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403 Cards in this Set

  • Front
  • Back
Define the ‘p’ and ‘q’ arms of a chromosome.
‘P’ is the short, or petite, arm and ‘q’ is the long arm of the chromosome on either side of the centromere.
What is the name used to describe a chromosome with the centromere in the middle?
Metacentric
What is the name used to describe a chromosome with a centromere that is slightly off center from the middle?
Submetacentric.
What is the name used to describe a chromosome with a centromere that is toward the end of the chromosome, leaving a very small p arms?
Acrocentric
What is a defining feature of the q arm of the acrocentric chromosomes?
They have satellites at the top end of the short arm, which contains multiple copies of rRNA genes; they are called Nucleolar Organizing Regions (NORs).
What do we call the regions just adjacent to the telomeres?
Sub-telomeric regions.
What sorts of conditions are necessary to obtain dividing cells?
In short, the cell must be living and dividing, not frozen, dried out, etc!
What type of tissue samples are used to study an individuals chromosomes?
Usually WBC’s, but occasionally skin cells.
What type of tissue sample is used to study a fetus’ chromosomes?
Amniotic fluid or chorionic villi.
What exogenous inclusion is necessary for WBC culture?
A mitogen, like phytohemaggutinin.
How is a dividing cell arrested at metaphase?
Add something that destroy’s the mitotic spindle, such as colcemide.
Describe G-banding.
AT regions stain dark, GC regions stain light or do not stain. It is very commonly used.
Describe high-resolution analysis of chromosomes.
Instead of arresting in metaphase, arrest at an earlier stage with a less condensed form of DNA, allowing for higher resolution and more visible sub-bands.
What does the following mean:
46,XY,dup7q11q31?
What does the following mean: 46,XY,del 22q11.2?
46 male genotype with a deletion on chromosome 22 of region 11.2.
How do we approximate the degree of resolution of a karyotype?
We refer to the ‘band level’, i.e. the number of bands visible.
How do we test for the presence or absence of a specific chromosomal agent?
DNA probe
Does a cell have to be in a mitotic state in order for abnormalities to be identified?
No.
What is a common method for detecting specific chromosomes by hybridization of labeled probes?
FISH (flouresence in situ hybridization).
What are the three types of FISH?
(1) Satellite repeat-sequence probes (2) whole chromosome paint pairs (3) unique sequence probes
Which analysis technique can we use to determine the proportion of self vs. donor bone marrow cells?
Donor is of opposite sex, and we can use FISH satellite repeat-sequence probes (which target the centromeres of specific chromosomes) to determine the XX vs XY ratio.
Which FISH analysis technique covers an entire chromosome?
Whole chromosome paint probe.
Which FISH analysis technique identifies specific gene loci?
Unique sequence probes.
What is the significance of the subtelomere region?
It’s as close as functionally possible to the border of the coding-non-coding region of the chromosome.
What is the clinical significance of subtelomeric region abnormalities?
A 2-8% proportion of people with idiopathic retardation have subtelomeric region abnormalities.
Describe aCGH.
Array-based Comparative Genomic Hybridization. Very high resolution molecular cytogenetic technique used to detect submicroscopic chromosomal duplications and deletions; comprises hundreds or thousands of FISH tests done at one time.
How can aCGH be used to determine copy number issues?
Duplications and deletions are detected (copy number variations) by the difference in subject vs. standard DNA readings in the aCGH analysis.
What is the function of a targeted array?
It’s a type of CGH array that looks for defined regions of microdeletion and/or duplication syndromes and all centromeric and telomeric regions. Most BAC arrays are targeted arrays.
What is the function of a constitutional array?
Uses probes from the whole genome; can function as targeted arrays or to increase resolution in a specific genomic region of interest.
What is an SNP array and how does it differ from a CGH array?
It looks at single nucleotide polymorphisms and can even distinguish uniparental disomy, where chromosomal arrays cannot. Uses allele-specific oligonucleotide probes (ASO)
What are some major advantages to microarray analysis?
Detects additional 5-20% of patients with idiopathic retardation and/or congenital anomalies compared to subtelomere FISH analysis because it is a multiple, concurrent FISH analysis over hundreds or thousands of loci
What are some major disadvantages of microarray analysis?
Cannot detect balanced chromosome anomalies since it isn’t comparative in nature. Regions not represented on an array are not assayed. Can identify benign polymorphisms. Very expensive
What would we use to detect a disorder of whole chromosomes?
Karyotype.
What would we use to detect microdeletions or microduplications are suspected?
FISH or targeted high-resolution karyotype.
What would we use to detect a likely translocation?
Karyotype + FISH; note that a translocation won’t change a result in a microarray, so it’s not a useful alternative. E.g. a parent with repeated miscarriages (likely have balanced translocation) or the parent of a patient with an unbalanced translocation.
What would we use to test a patient with idiopathic retardation and/or multiple congenital abnormalities?
aCGH is a good place to start.
When do you use a BAC/oligo aCGH?
BAC covers less area, but gives fewer false positives; Oligo covers more area, but gives more false positives.
Describe haploid.
1 set of chromosomes set.
Describe euploid.
Any exact number of chromosomes set (complete sets).
Describe aneuploidy.
Any non-exact number of chromosome sets
Describe diploid.
A pair of chromosomes sets.
Describe polyploidy.
Any number greater than two sets of chromosome sets
Describe nullisomy.
Both copies of a chromosome (referring to a single chromosome) are missing.
Describe monosomy.
A single chromosome is missing it’s homologue.
Describe trisomy.
There is one additional chromosome in a pair.
Describe a constitutional chromosomal abnormality.
Abnormality present from conception or early fetal development and involves entire body.
Describe an acquired chromosomal abnormality.
Was not inherited. Often important in analyzing cancer cells.
Describe a numerical chromosomal abnormality.
Number of chromosome present is abnormal; e.g. 47 XXY
Describe a structural chromosomal abnormality.
Structural, just like it sounds. E.g. partial trisomy.
Describe mosaicism.
One or more additional cell lines with different chromosome compliments which arise in embryonic or pre-embyonic life; i.e. more than one type of cell.
Describe a chimera.
An individual with 2 or more cell ines, originally due to fusion of separate zygotes!
Provide an example of chromosomal mosaicism.
47,XY+21[8]/46,XY[42]  a person with chromosomal mosaicism where 8 of 50 cells had a 47XY+21 chromosomal makeup and the other 42 has a normal 46XY makeup.
Describe a somatic mosaicism.
Body consists of more than one cell type.
Describe a germ line mosaicism.
Only the germ line has more than one type of cell.
Describe placental mosaicism.
Fetus can have a different chromosomal makeup from the fetus. Usually a mosaic fetus with normal placenta goes to term, and not the other way around, since the placenta can support the fetus when it’s normal.
Describe trisomy rescue.
A zygote or early embryo may lose an extra chromosome that was accumulated somewhere along the line, probably during cleavage or early mitotic divisions.
Describe chromosome heteromorphisms.
These are normal variations not associated with phenotypic abnormalities.
Write out notation for a partial monosomy.
Deletion of a gene segment could lead to the following: 46XY,del(22)(q11.2), where the q11.2 segment is missing from one of the chromosomes 22.
What condition might we find in a 46,XX,del5p?
Cri du Chat syndrome.
How can one diagnose a microdeletion?
FISH is a good technique because it’s so small; often includes multiple genes.
What do you call a genetic abnormality where more than one gene in a row is abnormal?
Contiguous gene syndrome.
What are three examples of contiguous gene syndrome?
(1) Williams Syndrome (del 7q11.2), (2) Prader-Willi Syndrome (either paternal del 15q11-q13 or maternal uniparental disomy 15), (3) Angelman syndrome (either material del 15q11-q13 or paternal uniparental disomy 15).
What is the result of paternal uniparental disomy of chromosome 15?
Prader-Willi Syndrome
What is the result of maternal uniparental disomy of chromosome 15?
