Genes
hereditary units of DNA transmitted from one generation to another; code for proteins
Locus
the specific location of a gene on a chromosome
Alleles
different versions of a gene; humans have 2 alleles for each autosomal gene
Chromosomes
structure composed of genes located in nucleus of a cell
How do you distinguish chromosomes from each other?
Overall length and position of the centromere(divides chromosome into 2 arms: short:p, long:q)
Homologous chromosomes
have the same genes at the same loci, one maternal and one paternal
Genome
the genetic information contained in the cells, on the chromosomes, for a particular species
How many chromosomes in the nucleus of a human somatic cell?
46(23 pairs)
Mutations
A change in some part of the DNA code
- Spontaneous/Induced: exposure to mutagenic chemical or radiation
- varying effects based on location
- net result can be a physical change or other trait
Autosome
any chromosome that is not a sex chromosome (humans have 22 pairs of autosomes)
Allosome
Sex chromosome pair, humans have one
Somatic cell
contain one homologous set of chromosomes from mother/Father
-22 pairs in humans
Haploid vs Diploid
Haploid(n): # of chromosomes in sex cells/gametes(n=23)
Diploid(2n):# of total chromosomes in somatic cells(2n=46)
What are the parts of the human chromosome?
- short arm= p
- long arm= q
- chromosomes numbered consecutively by length: longest first.
Sex Chromosomes
Human males have one morphologically dissimilar pair of chromosomes – the sex chromosomes
Heteromorphic (contrast with homologues)
Labeled X and Y
Genetic factors on the Y determine maleness
Human females have two morphologically similar X’s
karyotype
picture of a person’s chromosomes
Mitosis
- The process by which all somatic cells become descendants of one original cell
- One exact copy of each chromosome is made and distributed through the division of original cell into two daughter cells
Meiosis
-The process by which gamete cells are produced (egg and sperm)
-Resulting gametes have 23 new chromosomes (one member of each of the pairs), with new combos of the original maternal and paternal copies
-Occurs only in specialized germ cells of gonads
-2 consecutive cell divisions producing cells with half the original chromosome number
diploid 2n—>haploid n
Gametogenesis
- Diploid primordial cells in testes become spermatogonia
- 4 sperm cells (spermatozoa), each is haploid (n)
-Diploid primordial cells in ovaries become
oogonia
-1 haploid ovum (n), and polar bodies which degenerate
Genotype
all of the alleles of an organism
- Homozygous – contains the same alleles at a single locus
- Heterozygous – contains 2 different alleles at a single locus
Phenotype
a measurable trait an organism has
-Result of gene products that interact in a given environment
Dominant allele
phenotype can be seen in both the heterozygote and homozygote
-Carrier – heterozygous individual with a recessive allele that’s hidden from phenotypic view by the dominant, normal allele
Recessive allele
produces this phenotype only when its paired allele is identical
Single gene disorders (Mendelian disorders)
Classified by whether they are
- Autosomal or x-linked
- Dominant or recessive pattern
Punnett square
illustrates a monofactorial cross – a mating in which a single gene is analyzed
-This type demonstrates Mendel’s principle of segregation: one parent has 2 copies of a gene for each trait, but transmits only one via a gamete
Albinism
AA(homozygous dominant)=Pigmented
Aa(heterozygous)=Pigmented
aa(homozygous recessive)=Albino
Codominance
when two alleles for a trait are equally expressed (example: AB blood type)
- When alleles lack complete dominant and recessive relationships and are both observed phenotypically (expressed at the same time)
- Seen in chickens and cattle as well
Incomplete dominance
heterozygotes have phenotypes that have both alleles visible as a blend (one allele isn’t expressed over the other)
- Makes a third phenotype that’s a blending of the two
- Human examples: wavy hair – it’s a blend that’s seen when a person with straight hair has a child with a person with curly hair; skin color
Penetrance
