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M2M Unit II > Unit II > Flashcards

Unit II Flashcards

1
Q

What is important about meiotic prophase I?

A

Reciprocal recombination occurs here

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2
Q

What are bivalents?

A

Maternal and paternal homologs of
each chromosome become paired or synapsed along their entire lengths, forming
structures known as “bivalents”.

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3
Q

What is the synaptonemal complex?

A

a proteinaceous structure which promotes inter-homolog interactions.

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4
Q

Define chiasmata

A

attachments or crossovers

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5
Q

Which step of meiosis is most error prone?

A

Meiosis I during chromosome nondisjunction

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6
Q

What is the proband?

A

The affected individual through whom a family with a genetic disorder is ascertained

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7
Q

What is the consultand?

A

The individual (not necessarily affected) who presents for genetic evaluation and through whom a family with an inherited disorder comes to attention.

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8
Q

Define consanguinity

A

identifies cases of genetic relatedness between individuals descended from at least one common ancestor.

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9
Q

Define Phenotype

A

The observable expression (of a genotype) as a morphological, clinical, cellular, or biochemical trait

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10
Q

Define Genotype

A

The set of alleles that make up his or her genetic constitution

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11
Q

Mendelian Inheritance

A

disorders that are due to the predominant effects of a single mutant gene

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12
Q

Mendel’s First Law

A

The Law of Segregation

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13
Q

What is the law of segregation?

A

At meiosis, alleles separate from each other such that each gamete receives one copy from each allele pair

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14
Q

What is Mendel’s Second Law?

A

That Law of Independent Assortment

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15
Q

What is the Law of Independent Assortment?

A

At meiosis, the segregation of each PAIR of alleles is independent.

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16
Q

Define Codominant

A

If both traits (alleles) are expressed in the heterozygous state

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17
Q

Define Semi- Dominant or incomplete dominant

A

The heterozygous phenotype is intermediate between the two phenotype. A degree of both phenotypes combined.

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18
Q

Define hemizygous?

A

A chromosome in a diploid organism is hemizygous when only one copy is present.

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19
Q

Define Expressivity

A

The degree to which a trait is expressed in an individual (is a measure of
severity). Expressivity is analogous to a light dimmer (the light is ‘on’ but the brightness
(expressivity) exists along a spectrum (of severity)). The variation in phenotype is
explained (in part) by sex influence, environmental factors, stochastic effects, and
modifier genes.

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20
Q

Sex Influence

A

Phenotypic expression in some conditions is
dependent on the individual’s sex (e.g. gout is more common in males than
premenopausal females)

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21
Q

Sex limitation

A

occurs if only one sex can express a phenotype

e.g. unicornuate uterus

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22
Q

Environmental factors

A

Some environmental factors can affect the expression of
Mendelian diseases. The disease may only manifest in individuals if particular
environmental factors are present.

Example: In acute intermittent porphyria, episodes of
abdominal pain and psychiatric illness are dependent on exposures (alcohol,
medications).

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23
Q

Stochastic Effects

A

Stochastic (random) effects can influence the expression of
phenotypes. This concept pays homage to the fact that some phenotypes may be
influenced by chance events/processes absent any obvious genetic/environmental factor.

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24
Q

Modifier genes

A

Genetic factors outside of the genetic locus causing a disease can be
important for the expression of Mendelian diseases.

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25
Q

Phenocopies

A

Diseases (traits) that are due to non-genetic factors.

Example: A thyroid
cancer due to radiation exposure cannot always be distinguished from a thyroid cancer
due to mutations in RET gene.

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26
Q

Pleiotropy

A

Used to describe multiple different phenotypic effects due to mutation(s) in a
single gene. Often used, when the phenotypes are seemingly unrelated and/or in
multiple different tissues.

Example: Neurofibromatosis Type I leads to: café au lait spots
(skin), neurofibromas (peripheral nervous tissue), hammartomas in the eyes (ocular),
abnormal freckling (skin again), and learning difficulties (central nervous system).

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27
Q

Penetrance

A

The fraction of individuals with a trait (disease) genotype who show
manifestations of the disease.

Penetrance is analogous to a light switch (can be ‘on’ or ‘off’).

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28
Q

How frequently is a SNP likely to occur between two individuals?

A

1 in every 1000 bp

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29
Q

Name a chromosome that is gene rich?

A

Chromosome 19

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30
Q

Name a chromosome that is gene poor?

A

Chromosome 13, 18, 21

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31
Q

Is most of the genome stable or unstable?

A

stable

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32
Q

Percentage of genome that is GC rich?

A

38%

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33
Q

Percentage of genome that is AT rich?

A

54%

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34
Q

What percent of genome is protein coding?

A

1.5%

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35
Q

What percent of the genome is represented by genes?

A

20-25%

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36
Q

percent of genome that is repeptitive dna?

A

40-50%

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37
Q

alpha satellite repeats

A

171 bp repeat unit near the centromere.

may be important to chromosome segregation in mitosis and meiosis.

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38
Q

Alu family

A

example of DISPERSED DNA repeats about 300 bp in length.