Angelman syndrome
What is the result of paternal del 15q11-q13?
Prader-Willi syndrome
What is the result of maternal del 15q11-q13?
Angelman syndrome
What is the functional equivalent of duplication?
Patrial trisomy. 46,XY,dup(1)(q22q25) is a duplication of chromosome 1 over regions q22 to q25. Note: add can be used in place of dup in the above example.
What does a structural abnormality clinically allow us to rule out in the parental generation?
Rearrangment must be ruled out.
If a chromosomal translocation produces a result which has no missing genetic material, but the gene has been translocated to a region where it cannot be properly expressed, what type of chromosomal translocation is this?
Unbalanced
What can result from reproduction of a balanced translocation patient?
Their offspring may be unbalanced—in fact, they likely will be.
What do we call a transfer of genetic material between non-homologous chromosomes?
Reciprocal translocation.
What are some common genetic risks for carriers of reciprocal translocation?
Offspring with partial trisomy or monosomy.
What does the following mean: 46,XX,t(1;9)(q12;p12)?
46 chromosome woman where chromosome 1q12 transferred to the chromosome 9p12 position, and vice versa. This is likely balanced.
What does the following mean: 46,XX,der(1)t(1;3)(p22;q13)?
46 chromosome woman where the derivative chromosome 1 result from a translocation nof the portion of chromosome 3 distal to 3q13 onto the short arm of chromosome 1 at band 1p22. Der(1) essentially replaces a normal chromosome, signifying it is unbalanced.
Describe a Robertsonian translocation.
Two acrocentric chromosomes or nonhomologous chromosomes which have joined at or near the centromere and the ‘p’ arm material is lost.
What is the risk of a Robertsonian translocation of acrocentric chromosomes?
No real risk in the carrier since the p arms in acrocentric chromosomes is primarily rRNA coding. However, there is a risk of an unbalanced offspring, or trisomy in offspring.
What might the written karyotype of a balanced robertsonian carrier look like?
45,XX,der(14;21)(q10;q10)—there are 45 chromosomes (two have merged), where the two long arms have merged and a new one is “der”ived from chromosomes 14 and 22.
What might the written karyotype of an unbalanced robertsonian carrier look like?
46,XX,der(14;21)(q10;q10)+21 – 46 chromo, but one of her 14’s has a 21 attached to it, so there is a trisomy effect despite only being 46 physical chromosomes.
How does mitosis deal with inversions?
Inversion loops are made during crossing over, and this can lead to partial trisomy or partial monosomy.
How can an inversion loop create a partial trisomy or monosomy?
The inversion loop doesn’t have exactly equal genetic material, so more or less is picked up / replicated.
Describe the two types of inversions.
Pericentric inversions: inverted segment includes the centromere. 46XY,inv(7)(p14.2q36.3) describes a pericentric inversion—note the p and q arms both being mentioned. Paracentric inversions: inverted segement does not include the centromere. 46,XY,inv(3)(q13q24)—note that only the q arms is mentioned.
Describe an isochromosome.
It’s a chromosome that divided incorrectly and resulted in a chromosome that has identical arms on either side of it’s centromere; e.g. only p arms or only q arms. E.g. 46,XisoX(q10) is a woman with one normal X and an isochromosome copy of X
Describe a ring chromosome.
Telomeres are lost and resulting sticky ends anneal with one another. Results in a partial monosomy in both the q and p arms. E.g. 46,XX,r(13)(p12q34) is a woman whose chromosome 13 broke at p12 and q34 and those two ends joined together.
What do we call an abnormal, usually smaller, chromosome and how would one annotate it?
Marker chromosome; identify with FISH or aCGH. 47,XY,+mar (15) is a male with 47 chromosomes, the 47th being a marker chromosome derived from chromosome 15. If the “(15)” is left out, we just assume the marker is of unknown origin.
What do we call a loss of pregnancy up to 20 weeks gestation?
Spontaneous abortion (SAb).
What is the estimated loss of pregnancy frequency?
10-50% of all conceptions.
What is the most common cause of miscarriage?
Chromosome abnormality. 50% of all SAb’s and 70% of all first trimester SAb’s. 50% of these chromosome abnormalities are trisomies!
What might we expect in a couple where at least 3 SAb’s have occurred?
One person might be a carrier of a balanced chromosomal rearrangement.
Why can the Y chromosome vary greatly in size?
The Y long ar1m (q) can vary greatly because there is a variable distal segment, and on that q arm there are no genes
What relation to sexual development and function do most genes on the X chromosome have?
None
What is the significance of the “Lyon Hypothesis”?
It suggests that the body can mediate dosage differences that could potentially exist between men (one X) and women (two X’s) via Barr body formation. This is the reason that trisomy or monosomy for X is not as big a deal as it could be. MOST, not all, of the genes will be inactivated by Barr body formatoin
What genes and gene regions are responsible for X-inactivation?
XIST (X-inactivation-specific transcript), a specific gene responsible and necessary for gene inactivation, and XIC (X inactivation center), a region on the X chromosome.
What sorts of tests do we perform on parents of children who have numerical abnormalities in their chromosomes?
None, it’s not necessary since those are spontaneous meiotic events.
What sorts of tests do we perform on parents of children who have structural abnormalities in their chromosomes?
Start with a karyotype, then look toward FISH, aCGH, and even toward considering mosaicism.
How does triploidy typically occur?
Most due to dispermy, many to fertilization with diploid sperm, and some with fertilization of diploid egg.
Write the notation for trisomy 21, and describe its major features.
Down syndrome is 47, X_+21; intellectual disabilities, and recognizable physical features, including hypotonia.
What is the most type of chromosomal abnormality is trisomy 21?
Nondisjunction. It is followed by a distant combination of translocation and mosaicism.
How does one determine the probability of recurrence of trisomies?
By mechanism. If the affected person has a translocation, then recurrence is very probable.
Write the notation from trisomy 13, and describe it’s major features.
47,X_,+13; multiple anomalies, including cleft lip/palate, polydactylism, mirophthalmia, organs, etc. Severe/profound intellectual disabilities, and a shortened livespan.
Write the notation for trisomy 18, and describe it’s major features.
47,X_,+18; Edwards syndrome; multiple anomalies, including clenched hand position and facial features; may have ccleft palate/lip, and organ issues. Profound intellectual disabilities and a shortened lifespan.
Write the notation for turner syndrome and describe it’s major features.
45,XO; physical and behaviorally female, normal intelligence, short stature, ovarian dysgenesis at early age (therefore infertility).
What is the probability of recurrence in Turner syndrome?
Unlikely due to it’s mechanism, which is usually nondisjunction.
Write the notation for Klinefelter’s syndrome and describe it’s major features.
47,XXY. Physically and behaviorally male, but with small testes without sperm, gynecomastia, and tend to have long limbs. Some learning disabilities, speech delays, and behavior problems common.
How does pre- vs. postnatal testing of children with Klinefelter’s change the outcome of their disorder?
Typically prenatal allows for things to occur which usually result in better intellectual performance
Describe 47,XXX.
Physically and behaviorally female, normal appearance, but tend to be tall and awkward with poor coordination. Intelligence is often low, but many are normal. Often speech delays and/or behavioral problems.
Describe 47, XXY
Physically and behaviorally normal, with a normal appearance. Often dull, with speech delays and learning disabilities, but with normal full-scale IQ.
What is the risk of recurrence like in 47XYY and 47XXX.
47XYY has no risk of recurrence that is above the normal population. 47XXX becomes more common with age of the mother, like other trisomies do.
Write the shorthand for Cri Du Chat syndrome and describe it’s major features.
Del(5p); cat-like cry in infancy; intellectual disabilities, an dmicrocephaly with typical facial features and cardiac abnormalities.
Write the shorthand for William’s syndrome, and describe it’s major features.
Del7q11.23; characteristic facial features, elastin gene is deleted! Develop behavioral / neurodevelopmental phenotype with mild/moderate intellectual disability and distinctive, friendly, loquacious personality.