the probability that individuals in a population who have a particular gene combination will show the condition
Example: if a mutation causing diabetes has 95% penetrance, 95% of people with the mutation combo will develop diabetes
Genetic marker
Sequence of DNA with a known location on a chromosome
Expression
the components of the phenotype that are exhibited in an individual
- Example: myotonic muscular dystrophy
- Phenotype may include myotonia, cataracts, narcolepsy, balding, infertility
- 2 people carrying this gene may express it differently: one may have cataracts and one has narcolepsy and grip myotonia
Anticipation
Genetic diseases that increase in severity or have earlier onset with each successive generation
-Examples: Fragile X, Huntington, myotonic muscular dystrophy
Chromosomal Abnormalities
Can be numerical or structural
-Most common type is aneuploidy – abnormal number
Balanced chromosomal abnormalities
No net loss or gain of chromosomal material
- Balanced translocation – rupture of a chromosome resulting in the pieces “re-sticking” in the wrong combinations
- Inversion – a chromosome piece is lifted out, turned around, and reinserted
Unbalanced chromosomal abnormalities
Additional or missing information
- Deletion
- Insertion
Unbalanced translocation
-Tends to arise as an offspring of a balanced carrier
Robertsonian translocation
- Involve any 2 out of chromosomes 13, 14, 15, 21, and 22
- They are all acrocentric (centromeres are close to the end)
- Results in formation of a “new” chromosome
- The bigger chromosome can produce an unbalanced gamete
- Those involving chromosome 21 can produce gametes with 2 copies; upon fertilization, can produce Trisomy 21
Why use pedigrees?
- Provides a concise visual tool
- Multifactorial genetic conditions now require that treatment and prevention measures be highly individualized
- Primary care provider is at front line playing integral role in prevention and treatment of genetically based diseases
- Many software pedigree programs available are actually less user friendly than drawing it out – harder to record nuances such as multiple relationships, > 3 generations, and tracking multiple diseases
- Creation and analysis of a pedigree is important in today’s medical environment because:
- Genetic testing is more available to patients
- Getting cheaper
- Fascinating
- Patients want to know if they should be concerned about a disease in pregnancy, their children, or their own health care
- Many diseases with genetic links have been discovered and clarified
- More clinicians are needing to understand the genetic basis of disease to effectively understand disease processes and treatments
Three-Generation Pedigree
- Making a diagnosis
- Deciding on testing strategies
- Establishing the pattern of inheritance
- Identifying people at risk
- Educating the patient
- Determining reproductive options
Consultand -The person seeking genetic advice -Represented by an arrow on pedigree -Can be healthy or a person with a condition Proband -The affected individual
Standard Pedigree symbols
Male -square Female – circle Diagonal line through symbol – deceased Shaded symbol – affected with trait Half-shaded symbol – carrier of trait
Standard Pedigree lines
Relationship – line between individuals
Sibship – horizontal line showing siblings
Line of descent – line showing offspring
Individual line – attaches to sibship line
Two hash marks – divorced or separated (or no longer in a relationship)
Autosomal dominant
-65% of human monogenic disorders
-Mutation in a single allele can cause disease
-Examples:
Huntington’s Disease
Affected individuals are HH or Hh (homozygous dominant or heterozygous)
Those with genotypes hh are normal
Autosomal Dominant: Characteristics
Vertical pattern
-Transmission passes from parent to offspring
Multiple generations affected
Variable expressivity
-Affected individuals in same family may show varying degrees of phenotypic expression (severity)
Reduced penetrance
-Some with the genetic mutation may not show phenotype, making it appear that it “skipped” a generation
Males and females affected equally
Male to male transmisson can be seen
Autosomal Recessive
