Genetics Exam 2

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Karyotyping

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process of identifying the chromosomal composition of cells.

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Giemsa banding

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most common used to stain and visualize bands in prophase or metaphase chromosomes.

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Metacentric

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chromosome with centromere near the midpoint.

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Submetacentric

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chromosome with centromere between the midpoint and one of the ends.

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Acrocentric

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chromosome with centromere very near one of the ends; chromosomes 13,14,15,21, and 22.

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Fluorescence in situ hybridization (FISH)

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method used to detect aneuploidies, deletions, duplications, and rearrangements; relies on fluorescently-labeled probes which hybridize with complimentary sequence on the chromosome.

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Spectral karyotyping

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uses hundreds of labeled probes to ‘paint’ an entire chromosome the same color; most often used to detect small rearrangements.

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Comparative genome hybridization (CGH)

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uses an array of oligonucleotides representing parts of the entire genome; patient and control DNA compete to hybridize to oligos; useful for detecting deletions or duplications but not where the abnormality is located.

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Euploid

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multiple of 23 chromosomes is present in a cell.

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Polyploidy

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complete extra set-s of chromosomes present in a cell

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Triploidy

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3 sets of chromosomes present in a cell (69,XXX).

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Tetraploidy

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4 sets of chromosomes present in a cell (92,XXXX).

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Aneuploidy

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missing or additional individual chromosomes

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Monosomy

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only 1 homolog of a chromosome pair present in a somatic cell

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giemsa banding (G-banding)

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most common

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reverse banding

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reverses black and white pattern of G-banding and is useful for see bands near the ends of chromosomes.

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Staining methods:
Produces light and dark bands

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useful to identify large deletions, duplications, and structural abnomalities

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Classic Galactosemia 

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most common single-gene disorder of carb metabolism; loss of function of GAL-1-P uridyl that converts glactose into glucose. Build up of galactone and galacitol 

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Hereditary fructose intolerance 

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inability to metabolize fructose, asymptomatic unless they ingest fructose or sucrose 

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PKU

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loss of function mutation of phenylaline hydroxylase which leads to increased level of phenylaline 

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Tyrosinemia 

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inability to metabolize tyrosine to fumarate and acetoacetate, leads to liver toxicity 

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Maple Syrup urine disease

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inability to utilize branched-chain AA for energy, leads to progressive neurogeneration and death

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MCAD defieciency 

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* medium-chain acyl-coenzyme A dehydrogenase deficiency

* leads to inability to utilize medium-chain faty acid for energy 

* FA intermediates accumulate, no ketones prd, exhaustion of glucose

* S/S episodic hypoglycemia when fasting - lethargy, vomiting

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LCHAD defieciency 

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inability to utilize long-chain FA for energy, leads to liver failure and death

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Lysosomal storage disease

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* caused by a lack of degenerative enzyme function in lysosomes or tansport of these enzymes into lysosomes

 

* accumulation of enzyme substrates in lysosomes causes disease

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Tay-Sachs

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* lysosomal storage disease where a loss of function  (4bp insertion) of hexosaminidase leads to accumulation of sphinogolipids, GM2 ganglioside in lysosomes

 

* leads to neurodegeneration and death

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Urea cycle disorders 

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caused by deficiencies in various enzymes involved in the urea cycle; leads to accumulation of nitrogenous wastes and hyperammonemia, lethargy, coma and death

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Cystinuria

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* defect in transport system.

 

* inability of gut and renal epithelium to transport dibasic AA

 

* most symptoms are complications arising from chronic nephrolithiasis 

 

* S/S: chronic nephrolithiasis, leads to infection, HTN, and renal failure.

 

* Tx: drinking water and alkalinizing the urine

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Hereditary hemochromatosis 

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tranport disease where toxic amounts of iron are stored 

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Menkes disease 

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transport disease where gut epithelial cells are unable to export copper to the liver

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Acrodermatitis enteropathica

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transport disease where the gut epithelium is unable to absorb zinc 

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hyperphenylalaninemia causes

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disrupts the myelination of neurons and protein synthesis, producing severe mental retardation if not treated. If in a pragnent women must be Tx immediatly to prevent birth birth defects and retardation. CAUSED by PKU

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Disorders of carb metabolism

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1) classic galactosemia

2) hereditary fructose intolerance

3) DM 1/2

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Disorders of AA metabolism

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1) PKU

2) Tyrosinemia

3) Maple syrup urine disease

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Disorders of lipid metabolism

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1) hyperlipidemia

2) MCAD and LCHAD deficiencies

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Lysosomal storage disorders

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1) Mucopolysacharidoses

2) Sphingolidoses

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Genetic disorders of tranport

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1) Cystinuria

2) Hereditary hemochromatosis

3) Menkes disease

4) Acrodermatitis enteropathica

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Pattern of inheritance for most single-gene disorders of metabolism?