Write the shorthand possibilities for Prader-Willi syndrome and describe it’s major distinctive features.
Del 15q from paternal side, or uniparental disomy for maternal
15. Abnormal methylation at 15q11-p13. Severe hypotonia, causing early feeding problems. Develop hyperphagia and obesity. Have typical physical features, including hypogenitalism, short stature, and small hands and feet. Have milk intellectual disabilities.
Write the shorthand possibilities for Angelman syndrome an describe it’s major distinctive features.
Deletion of maternal 15q, or paternal disomy for
15; abnormal methylation between 15q11-q13. Typical behavioral phenotype. Jerky, puppet-like gait with balance problems. Severe intellectual disabilities.
Compare and contrast Prader-Will to Angelman syndrome.
Their phenotype’s are vastly different, when they effectively have the same “chromosomes” that are affected. The difference is whether the issue is maternal or paternal in origin. PW is a paternal 15q deletion, or material uniparental disomy. AS is maternal 15q deletion, or paternal uniparental disomy.
Write the notation for DiGeorge/Velocardiofacial syndrome and describe it’s major features.
Del 22q11.2; markedly variable p physical features, but some common patterns. Learning or mild/moderate intellectual disabilities; many have normal intelligence.
Write the allelic makeup of an autosomal dominant, mendelian gene pair.
Aa
Write the allelic makeup of an autosomal recessive, mendelian gene pair.
Aa
Describe codominance and write the allelic makeup of an example.
It is where both gene products are expressed equally. E.g. Blood types. AB persons will express both A and B surface antigens.
Describe incomplete dominance and given an example.
The heterozygote is an intermediate between the homozygotes. E.g. in achondroplasia, AA is more affected than Aa which is still affected (and aa is not affected).
What is acondroplasia?
It’s a type of dwarfism, related to an autosomal dominant gene.
Are autosomal dominant disorders typically enzymatic or not? Explain.
Not enzymatic. Enzymatic disorders usually allow for the functioning allele to takeover the function of the mutant gene. This is “usually”, there are possible exceptions to this rule. E.g. imagine a situation where a mutant enzyme binds a substrate too tightly.
Are autosomal dominant disorders typically structural or not? Explain.
Yes, typically structural. Structural problems can interfere with wild type expression of normal genes. E.g. collagen requires a triple helix, so if one of the three pro-alpha collagen chains is mutated it can affect the overall structure since gene products from both maternal and paternal chromosomes are produced.
Explain “procollagen suicide”.
When one of the pro-collagen genes is mutated, and interferes with the others to forma proper triple helix.
What is an example disease which displays procollagen suicide and what are some major symptoms?
Ehler-Danlos syndrome; hyperflexibility, stretch skin, low bone density, etc.
Are autosomal recessive disorders typically structural or not? Explain.
No. Refer to procollagen suicide and Ehler-Danlos syndrome for an example.
Describe how PKU relates to mendelian genetics.
It’s an autosomal recessive disorder; it’s enzymatic. Therefore, heterozygotes may exhibit some traits (if at all) of a PKU patient, but the normally functioning allele typically keeps things working properly. Homozygote recessive individuals have no functioning enzymes.
Describe allelic heterogeneity.
Disorders of the same locus (same gene). I.e. most people have a different mutation, but of the same gene. This complicates testing and means there is variable expression of the disease.
Describe allelic Locus heterogeneity (non-allelic).
Mutations at different loci (different genes). Although the mutation may occur at different genes, it still produces the same phenotypic outcome. This complicates testing. An example is polycystic kidney disease, which has two major causes.
Describe allelic homogeneity.
Disorders of the same gene in the same exact spot. E.g. 99% of people with achondroplasia have a mutation in the FGFR3 gene. HbS is the result of the nucleotide mutation, which changes the amino acid.
Describe variable expressivity.
Degree to which an affected individual expresses the particular disorder.
What can explain intrafamilial and interfamilial variability in gene expression?
Intrafamilial variablility is probably the result of modifying genes, whereas interfamilial variability is likely the result of allelic heterogeneity.
What is an example disease for variable expression?
Van der Woude syndrome.
Describe variabile severity.
Affected individuals can have different levels of affliction. Very similar to variable expressivity.
What is an example disease for variable severity?
Treacher-Collins syndrome.
Compare and contrast congenital and genetic defects.
Congenital is something you’re born with, and may not be the result of inheritance. E.g. Down’s syndrome.
Describe familial adenomatous polyposis (FAP) and how is it classified?
Pre-cancerous colon polyps form in these patients. The mean onset of time is 16yr, thus it is a “delayed onset” genetic disorder.
Describe genetic pleiotropy.
A single gene is responsible for a number of distinct and seemingly unrelated phenotypic effects, in more than one organ system. It may show reduced or even non-penetrance
Describe sex-limited phenotypes.
Autosomally transmitted, but expressed only in one sex. E.g male limited precocious puberty.
Describe sex-influenced phenotypes.
Expressed in both sexes, but with varying frequencies. E.g. hemochromatosis.
Describe penetrance.
Percentage of people with a particular genotype actuall affected clinically. This relies on an “all or none” concept of the particular affliction. E.g. a person either shows a disorder or they don’t.
Describe reduce penetrance and nonpenetrance.
Not every person with the genotype will show the disorder. E.g. polydactylism—some people don’t show extra digits.
What common genetic phenomenon do people typically confuse with “skipping a generation”?
Reduced penetration.
On a pedigree, how might you see transmission of an autosomal dominant gene?
Vertical transmission, unless arising from a new mutation or we may see “skipped generations” in cases of nonpenetrance.
Explain germ-line mosaicism as it pertains to clinically unaffected parents producing an affected offspring.
It’s possible there is germ-line mosaicism. I.e. only the germ cells are carrying this mutation, so the somatic cells are unaffected and the parent is unaffected.
Describe Huntington’s disease in terms of time of onset.
It’s a delayed onset disease, sometimes not occurring until well after reproduction or into old age.
Explain 6 ways by which a family history may be negative for an autosomal dominant disorder.
(1) delayed onset (2) new mutation (3) germ-line mosaicism in parent (4) non-penetrance/mild expression unrecognized (5) genetic heterogeity—this one is tricky because it could be that the patient has another, similar disorder with different inheritance (autosomal recessive), (5) nonpaternity!
What is the risk of an affected parents passing on an autosomal dominant gene?
50%
On a pedigree, how might we see inheritance of autosomal recessive genes?
Horizontal transmission.
Explain uniparental isodisomy.
Two copies of a single chromosome inhereited from one parent and no copy from the other parents. This can lead to expression of recessive traits.
If a family has produced a child expressing a recessive mendelian trait, what is the probability we would expect for the trait for the next child?
1/4 (25%)
Define an obligate carrier.
Individual who may be clinically unaffected but MUST carry a gene mutation based on analysis of family history; usually seen in recessive disorders, but sometimes in dominant disorders with incomplete penetrance.
Describe pseudodominance and explain how we may see it.
A false appearance of dominance in a pedigree; can be the result of consanguinity or high gene frequency in the population (the problem with consanguinity!).
Describe Fragile X Syndrome.
Trinucleotide repeates of CGG for > 200 nt (6-54 is normal, 54-200 is permutation). It’s x-linked, and can be detected by PCR amplification.
When does x-inactivation occur?
First few weeks after fertilization.
Compare males and females in terms of severity of X-linked dominant condition expression.
Females tend to have a more mild version of the X-linked conditions.
How identical is DNA of different people?
99.9%
Describe a ‘locus’.
Specific place in a DNA sequence; can be a gene, non-coding region, or even a specific nucleotide.
Describe a ‘genotype’.
An individuals allelic constitution at a locus.
Describe an ‘allele’.
Variants seen at a locus in a population.
Describe a ‘haplotype’.
Series of closely linked loci that occur together on a chromosome and are usually inherited together.
Describe population admixture.