25% of human monogenic disorders
2 copies of diseased allele required for expressing the phenotype
Tends to involve enzymes or receptors
Rare
Males and females equally affected
Horizontal inheritance: Multiple affected offspring
Often occurs in the context of consanguinity(relatives having children)
Heterozygous carriers of a defective allele are usually clinically normal
Example: Cystic fibrosis
Autosomal Recessive: Characteristics
Horizontal pattern
Single generation affected
Males and females affected equally
Inheritance is from both parents, each being a heterozygote/carrier
Each offspring has a 25% chance of being affected, and a 50% chance of being a carrier
Higher association with consanguity
X-Linked: characteristics
No male to male transmission is possible
Unaffected males do not transmit the phenotype
All daughters of an affected male are heterozygous carriers
Males usually more severely affected than females
Examples:
-X-linked dominant: Alport’s Syndrome, Fragile X Syndrome
-X-linked recessive: Wiskott-Aldrich Syndrome, Duchenne muscular dystrophy
X-Linked
5% of human monogenic disorders
Risk of developing disease due to a mutant x chromosome differs between the sexes
Males are hemizygous (heterozygous) for mutant allele on the x
-More likely to develop a mutant phenotype regardless if the mutation is dominant or recessive
The terms “x-linked dominant” and “x-linked recessive” therefore only apply to females
Heterozygous females usually normal or mild
Multifactorial/Complex Disease
Caused by interactions of variations in multiple genes and environmental factors
Genetic susceptibility genes -These genes make a person susceptible to a disorder, and certain environmental factors trigger the susceptibility -These are increasingly being identified for complex conditions such as: Cancer Diabetes Asthma Heart disease Mental illness Cleft lip/cleft palate
Multifactorial/Complex Disease
Sporadic inheritance of a cancer vs. inherited cancer syndrome for which a genetic test may be available
- Sporadic cancer is more likely
- Most cancer is NOT inherited, but the predisposition to cancer IS inherited
The pedigree can help the clinician make more cost-effective, appropriate choices in genetic testing
-Determine who needs to be tested first, and who else needs to be tested
Down Syndrome
Trisomy 21 (95% caused by trisomy 21, 4% due to Roberstonian traslocation)
Most common chromosomal abnormality in live births
Increase incidence with advancing maternal age
-Age 35 1:400
-Age 45 1:35
Prenatal testing
-Quad screen
-Nuchal translucency
*most common non lethal trisomy (1:500 pregnancies)
Down syndrome: Characteristics
Intellectual disability Characteristic facial appearance 40% have cardiac defects 75% hearing loss >50% visual problems 7% have GI defects Increased social skills in childhood Half of adults with Down syndrome develop Alzheimer disease
Trisomy 18
1:5000 live born infants
Increased risk with advanced maternal age
IUGR
Highly lethal in-utero – 85% lost between 10 weeks’ gestation and term
50% die in first week of life
2% 1 year survival rate
Heart, GI, kidney defects
Trisomy 13
Patau syndrome
Increased risk with advanced maternal age
1:16000 live births
Severe intellectual disability
Many physical abnormalities
Cleft lip or palate
Seizures
Small jaw
Polydactyly
Heart defects, brain/spinal cord abnormalities
Many children die within first days or weeks of life
trisomy 13: etiology
Most cases of Trisomy 13 from 3 copies of chromosome 13
Some caused by Robertsonian translocation involving chromosomes 13 and 14
-When a part of chromosome 13 gets attached to chromosome 14 during formation of gametes
-Affected people have 2 normal copies of 13 plus an extra copy attached to another chromosome
Cri-du-Chat Syndrome
Chromosomal abnormality: deletion of part of short arm of chromosome 5
Partial monosomy – when only a portion of a chromosome has one copy instead of two
Most cases are from a spontaneous mutation
Cat-like cry of affected children due to abnormal larynx development
Intellectual disability, wide set eyes, low ears
1:50,000 births
Can be detected in utero with CVS
Klinefelter’s Syndrome
