Molecular Fundamentals - Cytogenetics and Chromosomal Basis for Human Disease

chromosomes can be identified by what?

• shape 

• size (position of centromere)

what does acrocentric mean?

centromere is located near the end

what does metacentric mean?

centromere is located near the middle

what does submetacentric mean?

centromere is located somewhere between the middle and the end

what is the short arm of the chromosome?

p

what is the long arm of the chromosome?

q

what is cytogenetics?

study of chromosomes and their abnormalities; alteration in number and structure

what are karyotype characterisitics?

main feature to identify and classify chromosomes:

• size

• location of centromere

• banding patterns

chromosomes are most easily visualized during what?

metaphase of mitosis

what tissues are appropriate for studying chromosomes?

tissues that can be stimulated to under go cell division in vitro

ex:

• amniotic fluid

• peripheral blood (lymphocytes)

• skin (fibroblasts)

• bone marrow

what is chromosomal banding?

treatment of chromosomes to identify individual chromosomes and structural abnormalities such as deletion or duplications

what describes fluorescence in situ hybridization (FISH)?

chromosome specific DNA segment is labeled with a fluorescent tag (probe), and probe will make presence of tested chromosome segment

fluorescence in situ hybridization (FISH) can detect what?

• deletion, duplications, translocation, and inversions

• prenatal detection of fetal chromosome abnormalities

what describes spectral karyotype?

• expansion of FISH; labels each chromosome with a different color

• detects small chromosome rearrangements

what comparative genomic hybridization (CGH)?

detects loss or duplication of whole chromosomes or specific regions of chromosomes (compares to normal individual)

what describes disturbance of chromosomes?

substantial changes in chromosome structure of number

disturbance of chromosomes can occur due to what?

• error in cell division

• non-disjunction of chromosomes and chromatids 

• maternal age

• environment

what describes numerical chromosomal abnormalities?

changes in the number of chromosomes or entire sets of chromosomes

what are types of numerical chromosomal abnormalities?

• aneuploidy

• polyploidy 

what does euploidy refer to?

normal chromosome number

• 2N (46 chromosomes) for somatic cells

• N (23 chromosomes) for gametes

what describes aneuploidy?

a change in the number of one or more chromosomes (not in the entire set)

in regards to aneuploidy, loss of autosome is what?

not viable (spontaneous abortion)

in regards to aneuploidy, gain of autosome is what?

can be compatible with life

what autosomal trisomies are viable?

ones involving chromosome 13, 18, or 21

loss or gain of sex chromosome is what?

viable (X0, XXY)

what is polyploidy?

the gain of an entire haploid set of chromosomes

what is triploidy?

3 copies of each chromosome, 69 total

what is tetraploidy?

4 copies of each chromosome, 92 total

chromosomal maldistribution refers to what?

changes in ploidy occur due to non-disjunction in meiosis during gamete formation

what usually results from aneuploidies of the sex chromosomes?

abnormal distribution usually results: minor impairment of mental and physical development

regarding aneuploidies of the sex chromosomes, what is required for survival?

at least 1 X chromosome

Turner Syndrome is an aneuploidy of sex chromosome caused by what?

an monosomy of the X chromosome (X0)

what are characteristics of Turner Syndrome?

• ovarian dysgenesis (absence of normal ovaries which means hormones do not form, estrogen deficiency, and infertility)

• short stature

• broad, shield-like shape of chest 

• webbed neck

• partial malformations of internal organs: heart, urinary tract, and kidneys

Klinefelter is an aneuploidy of sex chromosome in males caused by what?

an extra X chromosome in males (XXY)

what are characteristics of Klinefelter Syndrome?

• infertility

• reduced muscle tone

• gynecomastia (breast development)

• underdeveloped secondary sexual characteristics

• hypogonadism, low testosterone

• tall and thin stature with long arms and legs

what is triple X syndrome?

trisomy of the X chromosome (XXX)

what are characteristics of Triple X Syndrome?

