Lecture 2.1: Chromosome Disorders Flashcards
1) What does a Geimsa stain consist of?
2) What are the dark bands? Which are the light bands?
3) What are fragile sites?
1) G-banding; p and q segments
Considered “low res”
2) Dark bands (A,T); light bands (C,G)
3) Areas of no stain
What are two other types of imaging besides Geimsa?
1) FISH: next step up in resolution
2) Microarrays: further increased res
1) Define chromosomes mutation
2) The incidence of most chromosome disorders occurs __________ and is identified shortly after __________.
1) Changes in the number or structure of chromosomes
2) prenatally; birth
Define regional mutation
Change a portion of a chromosome, and might involve change in the copy number of subchromosomal segments or structural rearrangement involving parts of one or more chromosomes
1) True or false: Most genes are present in two forms, and the correct dosage comes from this
2) Two of nature’s ways of “fine tuning” gene dose are through _____________ and _______________.
1) True
2) x inactivation and genomic imprinting
True or false:
1) Having either one or three genes generally creates the wrong dose and disrupts normal gene function.
2) Having two active X chromosomes does not lead to a detrimentally high dose of these genes
1) True
2) False; it does
True or false: Having either one or three entire chromosomes disrupts the dose of SEVERAL genes and is usually incompatible with life
True
1) What happens when an X chromosome is inactivated?
2) What does X inactivation result in?
1) It’s methylated and becomes a “Barr body”
-It is now nonfunctional
2) Females will display some degree of mosaicism
1) Define mosaicism
2) Who does it commonly occur in?
3) Where else can it occur? What happens if this occurs early in development?
1) Having more than one cell line distributed throughout the body
2) Happens with all 46, XX females
3) Nondisjunction can also occur on any chromosome in a mitotic division after formation of the zygote
-a skewed mosaicism may result, carrying this abnormality into all clones, leading to abnormal phenotype
1) What are triploid infants?
2) How does this usually happen?
3) How could it also happen?
1) Have one extra set of all chromosomes
2) Fertilization of an egg by two sperm (dispermy)
3) Can also result from failure of one of meiotic division in either sex; diploid egg or sperm
1) What is tetraploid?
2) What can it result from?
1) 92, XXXX or 92, XXYY
2) Failure of completion of early cleavage division of early zygote
1) Define aneuploidy
2) What is monosomy? Is it always lethal? Give an example
1) MC clinically significant type of human chromosome disorder
2) A type of aneuploidy; lethal in every case except the X chromosome (Turner syndrome)
1) Autosomal Trisomy is absolutely lethal in all but 3 cases; what are they?
2) What causes it most often?
1) Chromosome 13, 18, 21
2) Meiotic disjunction, which can occur in either meiosis I or II
Autosomal trisomy:
1) What happens if If nondisjunction occurs during meiosis I?
2) What abt during meiosis II?
1) Gamete will have one copy of maternal and paternal homologue
2) Gamete will have both sister chromatids from either the paternal or maternal line
Triploid:
1) What happens to those resulting from extra set of maternal chromosomes?
2) What abt from extra set of paternal chromosomes?
1) Typically aborted spontaneously in early pregnancy
2) Partial hydatidaform mole (abnormal degenerative placenta)
1) What can large, structural abnormalities of the chromosomes result from?
2) Define balanced
3) Define unbalanced
1) Can result from chromosome breakage, recombination error, or exchange, followed by reconstitution into an abnormal combination
2) If the genome has normal complement (amount) of chromosomal material
3) If there is additional or missing material
____Unbalanced/ balanced_________ rearrangements pose a threat to offspring, because carriers are likely to produce a ____________ frequency of unbalanced gametes, causing phenotypically abnormal offspring
Balanced; high
Deletions:
1) When do they occur?
2) What does an individual with this mutation have?
3) What do the issues result from clinically?
1) When part of the chromosome is lost
2) One normal homologue and one with a deleted segment; they are monosomic for that segment
3) Haploinsufficiency
1) What is deletion severity entirely dependent on?
2) What are the two forms of deletions?
1) What was on that code, and how much was cut
2) Two forms: terminal (at end of chromosome) and interstitial (in middle of chromosome)
1) What do duplications cause?
2) How are ring chromosomes formed?
1) Partial trisomy and have some phenotypic effect because they change dosage and may, in fact, duplicate in an area of the code that breaks a gene
2) When chromosome undergoes two terminal deletions, and the broken ends come together, forming a ring
1) What are isochromosomes?
2) What is the result?