Races/peoples/etc mix, and this increasingly blurs the lines of genetic distinction. However, evidence of ancestry is still retained to various degrees.
Why do genetic counselors, etc, collect racial / ethnic data?
Ethinic background is important to following genetic susceptibilities / traits / etc.
How might ancestry affect screening?
Certain ancestries may warrant screening for certain disorders.
Why might we see highly inherited disorders, such as sicke cell anemia or familial Mediterranean fever?
Heterozygote advantage is a possible explanation—it’s pretty well proven for HbS.
What problem is typically associated with families that carry disorders commonly believed to be involved in “heterozygote advantage”?
The homozygotes for the mutant genes tend to be deleterious.
Describe the founder effect.
You may see a high frequency of a mutant gene in a population when that group is an “ancestral” (or founder) group of only a few people.
How might ancestry affect what tests a genetic counselor will order?
Different ancestries may have different genetic susceptibilities, and therefore will warrant different tests.
How might ancestry affect the way a genetic counselor interprets a test?
Different ethnicities will have varying detection rates, false positives/negatives, etc and that must be kept in mind when reading test results.
What does the hardy-weinberg equation allow us to calculate?
Allele frequency from genotype frequencies—used especially for mendelian loci.
What are some major assumptions of the hardy-weinberg principle?
1. Mating is random 2. No mutation 3. No selection 4. No migration
Provide the hardy-weinberg equation in it’s two major forms, and explain it.
Based on the fact that all possible allele’s of a locus add up to 100%. I.e. p + q = 1. By simple mathematics, we can expand this in a useful way to show that pp + 2pq + qq = 1 (note the clear homozygote, pp and qq, and heterozygote, pq, correlation).
What are some good reasons we may calculate carrier risk of carrier testing is available?
Understand inheritance pattern, perceived risk, decision-making about testing, waiting period for results of testing, and test may not be 100% sensitive!
What is the risk for congenital malformation in each pregnancy?
2-3%, and accounts for all possible malformations.
What type of genetic disorders are the major cause for congenital malformation?
Complex genetic disorders (multi factorial). Simple althernatives, such as single gene defects/chromosomal disorders/teratogens, are rarely the case.
What does recurrence risk among relatives of an individual and familial aggregation suggest about a disorder?
That it displays a complex inheritance.
How do we assess risk for complex inheritance disorders?
Empirical data, not calculations.
How does recurrence risk change, generationally, in complex disorders? What abound mendelian?
Complex disorders tend to show large, precipitous declines in recurrence risk over generations. (This makes sense considering it’s unlike a ‘threshold’ number of genes/factors will be reached with each successive generation). Mendelian disorders tend to operate on simple magnitudes of 2.
Describe “multifactorial threshold model” with regards to susceptibility of allelles.
There are a “threshold” number of factors that will sum to total disorder expression. These factors are “normally distribted” in a population, so only the upper end are “predisposed” to acquiring the disorder
How do we determine the risk for developing multi factorial congential malformations in families?
Take empiric estimates from observations of large collections of families and average them. The actual risk, of course, may actually be higher or lower for the family that is being counseled.
What 4 major factors increase the risk of recurrence of a congenital malformation?
1. Presence of more than one affected relative. 2. Severe form, or early onset, of disorder; likely related to the number of “factors” in the genetic soup of the family 3. An affected person of the sex that is less probable to have it; this indicates more “factors” are present, putting you closer to threshold 4. Consanguineous parentage.
What are qualitative traits in genetics/medicine?
They’re often traits that are “present or absent”.
What are quantitative traits in genetics/medicine?
They’re traits that have a continuous level of expression/change/etc. E.g. height, blood pressure, etc. Often have a normal distribution
Why do we tend to see correlations among family members?
Shared genetic and environmental factors.
Write out the heritability equation and describe it’s significance in genetics.
h^2 = (DZ variance – MZ variance) / DZ variance, where DZ is dizygotic and MZ is monozygotic. If h^2 is 0, then there is zero genetic factor. If h^2 is 1, then there is a perfect correlation between genetics and expression.
Does h^2 tell you how many genes interact?
No.
What are two related individuals both sharing a trait said to be?
Concordant.
What are two related individuals NOT sharing a trait said to be?
Disconcordant.
Which type of traits (quantitative / qualitative) does heritability help explain?
Both.
What is a very important consideration one must make about how quantitative traits and qualitative traits interact?
Quantitative traits (e.g. asthma, hypertension, etc) may lead to a qualitative trait!
What evidence might we see, when comparing MZ and DZ twins, for a strong genetic component?
High concordance percentage. If the concordance value is <100% in MZ pairs, there is evidence we have non-genetic factors at play.
How do we assess environmental influences?
Compare twins reared apart and twins reared together with one another.
What are some limitations of twin studies?
MZ twins may have different gene expression due to environmental factors, and other things such as lyonizatoin.
Define, and write the equation for, relative risk ratio.
A relative risk of some type “r” among relatives, compared to the population. Lamda_r = prevalence in relatives of type r / population prevalence.
Differentiate between a physical map and a genetic map.
Physical maps aer the location of genes or markerson chromosomes relative to landmarks on that chromosome. They can be based on position of the marker relative to a nucleotide sequence, or based on position relative to cytogenetic landmarks (q arm and p arm). A genetic map define loci relative to one another via observing patterns of inheritance.
Describe the significance of gene mapping.
It can help ID markers linked to diseases, which can help in isolation of the disease gene. Isolation, and subsequent characterization of the gene can lead to therapy. Genetic maps are also useful when mutation cannot be easily detected, and we can find a gene marker and then follow the mutation within a family.
Define a polymorphic marker.
It’s a marker for which there are two or more alleles which are maintained in at least 2% of the population.
What are some different types of markers?
SNPs, insertions/delations, microsattelite markers.
What physical features of a chromosome allow us to estimate their frequency of recombination (theta)?
The genetic distance between two loci.
What do you call two loci that are so close a recombination frequency of zero results?
Complete linkage.
What do you call two loci that are so far apart the recombination frequency is 50%?
Unlinked.
What is the recombination frequency for loci on different chromosmoes?
50%
What does recombination frequency max out at 50% and not 100%?
Because there are two copies of each chromosome, effectively halving recombination frequency.
How would one go about performing a linkage analysis, in simple genetics terms?
Ascertain a set of families who are ‘segregating’ a diseasge gene  genotype the family members for a set of polymorphic markers  analyze the data to find markers which are inherited together with the disease gene (cosegregation).
How is ‘chance’ error reduced in linkage studies?
Study multiple, or very large, families.
What are LOD scores, and what are significant values for LOD scores?
LOD scores provide a measure of the statistical evidence that two loci are a given distance apart. LOD > 3 suggests significant evidence for linkage at the value of theta; LOD <-2 is evidence against linkage against value theta.
Differentiate between two-point linkage analysis and multipoint linkage analysis.
Two point considers each marker for evidence of linkage. Multipoing considers each marker, and takes into accounts all genotype information.
How is linkage analysis performed?
By performing genotyping on multiple generations from a pedigree.
What is homozygosity mapping?
A variant of linkage mapping which maps autosomal recessive disorders from consanguineous pedigrees.
Describe a candidate gene region with respect to homozygosity mapping.
A region wherer all affected inbred individuals are homozygous for all markers.
What is a major limitation of homozygosity mapping?
Assumes no allelic heterogeneity within a family.
Describe a clinical application example of homozygosity mapping.
Imagine a consanguineous female parent who is Aa (heterozygous) for an autosomal dominant disorder. She is also Mm for a marker. Examination of her affected chromosome suggests that A-M and a-m are the makeup of her two chromosomes. Two children are born, and they are A-M and A-M, affected with the disorder. The recombination frequency for A/a and M/m is 5% (5cM). Concerned, they get this fetus checked. They identify the marker as ‘m’. So, the probability that the child will be affected is actually 5%, since there is only a 5% chance that recombination can produce A-m.
What are flanking markers, and what is their advantage in linkage analysis?