Extra X chromosome, 47 XXY
Occurs during gametogenesis
Affects male physical and cognitive development
Accounts for many first trimester losses
Physical traits become more apparent after puberty
Most common sex chromosome aneuploidy in males
Hypogonadism, infertility
Gynecomastia, reduced hair
Turner Syndrome
45 X, affects development in females Monosomy Gonadal dysgenesis: Non-functional ovaries Short stature Broad chest Webbed neck Amenorrhea Infertility Cardiovascular abnormalities
Huntington’s Disease: characteristics
- A neurodegenerative disease – progressive brain disorder
- Causes uncontrolled movements, emotional problems, and loss of thinking ability, changes in personality
- Early signs: depression, irritability, poor coordination, trouble learning
- Involuntary jerking movements: chorea
- Adult onset: genetic defect is latent for 3-5 decades, then manifests as progressive neuronal dysfunction
Huntington’s Disease:
Mode of inheritance: autosomal dominant
-If one parent has the disorder, each child has a 50% chance of manifesting it
-Only human disorder of complete dominance:
Heterozygotes are just as affected clinically as homozygotes (HH, Hh)
Huntington’s Disease: chromosome info
Genetic defect: HD gene on chromosome 4 that codes for a unique protein called huntingtin
-CAG trinucleotide repeat
Normal: 10-35 repeats
In HD: 36-120 repeats
-Abnormal protein causes microscopic deposits of protein in neurons
-Most cases are inherited, but some occur as new spontaneous mutations
Average time from symptom onset to death is 15 years
Referral
-Offspring of HD parents should be offered genetic counseling
Alzheimer’s Disease: general
A neurodegenerative disease
Most common form of dementia in older individuals
Dementia
-65% from Alzheimer’s Disease
-35% vascular in nature
Population
-Usually begins after age 60; risk increases with age
-Death usually occurs within 10 years
-People with parent, sibling, or child with AD are at increased risk
Alzheimer’s Disease
Pathophysiology
-Loss of cholinergic neurons in brain (loss of acetylcholine)
-Formation of plaques and tangles
-Atrophy of brain
-Resultant effect – blocked communication
Mode of inheritance
-Several gene mutations cause predisposition to AD
Clinical manifestations
-Progressive mental deterioration: memory loss, confusion, disorientation
2 forms of AD genes have been identified: familial (early onset) and sporadic (late onset)
Familial Alzheimer’s Disease
Also called early onset AD
- Many members of multiple generations affected
- Symptoms start before age 65
- Mutations on chromosomes 1, 14, or 21: Induce formation of a “sticky” protein that forms clumps in the brain
- Rare - <5% of cases of AD
- Autosomal dominant: 50% chance of developing early onset AD if one parent has it
Sporadic Alzheimer’s Disease
Also called late onset AD
-Usually develops after age 65
-Accounts for most cases of AD
One gene has been shown to increase risk
-Chromosome 19 apolipoprotein E (APOE) gene
-Not everyone carrying the gene develops disease
Definitive diagnosis: autopsy-plaques and tangles
Hereditary Breast and Ovarian Cancer Syndrome
Risk factors:Gender, Age, Family history
Mode of inheritance
-Up to 10% of breast and ovarian cancers are caused by known predisposing genetic factors
Hereditary Breast and Ovarian Cancer Syndrome: clinical manifestations
Early age of breast cancer onset (< 50)
FH of both breast and ovarian cancer
Increased bilateral cancers
Increased development of both cancers in same person
Increased incidence of prostate cancer in family
Male breast cancer
Hereditary Breast and Ovarian Cancer Syndrome: gene
2 major cancer susceptibility genes: BRCA1 and BRCA2 (Tumor suppressor genes)
- Normally control cell growth and death, and DNA repair and stability
- cancer risk goes up with a single mutated gene
BRCA1: breast cancer, chromosome 17, autosomal dominant
BRCA2: breast cancer, chromosome 13, autosomal dominant, male breast cancer, ovarian/prostate/pancreatic cancer
Inheritance doesn’t mean a person will develop cancer
Colorectal Cancer
Results genetic and environmental factors
-Genetic predisposition is the main risk factor in only a small proportion of people
