile X syndrome are examples of what?
X-linked dominant conditions
Vitamin D Resistant Rickets
Very rare; usually lethal to males
Short stature; bowed legs (unless placed on Vitamin D and phosphate prior to weight bearing)
Fragile X Syndrome
Most common cause of MR in males, and significant cause in females
Triple repeat expansion which occurs during gametogenesis
Long face, prominent jaw and forehead, large everted ears, hypergonadism, MR, hyperactive behavior, tendency to avoid eye contact, large body size overall
Describe how to take a 3-generation family history using standard pedigree nomenclature
Gender, disease status, name, DOB, age of death (or current), country of origin/ethnicity
Disease (age of onset and diagnosis, original site of cancer, site of metastasis, cause of death)--make sure you confirm the pathology of the disease
In a pedigree, what is indicative of a genetic codnition or inherited susceptibility?
Conditions in multiple generations involving severla siblings, early onset of disease, sudden death in seemingly healthy relative, individual or couple with more than 3 pregnancy losses, the cousin thing
What are some factors that influence inheritance patterns?
gonadal mosaicism (2 different kinds of DNA in sperm)
Locus and allelic heterogeneity
What are the non-Mendelian patterns of inheritance?
Mitochondrial (if mom has it, all of kids will have it)
What are the principles of multifactorial inheritance?
Polygenic traits (determined by the combined effects of many genes)
Multifactorial traits (determined by multiple genes and environmental factors)
Most inherited traits are multifactorial or polygenic
Mitochondrial, Trinucleotide repeat expansions, germline mosaicism, uniparental disomy and imprinting, and multifactorial or polygenic inheritance are all types of what?
Complex non-Mendelian inheritance
A mixture of mitochondria, some with normal DNA and some with abnormal DNA coexisitng within a single cell
An individual inherits more than just 1 abnormal mDNA; certain threshold must be crossed to have clinical effects; depending on the type of mutation, may only be present in certain tissues
Female with heteroplasmic mtDNA may transmit variable amount to her offspring
How many genes are encoded by mitochondrial DNA (mDNA)?
37, as compared to 25,000 by nDNA
What is the typical clinical presentation of a person with a mitochondrial disorder?
No typical presentation; odd combinations are common
Most common is diabetes mellitus, cardiac problems, ptosis (drooping of the upper eyelid), and other eye problems
Blot tests are best way to diagnose (difficult with heteroplasmy)
Treat with Riboflavin (complex I and II disorders) and other supplements (carnitine)
What is the difference between continuously variably traits and threshold traits?
Continuously variable have a normal distribution in the population; typically measurable traits like height; small effects of many genes plus environmental factors
Threshold traits are caused by the additive effects of genes to a threshold prior to clinical effect; the phenotype is typically all or none
A man has a multifactorial trait disorder. What is the risk that his first degree relatives will have the same disorder?
Population risk squared (higher if more than one family member affected or if defect is severe)
Diabetes mellitus, hypertension, cancer, coronary artery disease, psychiatric disorders, and autoimmune disorders are examples of what?
Multifactorial complex disorders in adults
Distinguish between germline and somatic mosaicism
Germline mosaicism is 2 or more genetic or cytogenetic cell lines confined to the precuros (germline) cells of the egg or sperm; formerly called gonadal mosaicism; recurrence risk is generally 1-5%; increase in spontaneous germline mutations in sperm of father with increasing age
Somatic mosaicism is characterized by a patchy distribution of genetically identically altered somatic cells; non-hereditary
What is the difference between uniparental disomy and imprinting?
UPD: usually comes from trisomy where paternal are excluded (maternal UPD) or maternal are excluded (paternal UPD); begins with a trisomic zygote with 47 chromosomes; undergo trisomy rescue and loss of a trisomic chromosome; causes an abnormal phenotype when the genes of one chromosome are imprinted
Imprinting: usually involves either the maternal or paternal copy of a gene being turned on, but not both
What is the difference between paternal imprinting and maternal imprinting?
Maternal imprinting: faulty gene copy is switched off (imprinted) when passed to the baby. Children on mother have a 50% chance of being a carrier, but there will be no affected children. Her male children will have 50% affected children (no carriers). Her female children will have 50% carriers (no affected). With males, it gets turned back on during gametogenesis and is not inhibited.