They’re simply markers, but they’re “flanking” each side of a gene. It allows us to further increase the power of our predictions. E.g. if A-B-C are a linked and A-B are 5 cM apart and B-C are 5cM apart, we know that if we see markers A and C, the probability that B was recombined with b is 5% x 5%, or 0.25%.
Differentiate between parametric and non-parametric linkage mapping.
Parameteric requires a known mode of inheritance and is good for mendelian genetics. Non-parametric is useful for complex disorders where no mode of inheritance is known.
How often do siblings, on average, share two alleles, one allele, zero alleles?
Both alleles = 1/4 time, one allele = 1/2 time, and neither allele = 1/4 time.
If we have a marker close to a disease gene, how does that affect the frequency with which we see two siblings with that marker sharing that diseased gene?
The frequency of both sibs sharing the gene is increased.
What phenomenon does linkage mapping rely upon?
Cosegregation.
How do we look at genetic mapping in populations where transmission of genes through families is no longer possible?
We look at co-occurrence of alleles, and it has the same implication as cosegregation. We utilize linkage disequilibrium mapping to do this analysis.
How can linkage disequilibrium testing occur?
Gather cases and controls  compare the allele/genotype frequencies  find genetic variangs with significantly different frequency between the two groups.
Describe linkage equilibrium and contrast it with linkage disequilibrium.
In linkage equilibrium, there is no association between which allele a person has at one locus and which allele at the other. In linkage disequilibrium, there is an association which preferentially links loci closely to one another.
Can two closely linked loci be at linkage equilibrium?
Yes! It’s still possible, just less likely.
How do linkage mapping and linkage disequilibrium mapping (association mapping) differ from one another in terms of related individuals?
Linkage mapping uses related individuals, and association mapping uses unrelated individuals.
How do linkage mapping and linkage disequilibrium mapping (association mapping) differ from one another in terms of distance between loci?
Linkage mapping allows for evaluation of loci far from one another (>5Mb), but association mapping relies on small distances (1Kb).
How do linkage mapping and linkage disequilibrium mapping (association mapping) differ from one another in terms of number of markers needed?
Linkage mapping requires few markers, association mapping needs more markers.
How do linkage mapping and linkage disequilibrium mapping (association mapping) differ from one another in terms of knowledge of mode of inheritance?
In linkage mapping, mode of inheritance is necessary. Not necessary in association mapping.
How do linkage mapping and linkage disequilibrium mapping (association mapping) differ from one another in terms of statistical power with allelic heterogeneity?
Linking mapping retains power. Association mapping quickly loses power.
How do linkage mapping and linkage disequilibrium mapping (association mapping) differ from one another in terms of gene penetration?
Linkage mapping is most powerful only when highly penetrant genes are analyzed. Association mapping is useful even when smaller effects are noted.
Do epigenetic changes affect genotype?
No
Do epigenetic changes affect phenotype?
Yes, they can.
Are epigenetic conditions heritable?
Yes, they are.
Define imprinting.
Alleles at a specific loci being expressed on the basis of their parent of origin. Note: genomic imprinting is unique to mammals.
What are athe four major epigenetic mechanisms?
1. Methuylation of DNA 2. Binding proteins 3. Chromatin structure modulation through histone modification (methylation / acetylation / deacetylation) 4. Regulatory non-coding RNA’s.
What are the two major proteins responsible for chromatin remodeling?
HDAC and HAT.
How can diet affect DNA methylation and what are the clinical manifestations relating to DNA methylation and malnutrition.
Hypomethylation can result from folate deficiency. This can lead to issues such as schizophrenia.
Can metabolic and environmental factors affect DNA methylation?
Yes.
What does phenotype difference in MZ twins suggest about DNA methylation?
Suggests that gene expression is not 100% identical in twins.
What epigenetic alternation is seen frequently in pre-cancerous lesions?
Changes in methylation. This is why there is some clinical use for HDAC inhibitors.
What are some hallmarks of imprinting disorders?
Parent of origin of the molecular defect influennces the phenotype, and uniparental disomy.
What happens to lineage specific methylation after fertilization?
It undergoes erasure.
What is a likely cause of the low success rate in cloning of mammals as it relates to epigenetics?
Imprinting, in the form of methylation.
What is a common marker seen in control regions?
Hypermethylation.
What is significant about the epigenetic patterns established after lineage erasure?
It’s sex specific; i.e. maternal and paternal copies will have different methylation (and silencing/expression) patterns.
Describe Beckwith-Wiedemann syndrome and it’s mode of inheritance.
Growth disorder with large body size, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, and renal abnormalities. It is an imprinting issue.
What is the function of most mitochondrial DNA?
“Wiring” for energy production in the cell.
Where does the structural mitochondrial protein originate?
Nuclear DNA.
What is a significant cause of the high mutation rate of mitochondrial DNA?
Oxygen radicals. ROS do some major damage!
What are the two major classes of mDNA mutations?
1. Insertions/deletion 2. Base substitutions
Describe maternally inherited diabetes and deafness?
mtDNA rearrangement with duplication on a systemic level – OR – mitochondrial tDNA mutations; onset in young adulthood. Causes sensory neural hearing loss and diabetes mellitus.
Describe chronic progressive external opthalmoplegia (CPEO).
mtDNA rearrangement, delation – OR – tRNA mutation. More severe mtDNA changes than maternally inherited diabetes and deafness, so phenotypic differences result. Opthalmoplegia, ptosis, and myopathy start in late 20s.
Describe Kearns-Sayre Syndrome (KSS).
mtDNA rearrangement and primary delation; similar to CPEO and maternally inherited diabetes and deafness, but more severe than both. Opthalmoplegia, ptosis, mitochondrial mypotaphy, retinitis pigmentosa, cariac conduction defects, cerebellar ataxia, elevated CSF protein; onset prior to 20s!
Describe Pearson Marrow / Pancrease.
mtDNA rearrangement, and primary deletion. Similar to KSS, CPEO, and maternally inherited diabetes and deafness, but more sever than all of them. Bone amrrow failure, pancytopenia, transfusion dependence as a result. IF survive, will progress to KSS. Onset in childhood!
What might we see on a southern blot of mtDNA from a person with maternally inherited diabetes mellitus with junction site fragmentation?
A 6.1kb band, indicative of an insertion into the mtDNA genome that is responsible for the pathology.
Describe myoclonic epilepsy and RRF (MERRF).
Mitochondrial tRNA mutation causing mitochondrial myopathy  deafness, cardiomyoptathy.
Describe mitochondrial encephaloyopathy, lacti acidosis and stroke like symptoms (MELAS).
Mitochondrial tRNA mutation; mitochondrial myopathy with RRF’s, stroke-like episodes, overlapping vascular beds, and cardiomyopathy.
When performing a genetic analysis of a person with a mitochondrial disorder, who must we consult?
Women only!
If you have an mtDNA tRNA pathology of 1-30% mutant DNA, what might you expect to see?
Diabetes I/II.
If you have an mtDNA tRNA pathology of 70-95% mutant DNA, what might you expect to see?
MELAS, CPEO, cardiomyopathy.
Descirbe neurogenic muscle weakness, ataia, and retinitis pigmentosa & leigh syndrome (NARP).
Missense mutation causing ataxia, weakness, peripheral neuropathy, ADHD.
Describe Leber hereditary optic neuropathy (LHON).
Sudden onsite, mid-life optic atrophy and cardiac conduction defects caused by missense mutations.
Describe dystonia.
Generalized dystonia, striatal necrosis caused by missense mutations.
How do mild mitochondrial disease affect men and women differently?
Stronger effect on men
How did we prove that mtDNA could cause disease?
Put “bad” mtDNA into an animal (create a chimera), give that animal offspring and see what is inherited.
What special role does the ovary play in selecting for healthy cells that is exceedingly unexpected in terms of genetics?
Screens for healthy mitochondria! Usually only ovulates cells with healthy mitochondria in them, selectively.