• usually does not show an abnormal phenotype

• sterility, menstrual irregularity, or milk intellectual delay

• tend to be taller than average

what is Jacobs Syndrome?

an extra Y chromosomes in males (XYY)

what are characteristics of Jacobs Syndrome?

• taller than average

• slightly lower than normal IQ

• aggressive due to high level of testosterone

• increase risk of minor behavior disorders, hyperactivity, and learning disabilities

what describes aneuploidy of autosomes?

syndrome or disorder that is not a sex chromosomes

• distinct mental and physical impairment

• majority of autosomal aberrations lead to spontaneous miscarriage before the 12th week of gestation

what is one of the most common chromosomal aberrations involving autosomes?

trisomy 21 (down syndrome)

what describes trisomy 21?

chromosomal aberration characterized by the addition of chromosome 21, causes Down Syndrome

what are characteristics of Down Syndrome?

• impaired intelligence

• specific phenotypic characteristic

  • flat face, epicanthus

  • small opened mouth with protruding tongue

  • small physical stature

• muscular hypotonia (reduced muscle tone) (floppy infant)

• organs systems and risk

  • gastrointestinal tract, heart, respiratory, risk of leukemia, risk of Alzheimer’s

what is Edwards syndrome?

• characterized by an additional chromosome 18, trisomy 18

• correlates with mother’s age

• 80% female

• low survival rate, majority die before birth

what are characteristics of Edwards Syndrome?

• organ systems:

  • heart abnormalities, kidney malformation defects in stomach/ intestines

• impaired intelligence 

• long and narrow skull

what is Patau syndrome?

• chromosomal aberration characterized by the addition of chromosome 13

• relatively rare compared with Downs syndrome

• correlates with mother’s age

what are characteristics of Patau Syndrome?

• microcephaly: abnormally small head

• cleft lip, alveolar ridge, and palate

• organ systems failures/abnormalities

  • heart, kidneys, and/or the urinary tract

polyploidy usually results in what?

• defects of the heart and CNS

• rarely results in a live birth and most common cause of early spontaneous abortion

what are attributed to malformation of the spindle apparatus during meiosis I or II?

polyploidy

what is the most common cause of fetal loss in the first 2 trimesters?

triplody

what are common causes of triplody?

• dispermy (egg is fertilized by 2 sperm)

• fusion of ovum and polar body

• meiotic failure (diploid sperm or egg produced)

tetraploidy is what?

rare: at conception and among live births

what is a common cause of tetraploidy?

mitotic failure in early embryo

tetraploidy could cause what?

• 1.2% of Acute Myeloid Leukemia (AML)

• 3% of Acute Lymphoblastic Leukemia (ALL)

what are characteristics of structural chromosomal aberrations? 

• occurs when chromosomes are broken by clastogens

  • radiation, viruses, chemicals

• unbalance alterations

  • gain or loss of genetic material

• balanced alterations

  • without loss or gain of genetic material

• structural alterations

  • germ cells (can be submitted to offspring)

  • somatic cells (can alter genetic material → cancer)

what are types of structural chromosomal aberrations? 

• deletion 

• duplication

• inversion

• translocation

what describes chromosome deletion?

loss of a specific segment of the chromosome

chromosome deletions may be accompanied by what?

• reconstitution with the same chromosomes

• truncated chromosome

• segregation of the broken segment, without a centromere

what are the categories of chromosome deletions?

• terminal: end of chromosome lost

• interstitial: material within the chromosome is lost

what is Cri-du-Chat Syndrome (Cry of the Cat)?

deletion of the distal short arm (p) of chromosome 5

what are characteristics of Cri-du-Chat Syndrome (Cry of the Cat)?

• distinctive cry that becomes less obvious as the child ages (most survive to adulthood) 

• excessive drooling

• feeding problems due to difficulty in swallowing and sucking

• intellectual disability

• behavior problems: hyperactivity, aggression, tantrums, and repetitive movements

what is Wolf-Hirschhorn Syndrome?

deletion of P arm of chromosome 4

what are characteristics of Wolf-Hirschhorn Syndrome?