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Autosomal recessive, loss of function

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Galactosemia S/S

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* poor suckling

* failure to thrive

* jaundice

* W/O Tx hyperammonemia, sepsis and death

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Mucopolysaccharidoses (MPS)

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* reduced ability to degrade glycosaminoglycans

* Vision, hearing, joint, and cardiovascular dysfunction, and mental retardation

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Sphingolipidoses

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* reduced ability to degrade sphingolipids

* multiorgan dysfunction

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Two hit modal

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* A.G. Knudson 1971

* inherited vrs sporadic retinoblastoma

* 1st hit is inherited while the second hit is somatic in offspring

* in sporatic form both hits occur somatically

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Familial cancer

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inherited cansers transmitted through germline, occur rarely, dominant phenotype

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Sporadic cancer

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* common

* not transmitted through germline

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Tumor supressor gene

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caner-causing gene whemo homozygous LOF mutations allow unchecked cell proliferation

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Gatekeeper gene

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type of TSG that encodes proteins that restrain progression of a cell throught the cell cycle

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Caretaker gene

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type of TSG that correct mutations and repair DNA

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6 essential characterisitcs of tumor cells

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1) divide independently of external signals

2) ignore anti-growth signals

3) avoid apoptosis

4) divide indefinitely w/o senesence

5) stimulate sustained angiogenesis

6) invade tissue and establish distant secondary tumors

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RB1

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* gatekeeper gene

* encodes pRB protein that restrains progression of the cell through G1 to S

* homozygous LOF causes retinoblastoma

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BRCA1 and BRCA2

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* caretaker gene

* enzymes that repair DS DNA breaks

* homozygous LOF increases RF for breast cancer

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Proto-oncogenes

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genes that when mutated are reffered to as oncogenes

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Oncogenes

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* mutated proto-oncogenes that causes unrestrained cell proliferation

* mutations are GOF and only one mutant allele is needed

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W/O pRB what will happen?

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pRB is a gatekeeper prt that binds with E2F to inhibit transition from G1 to S. W/O uncontrolled growth occurs

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Examples of oncogenes

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* GF that becomes even more potent

* Signal cascade prts to amplyfiy signal

* Telomerase that starts adding to much DNA

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Polygenic

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traits where variation is a result of multiple genes

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Multifactorial

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traits where variation results from a combination of both genetics and environment

 

* most congenital malformations and common adult disase are multifactorial

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Threshold of liability

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threshold at which a nuber of disease-causing alleles are present to lead to disease

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Quantitative traits

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BP, height, usually have a normal distribution, often multifactorial

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Concordance

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when 2 individuals share a trait, often applied to twin adn adoption studies

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Heritability

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% of trait variation in a population due to genes

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2 properties of quantitative traits

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1) often have a normal distribution in a population

2) often determined by multiple genes and environmental factors

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?

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Emprirically by measuring incidence rate in large families

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Criteria involving recurrence risk that are true for multifactorial conditions -

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1) Recurrence risk is higher if more than one family memeber is affected

2) If expression of the disease is severe, than the recurrence risk is higher

3) Recurrence risk is higher if the affected is of the less commonly affected sex

4) Recurrence risk decreases rapidly more distance from proband

5) Recurrence risk when a first degree relative is affected is about the square root of the recurrence risk in the general population

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Formula for heritability

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h = 2(Cmz-Cdz)

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Positive predictive value

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fraction of those testing postive who actualy have the disease

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Cutoff value

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screeening test value to indicate the point after which a value indicates a postive result 

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Tandem mass spectrometry 

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test for protein variants associated with metabolic genetic disorders; performs many screens quickly 

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Chorionic villus sampling

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biopsy of fetal trophoblastic for use in same tests as amniocentesis; performed 10-11wks after last menstural cycle. Amniocentesis @ 15-17. Higher risk of lossing fetus. Pseudomosaicism possible. 

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Pseudomosaicism

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mosaicism that originates in cultured fetal cells and is not present in the fetus, after aminocentesis

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Confined placental mosaicism 

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mosaicism confined to fetal trophoblastic cells but not the fetus itself 

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Alpha-fetoprotein (AFP) 

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fetal protein where abnormally high or low levels may indicate genetic defects or malformations. Low AFP are usually neruotube problems. 

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Maternal serum testing 

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Noninvasive testing of substances in maternal serum, such as AFP, to screen for malformations or aneuploidies, may be performed 1st and 2nd trimesters

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Quadruple screening 

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measurement of AFP and other maternal serum markers to better ID malformations and aneuploidies 

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Criteria for population screening 

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1) Dx should be serious and rel. common

2) Dx should be well understood

3) test should be acceptable and effective Tx of the Dx

4) test should be acceptable, easy to perform and inexspensive 

5) test should be valid and reliable

6) Resources must be available for Dx and Tx of the disease

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Africans 

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Sickle Cell

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Tay-sachs 

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Jews

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Beta Thalassemia 

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Greeks and Italians 

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Chinese and SE Asians

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Alpha thalassemia

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N. European 

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CF

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PKU 

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N. Eurpean

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Tests performed in all states 

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1) PKU

2) Hypothyroidism

3) Classic galactosemia

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Indications for aminocentesis

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1) Maternal age >35 y/o

2) Previous child w/ chr abnormality 

3) Hx of chr structure abnormality in one parent

4) Postive FmHx of genetic defect that is diagnosable

5) Postive FmHx of neural tube defects

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Teratogens 

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agent external to fetus' genome that induces structural malformations, growth deficiency, and/or functional alterations during prenatal development 

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Malformations

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primary morphologic defect of an organ or body part resulting from an intrinsically abnormally developmental process

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Dysplasia 

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primary defect involving abnormal organization of cells in a tissue

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Sequence 

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primary defect that leads to secondary structural changes

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Syndrome 

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pattern of multiple primary malformations with a single cause

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Deformation 

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alteration of the shape or position of a body part by mechanical forces; occurs in fetus not embryo; extrinsic or intrinsic causes 

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Disruption 

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a secondary malformation of an organ or larger body region resulting from interference with a normal developmental process