What sort of genetic mutations do we see in 65% of alzheimers patients?
Somatic mtDNA mutations.
By what mechanism my Alzheimer related changes occur, with respect to mitochondrial genetics?
The somatic mutations will accumulate over time and mtDNA copy number (and therefore mtRNA) levels will decrease.
What is the “interface” between genes and the environment, according to Dr. Wallace?
The mitochondria.
What are the 3 ways to adjust energy consumption / metabolism at its most fundamental level?
1. Change gene expression via the epigenome 2. Change protein production via mtDNA mutation 3. Change, slowly, nuclear mtDNA genes.
Where do major histone modifications factors, such as acetyl coA and phosphates, come from?
The mitochondria!
Which four trisomies produce viable offspring?
13,18,21,X. anything else is incompatible with life.
What is the least common type of inborn error of metabolism?
Block results in lack of metabolite (e.g. glucose)
What is the most common type of inborn error of metabolism?
Block results in overproduction of downstream metabolite (e.g. ammonia).
How common are inborn errors?
Individually, very rare, but cumulatively fairly numerous. Consider them in diagnoises!
What do we consider to be the paradigm of all molecular medicine?
Inborn errors of metabolism.
What are the three types of phenotypes associated with inborn errors of metabolism?
1. Intoxication phenotype 2. Energy deficiency phenotype 3. Storage phenotype.
When does the intoxication phenotype onset?
About 2 days fter birth, because the mother serves as a filter (dialysis across placenta). Death can be rapid thereafter—as soon as 3 days.
When does the energy deficient phenotype for inborn errors onset?
Prenatally, born with dysmorophology.
What are some symptoms of a neonate with intoxication phenotype with inborn errors?
Initially symptom free; poor feeder w/ weak suckling; weight loss / vomiting; muscle tone abnormalities; seizures / coma; loss of normal vegetative functions resulting in symptoms such as bradycardia or apnea. Additional clues include consaguinty, sib deaths, abnormal cry/urine, metabolic inborn errors in screening.
What are the 4 major intoxification phenotypes?
1. AA disorders 2. Organic acid disorders 3. Urea cycle defects 4. Sugar defects.
Where do we measure AA and organic acids?
AA in blood, organic acids in urine.
What is maple syrup urine disease (MSUD)?
An inborn error with an intoxication phenotype. The BCAA’s ar elevated, and pee may smell like maple syrup.
How can MSUD be treated?
Limit BCAA intake, use custom food formulas, pharmacologic doses of cofactor thiamine, and washout with high glucose IV fluids when sick.
Wha tis Isovaleric academia (IVA)?
An inborn error with an intoxication phenotype (a BCAA error). It is associated with severe acidosis, pancytopenia, sweaty feet odor. Treat with diet & glycine, and child will be normal.
Describe propionic academia.
An inborn error with an intoxication phenotype. Can be confused with multiple carboxylase deficiency. Not easily treated with biotin, unlike multiple carboxylase deficiency which is easily treated.
Describe methylmalonic academia.
An inborn error with an intoxication phenotype. Sometimes completely cured with very high levels of B12 (and diet), but not always B12 responsible. Presents with acidosis, hyperammonemia.
Wjhat type of phenotype are in the inborn urea cycle defects classified as?
Intoxication phenotype of inborn error.
What are some common results seen in Urea cycle defects?
High blood ammonia—only major clue. Routine blood chemistry is otherwise normal!!!
What are the two clinically significant urea cycle defects?
Ornithin transcarbamylase (OTC) is the most common and carbamyl phosphate synthetase (CPS) is the next most common.
What is the mode of inheritance for ornithine transcarbamylase deficiency and how does it present?
X-linked codominant. High orotic acid accompanying the standard high ammonia in this urea cycle disorder (most common one) with an intoxication phenotype.
What is the mode of inheritance for carbamyl phosphate synthetase?
Autosomal recessive. Presents with high blood ammonia, like other urea cycle disorders in the intoxication phenotype for inborn errors
Describe galactosemia and it’s mode of inheritance.
Autosomal recessive, often found in newborn screening but if not an lead to acute illness, liver failure, cataracts, etc. Dietary changes are necessary to control.
Describe nonketotic hyperglycinemia.
Diagnosed in newborns with profound lethargy and seizures. Microcephaly, and is lethal at 3yrs. Excitotoxicity and neuro-degeneration. It is a type of inborn error with toxicity phenotype.
Describe PKU and how it is a bit paradoxical.
It’s an inborn error which can cause extreme mental retardation and light pigmentation that is only identifiable at birth by screening. However, it’s paradoxical because despite being an intoxication phenotype, patients are never actually “sick”. Treat with diet low in phenylalanine.
What are some risks of PKU pregnancy?
Risk for mental retardation in child, microcephaly, cardiac defects, intrauterine growth retardation, and low birth weight.
How must PKU pregnancies be managed?
Via diet, need to maintain physiological levels of Phe! They can have a healthy outcome.
What are 4 ways that we can treat the intoxication phenotype of inborn errors?
1. Diet 2. Pharmacologic doses of cofactors 3. Stimulate alternative biochemical pathways 4. Prevent catabolism via hydration.
What are some common birth phenotypes for people with energy deficiency phenotypes of inborn errors of metabolism?
Prenatal abnormalities such as small fo rgestation age, microcephally, cardiomagally, poor respiration effort, severe generalized hypotonia, dysmorphology.
What are the two major sub-categories of peroxisomal diseases found in energy deficient phenotypes of inborn errors of metabolism?
1. Zellweger syndrome 2. Isolated enzyme disorders
What is adrenoleukodystrophy (ALD) and what is one of it’s major methods of inheritance?
It’s an inborn error of metabolism, of the energy deficiency phenotype. It is inherited in a X-linked manner and has a progressive behavioral, cognitive, and neurological loss with an onset in 3-10yo.
Describe fatty acid oxidation disease with respect to carnitine and it’s method of inheritence.
It’s an inborn error of metabolism in the energy deficiency class. Carnitine is required for FA transport into mitochondria, and low systemic carnitine can be an issue for that reason. It leads to muscle weakness / rhabdomyolysis. It, like all other fatty acid oxidation disorders, is autosomal recessive.Also associated with non ketotic hypooglycemia
What are the two types of inborn errors of metabolism that have to do with storage?
1. Glycogen storage 2. Lysosomal storage.
Describe glycogen storage disorders.
Defects in glycogen metabolism, hypoglycemia, hepatomegaly.
Describe lysosomal storage disorders.
Defect in host of lysosomal degradative enzymes. Progressive decrease of function in CNS, liver/spleen, bone and skin.. Corneal clouding (cataracts), cardiac valve abnormalities, optic atrophy all common in patients.
What physical finding would allow one to easily differentiate between lysosomal storage disorders and glycogen storage disorder?
Lysosomal has heptosplenomegaly, and glycogen is only hepatomegaly since storage doesn’t involve the spleen.
What major metabolic disease are associated with acidosis?
Most are, but they include organic acidemias, primary lactic acidosis).
What major metabolic diseases are associated with ketosis?
Organic acidemias and maple syrup urine disease.
What major metabolic diseases are associated with hypoglycemia?
Fatty acid oxidation and glycogen storage.
What major metabolic disease are associated with hyperammonimia?
Urea cycle disorders, and somewhat in organic acidemias and fatty acid oxidation disorders.
What are the three main levels of treatment for inborn errors of metabolism?
1. Impact biochemical lesion 2. Treat acute metabolic crisis 3. Pharmacological treatment of major manifestations.
What are 7 means by which treatment of metabolite accumulation can be carried out?
1. Substrate restriction 2. Stimulation of alternate metabolic pathways 3. Stimulation of enzymatic function by large amounts of cofactors 4. Inhibit action of toxic metabolite 5. Administration fo normal enzyme or protein 6. Organ transplant 7. Gene therapy.
How do lysosomal storage disorders inherit?
All of them are autosomal recessive EXCEPT Fabry and MPSII (Hunter), which are both X-linked recessive.