-Diet, exercise, smoking, obesity are stronger risk factors in most people
May occur sporadically or from familial inheritance
-Most are from sporadic mutations and occur randomly
-Many cancer syndromes include colon cancer
Types of colon cancer
Familial colorectal cancer
Hereditary colorectal cancer syndromes
-Arise from specific mutations in genes that code for susceptibility to cancer
*Familial adenomatous polyposis (FAP) <1%
*Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch Syndrome) 2-3%
Familial adenomatous polyposis (FAP)
<1% of all colorectal cancers
Pattern of inheritance: autosomal dominant
-50% chance of passing it to each offspring
Genetic mutation: mutation in APC (adenomatous polyposis coli) gene
-Hundreds to thousands of polyps in colon beginning in adolescence
-APC is a tumor suppressor gene on chromosome 5
-Cancers develop in 20’s
-Risk of developing colorectal cancer is near 100%, usually before age 50
-Time from polyp to cancer development is 10+ years
Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
Also called Lynch Syndrome
2-3% of all colorectal cancers
Pattern of inheritance: autosomal dominant
Genetic mutation: a mutation in one of many genes that code for DNA repair
More rapid transition from adenoma to cancer than FAP – cancers occur earlier, 30’s and 40’s
Nonpolyposis: cancer can occur when a small number or no polyps are present
Approx. 50% chance of cancer in women, approx. 70% in men
Associated with the formation of other cancers:
Uterus, ovaries, stomach, urinary tract, small bowel, bile ducts
HNPCC gene mutation: start screening for gastric/ovarian cancers early if present
Chronic Myelogenous Leukemia
A myeloproliferative disorder Population -More common in men -Median age at presentation is 55 years Genetic defect -Translocation between chromosomes 9 and 22 -Philadelphia chromosome (22) Produces a protein that codes for an enzyme that causes too many stem cells to develop into WBCs
Chronic Myelogenous Leukemia: Patho/clinical
Pathophysiology
-Increased production of abnormal white blood cells that are nonfunctional
-These large numbers of abnormal WBCs take up bone marrow space meant for healthy WBCs, RBCs, and platelets
Clinical presentation
-Insidious onset, slow progression over months to years of infections, anemia, bleeding
-Fever, night sweats fatigue
Diagnosis involves bone marrow aspiration for karyotype
Hemophilia
Bleeding disorders caused by mutations in genes that code for coagulation proteins
Mutation on F8 or F9 genes, located on the X chromosome
Mutation in F8 gene causes factor VIII deficiency
-Results in hemophilia A (classic hemophilia)
-More common
Mutation in F9 gene causes factor IX deficiency
-Results in hemophilia B (Christmas Disease)
Hemophilia:gene
Pattern of inheritance: X-linked recessive pattern
-Genes associated are on the X chromosome
-Most people affected are males
Clinical manifestations: hemarthroses (spontaneous bleeding into a joint), bleeding into muscles, and other soft tissues; -prolonged bleeding or oozing of blood after injury or surgery
-Severity of symptoms can be variable
Sickle Cell Disease
Pathophysiology
-Atypical hemoglobin molecules (hemoglobin S)
-Distorts the red blood cell into a crescent shape
-Abnormally shaped RBCs break down prematurely
-Mutation on HBB gene
Clinical manifestations
-Anemia, infections, episodic pain
-Shortness of breath, fatigue, delayed growth
Inheritance
-Autosomal recessive
Most common in people whose ancestors came from Greece, Africa, Turkey, Italy, Arabian Peninsula, India, South America, Central America, Caribbean
Cystic Fibrosis
Pattern of inheritance: autosomal recessive
Genetic mutation: mutation in the CFTR gene (cystic fibrosis transmembrane conductance regulator)
-CFTR codes for a protein that regulates chloride channels in epithelial cells
-When mutated, a defective protein is made, causing a disruption of chloride and water transport - water balance in secretions is disrupted
*common in white people 1 in 3500 white babies
carrier incidence 1 in 25
diagnosis: sweat chloride test (concentration of sweat is elevated in CF)
Cystic Fibrosis:clinical manifestations