1) One arm of chromosome is missing and the other is duplicated
2) Partially monosomic for the missing arm; partially trisomic for the duplicated arm
1) When do translocations occur?
2) What happens in reciprocal translocation?
3) Do reciprocal translocations always affect phenotype? Explain.
1) Chromosome segments are exchanged between two chromosomes
2) A back-and-forth exchange of the effected segments
3) Usually w/o phenotypic effect, but pose risk to progeny
1) What is a big downside to having a translocation?
2) What do they have to do?
1) Difficult to pair during meiosis; can’t form a tidy “bivalent”
2) Form a “quadrivalent” instead, in order to pair homologous sequences
Dicentric Chromosomes:
1) What are they?
2) How can they remain stable? (2 things req.)
3) What is the medically significant version of this?
1) Two chromosome segments, each with a centromere, fuse end to end (aka they get really tall).
2) If one of the two centromeres is turned off epigenetically AND if the two centromeres move to the same side during anaphase
3) the “Robertsonian translocation”
1) What is the most common rearrangement in the human species?
2) What is the resulting karyotype? What does this include?
3) What do the short arms of acrocentric chromosomes contain?
4) Are these chromosomes balanced? Explain
1) Robertsonian translocation
2) 45, including the translocation chromosome, which is made up of all the genetic material from the two joined chromosomes
3) Mostly “junk”; satellite DNA and copies of ribosomal RNA genes
4) Yes, but risky for offspring
1) Insertions occur when a segment from one chromosome breaks off and does what?
2) Why are they rare?
1) Is inserted into another
2) Require 3 segmental breaks
1) When do inversions happen?
2) What are the two types?
3) Is recombination of these chromosomes easy? Explain
4) _______________ inversions especially lead to unbalanced gametes
1) Single chromosome undergoes two breaks and is put back together with the broken segment “upside down”
2) This can either include the centromere or not
-If it does it is pericentric
-If not, paracentric
3) Very difficult and prone to abnormality
4) Pericentric
1) What is the most common chromosome disorder?
2) What else is this disorder the most common genetic cause of?
3) How common is it? When is the incidence higher?
4) Give an example of a Sx of this at birth
1) Down syndrome
2) Moderate intellectual disability
3) 1/ 850 children; in mothers over 35
4) Hypotonia
1) Besides hypotony, list some other Sx of down syndrome
2) How do you treat it?
1) Intellectual disability, dysmorphic facial features, bradycephaly with flat occiput, short neck with loose skin on nape, single transverse palmar crease (“Simian crease”), & clinodactyly
2) Manage complications
1) How common are congenital heart defects in living infants with down syndrome?
2) What does down syndrome increase the risk of by 15 times?
3) What else does it increase risk of?
1) 1/3
2) Leukemia
3) Premature dementia
1) How is down syndrome detected “early”?
2) What increases risk of it?
1) Amniocentesis
2) Risk increases with age
1) What is down syndrome (can be 3 things)
2) How is it diagnosed?
1) Trisomy 21, Robertsonian translocation, 21q21q translocation
2) Clinical dx confirmed with karyotyping
-Cytogenic analysis helps to delineate recurrence risk
1) Trisomy 21 has what set of chromosomes?
2) What % of Down Syndrome cases does this make up?
3) What is the cause?
1) Trisomy 21 (47 XX, XY +21)
2) 95% of cases
3) Non-disjunction during meiosis
1) Robertsonian translocation is the cause of what percent of down syndrome pts?
2) What is the genotype in Robertsonian down syndrome?
3) Describe the cause of Robertsonian translocations in general.
1) 4%
2) (46, XX or XY, rob(14;21) +21
3) Two acrocentric chromosomes lose their “knubbins” and recombine with two centromeres and the long ends of each recombined
All gametes of a carrier with 21q;21q translocation (cause of Down Syndrome) will have one of two possibilities; what are they?
1) It will contain the translocation chromosome 21q;21q and get “double dose” of 21 from mom = baby with down syndrome
2) It will not have this chromosome and get no genetic material from mom regarding chromosome 21 = baby not viable
1) Is partial trisomy (Down syndrome) rare?
2) What is it?
3) Why is it useful?
1) Very rare
2) Only part of the long arm of 21 is present in triplicate
3) Help geneticists to study which parts of the chromosome are responsible for certain phenotypic traits
Recurrence risk of down syndrome:
1) After having one baby with down syndrome, risk is ___% overall
2) Risk overall is _____% for mothers younger than 30 years – not understood why
1) 1% overall
2) 1.4%
Genetic study and counseling is key for Down syndrome: Recurrence risk is much higher in case of _________________
translocation
What is Trisomy 18 also called? What are its characteristic?