Which lysosomal storage disorder is the most common?
Gaucher
What phenomenon leads to the characteristic pathology of lysosomal storage disorders? And, what are those characteristic pathology?
Accumulation of glycosphingolipids in intracellular lysosomes -> splenomegaly, pancytopenia, hepatomegaly, short stature, pulmonary disease.
Describe Tay-Sach’s including it’s mode of inheritance.
Autosomal recessive diroser, which leads to GM2 ganglioside accumulation  weakness and loss of motor skills at 3-6mo, cherry-red spot of the voea of the macula retina, normal liver / spleen (not characteristic of lysosomal storage disorders), neurodegeneration, death before 4yo. Haxaminadase (HEX) deficiency causes the problem.
What is the current treatment for Tay Sach’s?
None.
Which major lysosomal stoage disease are treated by enzyme therapy?
1. Gaucher, 2. Fabry 3. MPS I/II/IV/VI, Pomp, Niemann-Pick B.
How is Gaucher disease classified? Specify mode of inheritance and treatment as well.
Multi-system disorder with visceral progressive visceral enlargement, replacement of hematopoetic system with lipid-laden macrophages. Hepatosplenomegaly, thrombocytopenia and anemia, fatigue, aseptic necrosis of hip, growth retardation. Can be treated by enzyme replacement therapy. Autosomal recessive.
How is Fabry disease classified? Specify mode of inheritance and treatment as well.
Progressive GL3 accumulation leading to end-organ impairment, X-linked recessive inborn error, characterized by vascular endothelial deposition, corneal opacity, and angiokeratomas. Treated with enzyme therapy
How does Fabry disease differ from most lysosomal storage disorders?
It looks more like atherosclerosis than a lysosomal disorder.
How is mucopolysaccharidosis I (MPS I) classified? Specify mode of inheritance and treatment as well.
Accumulation of GAG, multi systemic, sever morbidity and early mortality, very rare. Shows corneal clouding, optic nerve compression, retinal disease, glaucoma, myopia. Autosomal recessive.
Describe the “spectrum” of MPS I’s clinical presentation.
It ranges from Hurler (most severe) to Hurrler-Sheie (mid) to Scheie (least). The mental retardation, progression, respiratory disease, and early death occur more with higher severity. Scheie actually has normal intelligence. Treated with enzyme replacement therapy. Autosomal recessive
How is mucopolysaccharidosis II (MPS II) classified. Specify mode of inheritance and treatment as well.
X-linked disease without corneal clouding. Hepatosplenomegaly, and may or may not have CNS issues. Enzyme replacement therapy for treatment.
How is mucopolysaccharidosisv VI (MPS VI) classified? Specify mode of inheritance and treatment as well.
Coarse features, corneal opacities, normal intelligence, urine excretion of dermatan sulfate. Autosomal Recessive
Describe Niemann-Pick disease. Specify mode of inheritance and treatment as well.
Lysosomal storage disorder where shingomyelin accumulates. Type A is neuropathic, B is non-neuropathic. Type A survival is 3yrs, B is beyond childhood. Pancytopenia, hepatomegaly, splenomegaly, short stature, dyspnea, coronary diases, mental retardation in type A. Autosomal recessive. No effective treatment. There is a Type C that is characterized by cholesterol in lysosomes; dystonia and seizures aare common, death in 2nd to 3rd decade, impaired cholesterol esterification.
How is Pomp disease classified. Specify mode of inheritance and treatment.
Lysosomal storage disorder, accumulation of glycogen. No ethinic predilection. It has a classic infantile form, with death in 1st yr and severe hypertrophic cardiomyopathy and myopathy, and an adult form with no cardiac involvement and only mild-moderate myopathy—may become ventilator dependent. Enzyme replacement has very successfully treated even the infantile Pompe patients
Describe mucopolysaccharidoses as a group.
Lysosomal storage disorders with autosomal recessive inheritance. Glycosaminnoglycans accumulate to very high levels in lysosomes and result in cell death, severe CNS degeneration, sleep disorders and hyperactivity. No treatment available.
How do ALL cancers arise---by what mechanism?
DNA alternations leading to loss of cell cycle control.
What is the major gene seen in familial adenopolyposis?
APC—it is lost.
What percent of cancers are familial / hereditary?
10-15% hereditary, 15-20% familial.
What differentiates familial and hereditary cancers?
Environment.
Describe a pre-neoplastic syndrome.
It’s a syndrome where predisposition to certain malignancies is only ONE of the many features of the syndrome.
What are eight major features seen in inherited cancers ?
1. Syndromically related 2. Rare tumors 3. Early age onset 4. Dominant pattern of transmission 5. Bilateral cancer 6. Multiple primary cancers 7. Lack of obvious environmental risk 8. Physical features consistent with hereditary cancer.
When seeing a family history with extensive cancer, why must we remain cautious that there is a familial link?
Age: if many of the people with cancer were old, that’s to be expected. Type of cancer: if the types of cancer are not typically seen together, then risk factors may not exist. Relation: if someone in your family tree has cancer and isn’t related to you, then that obviously doesn’t matter. Primary cancer location: if someone is worried about breast cancer risk and a family member has a secondary breast cancer, maybe it’s not such a large risk.
What must one be wary of not considering when looking for familial cancers?
Penetrance (incomplete penetrance ~ skipping generations), and primary cancer vs. secondary/tertiary locations, possibility of new mutations, mutations with links to multiple cancers
What factors influence pentrance of cancer?
Age, damaged DNA, hormones, carcinogens, severity of mutations
Define a proto-oncogene.
Promote and accelerate cell division  when stuck in “on mode”, can lead to cancer.
Define gatekeeper tumor suppressor genes.
Cells’ brakes for tumor growth (apopotosis)
How many proto-oncogene mutations are necessary to produce cancer ?
Just one because it upregulates transcription, etc.
How many tumor suppressor genes (e.g. p53) must be mutated to produce cancer?
Two because one can makeup for a lost copy. But, having one copy will predispose to cancer considering that means only one more gene must be mutated in that cell, instead of two.
What are some products of proto-oncogenes?
Growth factors, cell surface receptors, transduction components, DNA binding proteins, cell cycle proteins
What significant genetic aberration exists in chronic myelogenous leukemia?
9:22 translocation—the philidelphia chromosome.
Describe loss of heterozygosity as it pertains to cancer.
If you have, for example, a tumor suppressor gene mutant via inheritance and then a cell undergoes some sort of change that leads to the homologous chromosome or the tumor suppressor gene compliement being lost, then we can have a “loss of heterozygosity”, which can obviously increase risk of cancer.
What type of gene is linked to familia adenomatous polyposis?
A tumor suppressor gene: APC.
What type of gene is linked to retinoblastoma?
Tumor suppressor gene.
What type of gene is linked to breast cancer?
Tumor suppressor: BRCA1/2.
What type of gene is linked to endocrine neoplasia?
Oncogene
How can one explain the rare occurrence of germline (constitutional) mutations of oncogenes?
They’re rare because they are typically lethal to the organism at a young age.
Describe Li-Fraumeni Syndrome.
Germline P53 mutation, rare. 50% risk by age 40. Breast, osteo, soft tissue sarcomas, brain tumors, adrenal cortical cancer, and acute leukemia commonly associated. Autosomal dominant.
What is TP53 and what pathology is it associated with in germline cancers?
It’s a tumor suppressor gene, and when germline mutatinos are noted there are high rates of childhood tumors.
What is Cowden disease?
Germline mutation in PTEN associated with breast cancer, goiter adenomas, polyps in colon and oral papillomas.
What is Peutz jeghers syndrome?
Germline mutation in STK11 associated and with polys, ovarian cancer, and breast cancer and perioral brown macules.
What is Lynch syndrome?
Non-polyposis associated hereditary colorectal cancer syndrome. Associated with mutations in mismatch repair genes. CRC usually in proximal colon, and associated with extracolonic cancers in the endometrium, ovary, stomach, urinary tract, small bowel, bile duct, and sebaceous skin tumors
What is muir-Torre syndrome?