Paternal imprinting: faulty gene copy causing disorder is turned off (imprinted) when passing to offspring (only carriers); remains active when passed by a carrier mother to her children
What are some examples of uniparental disomy disorders?
Prader-Willi Syndrome; Angelman syndrome; Transient neonatal diabetes; and Beckwith-Wiedman syndrome
mUPD15; loss of function mutation
Hypogonadism in boys; uncontrollable increase in appetite; possible MR
pUPD15; loss of function mutation
Autistic features; development delays; seizures (epilepsy)
Explain triplet repeat disease
Abnormally large allels resulting from too many trinucleotide repeats; unstable and highly polymorphic
What are some clinical disorders with complex inheritance?
Fragile X and Huntington's (TRE)
Hemophilia and Duchennes MD (Sometimes germline mosaic)
Prader-Willi and Angelman (UPD)
the study of genetic defects, especially congenital malformations
Patterns of birthd efects that occur together with high frequency
abnormal embryogenesis that occurs within 11 weeks of gestation; the tissue or organ never had the chance to develop normally
Major has functional significance
Minor has no functional significance; most people have 1 or 2 of these
external forces secondarily deform the tissue; tissue would have developed normally had not the outside force acted on it; i.e. amniotic bands
The secondary breakdown of tissue; fetal tissue is growing normally, but then growth is arrested by something that comes in and disrupts growth
Periaucular pit, skin tags, Simian crease, cafe au lait spots, clinodactyly, polydactyly (thumb is worse), and syndactyly are are examples of what?
None of these are indicative of a syndrome by themself, but when paired with others, could indicate the presence of a disorder
What are the most common causes of congenital birth defects?
Monogenic disorders (AR, AD, XLR, XLD) and Non-Mendelian (mitochondrial and UPD)
Polygenic and multi-factorial
Unknown; shrinks as our knowledge increases
What are the different types of harmful teratogens?
Infections (toxoplasmosis, rubella, cytomegalovirus, herpes, and syphilis)
Microcephaly, hairy face, learning problems, thin pilthum, thin upper lip, large forehead, small eyes
no genetic testing yet
Folic Acid Deficiencies
Spina bifida and anenecephaly; most common nervous system anomalies and completely preventable
What are the 10 steps recommended by the March of Dimes to reduce certain birth defects?
Take folic acid; get a check-up prior to preg.; eat right and maintain healthy weight; stop smoking; stop drinking; no illegal drugs; avoid infections; limit exposure to hazards; learn about genetics; avoid stress and get fit
Describe the basic techniques used in conventional cytogenetics
metaphase analysis after culturing, so you need living cells; get lymphocytes from peripheral blood smear, hematopoeitic cells from bone marrow or blood, or tissues from lymph nodes and solid tumors
Advantages: You can view the entire genome easily
Disadvantages: limited resolution and need viable cells to grow in culture
Detection: chromosome abnormalities (numeric and structural)
Describe the basic technique for FISH
No culturing needed; any cell suspension of paraffin-embedded tissue; don't need living cells
Detection: constitutional microdeletions, aneuploidy, translocations, amplifications, and deletions
Describe the basic technique for array comparative genomic hybridization (aCGH)
Chromosomal imbalances (gains or losses); must use isolated DNA
Mix patient DNA with control DNA; they compete for hybridization; when there is gain, more patient, more green
Disadvantages: takes a long time
Detection: gains or losses; use this when there is a small gain or loss (difficult to see on metaphase analysis), developmental delay, intellectual disability, multiple congenital anomalies, autism spectrum
Trisomy 21 (Downs)
1/700-800; most common cause of moderate MR
Occurs through nondisjunction in meiosis; trisomy survives if fertilized, monosomy does notp; risk increases with maternal age though 2/3 cases are women under 35
severe disease; natural history of disease is understood; effective treatment depends on early diagnosis; enough incidence to make it reasonable; specificity and sensitivity; available to the at risk population; follow-up of positive results available; cost-benefit worthy
What are the main laboratory methods used in newborn screening?
Heel blood sample; tandem mass spec (AA disorders); isoelectric focusing; enzyme assays; DNA tests
What are the main metabolic disorders screened for in newborns?