1) Edwards syndrome
2) Most babies die at birth; intellectual disability, failure to thrive, but some live to 20 yo
1) What is Trisomy 13 also called?
2) What are some of its characteristics?
1) Patau Syndrome
2) Cleft lip, palate, polydactyly, microcephaly, microphthalmia, omphalocele
Trisomy mnemonics
You can see a PG-13 movie at age 13
Patau’s, trisomy 13
You are Eligible to vote at age 18
Edward’s, trisomy 18
You can Drink at age 21
Down Syndrome, trisomy 21
1) What is Uniparental Disomy? What are the 2 types?
2) What does it result from?
1) Both copies of a chromosome derive from the same parent
-From sister chromatids = idiosomy
-From homologues = heterodisomy
2) Nondisjunction
How does uniparental disomy happen? Describe
Trisomy “rescue”: Cells of a trisomic conceptus restore disomic state (by kicking out a chromosome, but they kick out the wrong one)
What are the 2 steps of uniparental disomy?
1) An original trisomy occurs through nondisjunction in one of the parent’s germline during meiosis
2) The rescue occurs when second nondisjunction event through mitosis early in post zygotic phase
The expression of some genes depends upon whether they are marked as paternal or maternal.
What does it mean if the gene is imprinted?
It’s marked based on donor sex and turned off.
1) Define paternal imprinting
2) Define maternal imprinting
1) Allele inherited from the father is not expressed in the offspring
2) Allele inherited from the mother is not expressed in the offspring
1) True or false: Regions that are imprinted from mom
and dad are never on the exact part of the chromosome
2) Can it occur on autosomes, gametes, or both?
1) True
2) Autosomes
Prader-Willi
1) What is the age at onset?
2) What are the typical symptoms?
3) Describe what it does socially
4) How is it treated?
1) Infancy
2) Infantile feeding difficulties, hypotonia, childhood hyperphagia and obesity, short stature, dysmorphism, small hands and feet, hypogonadism
3) IQ between 60-80; emotional outbursts
4) Control obesity
Prader-Willi:
1) Chromosome 15 has ____________ imprinted near ___________ normally.
2) In Prader-Willi there is a __________ deletion of 15q11.2-11.13
3) What is the result of these things?
4) Why may an affected child have lighter colored features?
1) maternally; q12
2) paternal
3) Now baby has NO GENETIC MATERIAL HERE
4) Occurs near OCA2 gene (codes for hair, eye, and skin color)
Parental disomy type of Prader-Willi Syndrome:
1) In rare cases, _______ can pass along both copies of Chromosome 15 in lieu of any ___________ copy.
2) Baby will lack the _____________ expressed genetic material in the 15q11-13 region and will be born with Prader-Willi
not super important, “if you want to play on hard mode”.
1) mom; paternal
2) parentally
Describe the symptoms of Angelman syndrome
Severe developmental delay, seizures, delayed walking, wide stance, stiff, clumsy gate
“Happy puppet syndrome”
Angelman syndrome:
1) In this disease, _________ chromosome 15 is passed along with a _____________ region.
2) ______________ normal, imprinted chromosome _________ ________ expressed genes in this region (as it should)
1) mother’s; deleted
2) Father’s; lacks any
1) Through deletion/duplication, we see diseases that create what is called “________________,” which means they have the wrong number of genes on ‘just a part’ of the chromosome
2) Often, when many different genes are next to one another on a chromosome, they are all affected; this is called what? When does this often occur?
1) segmental aneusomy
2) “contiguous gene syndrome”; during unequal crossing over
Deletions and duplications on chromosome 22:
1) There’s a common deletion on 22q11.2 leading to partial ___________________.
2) Give examples of syndromes this can cause
3) Give some symptoms of this genetic anomaly (facial features and other symptoms)
1) haploinsufficiency
2) DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome
3) Facial Features: retrognathia, long face, high broad nasal bridge, small teeth, down-turned mouth
-Immune disorders, intellectual disability, cardiac malformations, hypocalcemia (secondary to malformed parathyroid)
1) Give an example of an idiopathic autosomal deletion.
2) What types of abnormality can cause this?
3) What does degree of intellectual impairment correlate with?
4) Where does it occur near? When is severe intellectual disability more likely to occur?
1) Cri du chat syndrome
2) Either through terminal or interstitial deletion on long arm of Chromosome 5 (break points highly variable).
3) Size of deletion
4) Near band 5p15; in regions 5p14-5p15