• higher risk of seizures (50%)

• distinctive facial features

  • small head (microcephaly), wide spaced eyes (hypertelorism), broad beaked nose

• low muscle tone/development

• intellectual disability

• short stature

• malformation of hands, feet, chest, and spine

• organ defects or malformations: heart, urinary tract, and genitals

what is the most common microdeletion?

DiGeroge Syndrome (deletion of q arm of chromosome 22)

what are characteristics of DiGeorge syndrome?

• 80% have congenital heart defects

• functional defects of thymus

• cleft palate

what are characteristics of Williams Syndrome (microdeletion syndrome of q arm of chromosome 7)?

• mild intellectual disability

• cardiovascular defects

• poor visual-spatial abilities

• broad forehead, short opening between eyelids, low nasal bridge, full lips and cheeks, relatively large mouth

why does an individual with William’s Syndrome have cardiovascular defects?

the deleted region contained the elastin gene

why does an individual with William’s Syndrome have visual-spatial deficiencies?

the deleted region contained the LIMK1 gene, a kinase expressed in the brain

what describes chromosome duplication?

• chromosome that has two copies of a specific region

• leads to partial trisomy

how can chromosome duplication occur?

by uneven crossing over

what are symptoms of Charcot-Marie-Tooth (CMT) disease (multiple variations due to the fact that different gene mutations can occur)?

• slow, progressive muscle weakness and atrophy

• upper extremity ataxia and tremor

• GI problems

• Scoliosis

Charcot-Marie-Tooth (CMT) disease is a result of what?

chromosome duplication

what describes chromosomal translocations?

portion of one chromosome is transferred to another chromosome

• two types: reciprocal, Robertsonian

translocations can be what?

balanced rearrangement or unbalanced rearrangement

what describes balanced rearrangement?

no loss or gain of chromosome material

what describes unbalanced rearrangement?

causes a gain or loss of chromosomal material

what describes reciprocal translocation?

type of balanced translocation in which the genetic material of two different chromosomes in exchanged

reproduction by translocation carrier may transmit what?

genetic material to offspring causing partial trisomies and monosomies

what describes BCR-ABL translocation?

• a balanced translocation between chromosomes 9 and 22 

• small hybrid chromosome called Philadelphia Chromosome is produce

BCR-ABL is constitutively active and leads to what?

development of chronic myeloid leukemia (CML)

what describes Robertsonian translocation?

involves loss of short p arms and subsequent fusion of long q arms of chromosome

Robertsonian translocation has what kind of effect on carrier?

no effect because short p arms of acrocentric chromosomes contain no essential genetic material 

carriers of Robertsonain translocations have what?

karyotype with only 45 chromosomes

what describes Robertsonian Translocation Down syndrome?

• usually affects chromosomes 14 and 21

• leads to 3 copies of the 21 -q arm, which mimics the consequences of trisomy of the fully chromosome 21

what describes chromosome inversion?

portion of the chromosome has broken off, turned upside down, and reattached

what describes paracentric inversion?

does not involve centromere region

what describes pericentric inversion?

includes the centromere region

chromosomes inversions are considered what?

balanced rearrangements because no genetic material is loss

chromosome invasion can lead to what?

difficulties with homologous recombination during meiosis

40% of cases of Hemophilia A are due to what?

chromosome inversions

Hemophilia A is caused by mutations in what?

gene for clotting factor VII, an X-linked recessive disease

defects in clotting factor VII can lead to what (symptoms of Hemophilia A)?

• severe bleeding from wounds

• hemorrhages in joints and muscles

• bruising,

• hemathroses (bleeding in the joints)

• intracranial hemorrages

what describes ring chromosomes?

a portion of a chromosome breaks and forms a circle or ring

what can also be caused by a loss of ring X chromosome?

turner syndrome (X0)

what are symptoms of ring chromosome 14 syndrome?

• seizures

• lymphedema

• intellectual disability

• delayed cognitive and motor development

• slow growth

• short stature

• microcephaly

what describes isochromosome?

formed by the mirror image copy of a chromosome segment including the centromere (2 copies of one arm, no copy of the other)

20% of turner syndrome is caused by what?

isochromosome