-Causes thick, sticky mucous obstructing airways in lungs and ducts in pancreas
Symptoms:
-Difficulty breathing, infections in lungs
-Problems with nutrient digestion
-Buildup of mucous prevents pancreatic enzymes from reaching intestine
-Failure to thrive, poor growth rate
-Meconium ileus – newborn intestinal obstruction due to thick fecal waste products
Can affect pancreas, intestines, GU tract, hepatobiliary system, and exocrine glands
Most common cause of morbidity associated with CF
pulmonary disease
Pulmonary system can’t defend against pathogens well: leads to sinusitis and bronchitis
-Most common organisms: S. aureus, P. aeruginosa, Aspergillus
-Nasal polyps, nosebleeds, chronic sinus infections common in CF patients
-Thick mucous builds up in lower airways causing obstruction
Marfan Syndrome
Mode of inheritance: autosomal dominant
-Results from either an inherited mutation or a new mutation of the fibrillin-1 gene (FBN1)
-Causes defects in connective tissue affecting multiple systems
Bones
Ligaments
Muscles
Blood vessels
Heart valves
*key features: dislocated lens of the eye:vision problems, aortic aneurysm/dissection
*heart defects major cause of morbidity and mortality: mitral valvle prolapse, aortic valve regurg., can cause SOB, fatigue and palpitations
affected individuals advised to avoid contact sports, caffeine, and decongestants: due to increased stress on CV system
Marfan Syndrome: clinical
Clinical manifestations: Tall stature Long, thin arms and legs Arm span wider than body height Long, narrow face High arched palate Overcrowded teeth Scoliosis Hyperflexible joints Chest deformities
Neurofibromatosis Type I
Also called von Recklinghausen disease
Pattern of inheritance: autosomal dominant
Mutation on NF1 gene on chromosome 17(most common)
Tumor suppressor gene
Mutation results in:
-Growth of neurofibromas - benign tumors that grow on nerves of skin and brain
-Hyperpigmented skin lesions called café-au-lait spots
-Flat patches on skin darker than surrounding area
-Lisch nodules in iris
-optic glioma
-Freckles in axillae and groin(CROWE SIGN)
Polycystic Kidney Disease
Pathophysiology -Clusters of fluid filled sacs develop in kidneys -Affects ability to filter the blood properly -Kidneys become enlarged and can fail Clinical manifestations -Hypertension -Back pain -Hematuria -UTIs, kidney stones Other associations -Liver cysts -Heart valve abnormalities -Increased risk of aortic aneurysm and brain aneurysm 2 forms Autosomal dominant – sx start in adulthood -1 in 1000; PKD1 and PKD2 genes -Usually inherited (90% of the time) Autosomal recessive – rare, lethal early in life -1 in 30,000 -PKHD1 gene
Congenital Abnormalities
Approximately 10% of all newborns have some birth defect
-Ranges from minor biochemical problem to severe physical deformity
Caused by variety of biological, chemical, and physical agents
-Contributors: mutant genes, chromosomal defects, multifactorial components
Biggest cause of birth defects: unknown etiology
Teratology
study of abnormal development
-Teratogens-anything capable of disrupting embryonic or fetal development and producing malformations
-Teratogenic, teratogenicity
Critical period for teratogenic effects is 3-16 weeks’ gestation
Timing of exposure determines which systems are affected
Example – CNS begins to develop in 3rd week, while teeth and palate begin to form in 6th-7th week
Newborn Screening
Biochemical analysis that determines whether certain proteins (enzymes) are present or absent
These are typically autosomal recessive conditions
Referred to as “inborn errors of metabolism”
-Inherited defect in one or more enzymes
Newborn screening checks for many of these metabolic disorders
A law in 2008 was enacted to increase testing and make more uniform among states
Newborn screening: AZ
The Arizona Panel The federally recommended uniform screening panel of 30 disorders (including hearing loss) Endocrine Disorders Hemoglobinopathies Other Enzyme Deficiencies Amino Acid Disorders Fatty Acid Oxidation Disorders Organic Acid Disorders Cystic Fibrosis Hearing Loss 1st test: baby is 24-36 hours old 2nd test: 1st office visit, between 5-10 days