Non-polyposis associated hereditary colorectal cancer syndrome. Associated with mutations in mismatch repair genes.
What is Turcot syndrome?
Non-polyposis associated hereditary colorectal cancer syndrome. Associated with mutations in mismatch repair genes.
How can you compare the conclusions one might draw from developing a family history for two families with colon cancer (family A has an identified, known genetic link to this cancer and family B doesn’t have any identified known mutation) and comparing a negative result for a person from family A while testing for the known mutation and a negative result for the person from family B while testing for the same mutation?
Obviously, there are more possible mutations, so the person from family B has an inconclusive result while the person from family A is a true negative.
In a patient with FAP, what is the probability that the patient will develop cancer if a polyposis goes untreated?
100%
Describe attenuated FAP.
Associated with mutations at the 5’ or 3’ ends of the APC gene. Less severe than normal FAP, is later onset,a nd has few colonic adenomas.
Describe multiple endocrine neoplasia (MEN1/2).
Rare syndrome causing multiple endocrine tumors. 1 and 2 are distinct syndromes with distinct mutataions
What is the most common childhood eye tumor?
Retinoblastoma.
How does retinoblastoma inherit?
Autosomal dominant, with >90% penetrance.
What features define a heritable vs. non heritable retinoblastoma?
In the heritable form there is often family history (20% of cases), it’s usually bilateral, diagnosis is early (1yr vs 2 yr), and it has an increased risk of second primary tumors.
What is the inheritance pattern for pediatric bloom syndrome?
Autosomal recessive. Associated with adenocarcinoma, lymphoma, and leukemia.
What is the inheritance pattern for pediatric fanconi anemia?
Autosomal recessive. Associated with leukemia (AML), tumors, squamous cell carcinomas, hepatocellular carcinomas, and brain tumors.
What is the inheritance pattern for pediatric ataxia telangiectasia?
Autosomal recessive
What is the inheritance pattern for pediatric rothmund Thomson syndrome?
Autosomal recessive
What is the inheritance pattern for pediatric xeroderma pigmentosum?
Autosomal recessive
What is the inheritance pattern for pediatric dyskeratosis congenital?
X-linked recessive.
What are some characteristics of Bloom syndrome?
Characteristic facies, erythema, telangiectasias. Autsomal recessive disease. Cancers associated include adenocarcinoma, lymphoma, and leukemia.
What are some characteristics of Fanconi Pancytopenia?
Anemia, absent radii, absent thumbs, renal malformation, microcephaly, pigment abnormalities, even eventually aplastic anemia. Associated with leukemia (AML), tumors, squamous cell carcinomas, hepatocellular carcinomas, and brain tumors
Define dysmorphology.
Study of abberent structural development occurring primarily before birth.
How common are birth defects?
3%
When someone is diagnosed with simply “multiple congenital anomalies”, what information can be derived from this Dx?
None. It’s virtually useless.
Define teratogen.
Age that produces a permanent abnormality of structure/function in an organism exposed during embryonic / fetal developmental stages.
Define a syndrome.
A group of signs/symptoms that occur together and characterize a particular disorder. The significance is that these things occur “together”.
What is a single primary defect, and how does it differ from multiple malformation syndromes?
It’s an anomaly that tends to appear alone, like a cleft lip/palate. It differs in that it’s only one anomaly, simple!
Define malformation.
A defect in the structure of an organ/region resulting from an intrinsically abnormal developmental process (embryogenesis).
When do most malformations occur?
During organogenesis
Describe what a “sequence” is in clinical terms.
A pattern of anomalies that is derived from a single, or known/presumed defect or mechanical factor. E.g. A leads to B which leads to C, etc.
What is an example of a malformation sequence?
Pierre Robin sequence; mandibular hypoplasia causes failure of tongue descent, because the mandible is too small to retract the tongue, which causes a cleft palate.
Define deformation.
A defect in shape/form/position of a normally formed part of the body, caused by mechanical forces usually over al ong period of time.
When do deformations typically occur.
After organogenesis. Remember, it has to be normal before it can be “deformed”.
What is the prognosis for most neonatal deformations?
Excellent, often correct themselves over relatively short times.
What is an extrinsic deformation, in clinical terms?
Originating from an anomaly outside of the fetus, e.g. small pelvis/uterus, fibroids in the uterus, abnormal fetal position, oligohydramnios, large fetus, multiple fetuses.
What is an intrinsic deformation, in clinical terms?
Originating from the fetus itself. E.g. edema can cause swelling.
What is an example of post-natal deformation?
Rickets.
Describe a disruption, in developmental terms.
A destructive process that changes structures after they have formed normally; this is different from a deformation because it seems to be more “permanent”.
Define a disruption sequence, give an example.
It’s a disruption where a series of events follow which lead to a cascade of effects. E.g. amniotic leakage  loss of fluid  lack of cushioning  deformation AND failure in lung development
Describe dysplasia.
Abnormal cellular organization / function of specific tissue type throughout body. E.g. achondroplasia, Hurler syndrome.
Define association in clinical, developmental terms.
A group of anomalies that occur together more than expected by chance, but which do not represent a recognized syndrome, sequence, or developmental field defect. E.g. VATER association: vertebral, anal, trachea-esophageal fistula, radial/renal anomalies.
Describe developmental field defect.
Pattern of anomalies caused by disturbed development of a related group fo cells; e.g. midline cleft lip and absence of pre-maxilla (of upper gum / alveolar ridge).
What are major / minor anomalies?
Major >4% of gen pop and it has a medical and social/cosmetic consequence. Minor is less than or equal to 4% and no significant health consequences, tends not to have social/cosmetic burden. E.g. extra nipples.
What are minor malformations, and why are they important?
They are what they sound like. They are important because, as they accumulate, they can make large changes. And, a higher number of minor anomalies increases risk of one or more hidden major anomalies.
Describe normal variation.
This of a minor anomaly, but much less severe (so very insignificant), occurring in >4% of the population, and it has no functional / cosmetic significance. E.g. accessory spleen.
What does a “name” of a syndrome, for example, tell you.
Not much, it’s not a diagnosis, just descriptions.
How do genetic testing and genetic screening differ?
Screening is done as tests on a population, testing is done on an individual.
What is the major advantage to early screening?
Early intervention!
Describe sensitivity and specificity in terms of screening .
Sensitivity is the ability to correctly identify those who have the disease (i.e. few false negatives). Specificity is the ability to identify those without the disease.
What is screened for in the California screening program?
Important: PKU, primary congenital hypothyroidism, galactosemia, HbS; Other: Other Hb disorders, CAH, OA disorders, FAO disorders, biotinidase deficiency, hearing screening, cystic fibrosis.
How are positive screenings dealt with in the California newborn screening program?
1 month follow up with repeat screening, diagnostic testing if positive again, early intervention started.
What is an example of a routine prenatal screening?
Ultrasound, 1st/2nd trimester serum screening
What factors does clinical validity rely upon?
Sensitivity, specificity, positive predictive value.
Define clinical validity.
Extent to which a test is predictive for disease.
Define clinical utility.
Degree to which tests results will change medical care someone receives and improves outcomes.
Calculate sensitivity of a test.
True Positives/(True positives + False Negatives ); i.e. fraction of all positives who tested positively.
Calculate specificity of a test.
True negatives/(True negatives + false positives); i.e. fraction of all negatives who tested negatively.
Calculate positive predictive value.
True Positives that Tested Positive / (True positives tested positive + False positives); i.e. faction of all who tested positive that are actually positive. If there are very few false positives, then the PPV of a test would be close to 100%.
Are autosomal recessive disorders typically enzymatic or not? Explain.
Yes, enzymatic. This explains their ability to overcome a mutated allele. The normal allele product can make-up for the mutant gene’s malfunction. This is a “most of the time” situation, but there are exceptions.