500,000 copies in the genome

retrotransposition can cause insertional inactivation of genes via non-allelic homologous recombination

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39
Q

L1 family

A

An example of DISPERSED DNA repeats about 6 kb in length

100,000 copies in the genome

can lead to disease via non-allelic homologous recombination

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40
Q

Microsatellites

A

2-4 bp nucleotide repeats

5x10^4 per genome

aka short tandem repeat polymorphism

Useful in DNA fingerprinting

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41
Q

Minisatellites

A

tandem repeats about 10-100 bp

aka variable nucleotide tandem repeats.

useful in DNA fingerprinting

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42
Q

Gene Families

A

Gene family is composed of genes with high sequence similarity (e.g. >85-90%) that may carry out similar but distinct functions

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43
Q

Copy number variation

A

primary type of structural variation

may cover 12% of genome

involved in rapid & recent evolutionary changes

Link between evolutionary adaptive copy number increasing and increase in human disease. EX: 1q21

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44
Q

When does the synaptonemal complex disassemble?

A

At the end of prophase I

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45
Q

Define metacentric

A

the centromere is located in the middle of the chromosome,

such that the two chromosome arms are approximately equal in length.

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46
Q

Submetacentric

A

the centromere is slightly removed from the center

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47
Q

Acrocentric

A

the centromere is near one end of the chromosome

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48
Q

heterochromatic regions are right with what nucleotides?

A

AT

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49
Q

Euchromatin is __ rich?

A

GC

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50
Q

G banding uses what type of dye?

A

Giemsa

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51
Q

G banding stains what structures?

A

heterochromatic/ AT regions which are typically gene poor

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52
Q

Aneuploidy

A

the condition in which cells contain an abnormal chromosome number

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53
Q

Monosomy

A

the condition in which a cell lacks one copy of a chromosome

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54
Q

trisomy

A

the situation in which an extra copy of an entire chromosome is
present in the cell.

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55
Q

Most common cause of down syndrome?

A

nondisjunction during maternal meiosis I

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56
Q

Tolerated Aneuploidy conceptions?

A

45 X, trisomy 16, 21, and 22

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57
Q

Tolerated Live Birth Aneuploidy

A

Trisomy 13, 18 or 21

Gain of X and Y chromosome

Loss of X or Y chromosome

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58
Q

List the characteristics of Down Syndrom

A

Trisomy 21

Short stature
Hypotonia 
Moderate intellectual disability
Cardiac anomalies / congenital heart defect 
leukemia in infancy
early onset Alzheimers 
hearing loss
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59
Q

Trisomy 18

A 
Edwards syndrom
small for gestational age
small head
clenched fingers
rocker bottom feet
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60
Q

Most common chromosomal abnormality in spontaneous abortions?

A

Turner Syndrome (loss of X chromosome)

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61
Q

Phenotype of Turner Syndrome

A

(loss of x chromosome)

short stature
webbed neck
edema of hands and feet 
broad shield like neck 
gonadal dysgenesis 
renal and cardiovascular anomalies
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62
Q

Klienfelter syndrome

A

male with extra X chromsome

XXY

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63
Q

Mosaicism

A

Mosaicism is defined as the presence of at least two genetically different cells in a
tissue that is derived from a single zygote.

EX: mosaicism turner syndrome has a chromosomal change in only SOME of their cells. Some cells have 46 chromosomes and others have 45

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64
Q

Trisomy 13

A 
Patau Syndrome 
Most clinically severe of the 3  
CNS abnormalities  
Omphalocele (herniation of GI organs outside abdomen)  
Renal dysplasia  
Congenital heart disease
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65
Q

Describe a paracentric inversions

A

inversion that occurs outside of the centromere. During meiosis, an inversion loop is required for the associated regions to align. If a crossover occurs WITHIN the loop, you end up with a chromosome that has two centromeres (dicentric) and one WITHOUT a centromere (acentric)

= infertility

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66
Q

Describe a pericentric inversion

A

inversion that occurs within the centromere. During meiosis, an inversion loop is required for the associated regions to align. If cross over occurs WITHIN the loop, you end up with a chromosome that is unbalanced with both having some duplications and some deletions.

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67
Q

What is a Reciprocal Translocation?

A

results from the breakage and rejoining of non-homologous
chromosomes, with a reciprocal exchange of the broken segments.

creates quadrivalent so all four chromosomes can align

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68
Q

What is a Robertsonian Translocation?

A

the fusion of two acrocentric chromosomes within their

centromeric regions, resulting in the loss of both short arms (containing rDNA repeats).

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69
Q

What type of rearrangement is a Robertsonian translocation?

A

A BALANCED ONE.

It does result in a reduction of chromosome however the loss of ribosomal DNA is not considered deleterious

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70
Q

What is the outcome of a Robertsonian translocation

A

The carrier is phenotypically normal however the rearrangement may lead to unbalanced karyotypes in their offspring. Can lead to monosomies or trisomies in their offspring

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71
Q

What is an unbalanced rearrangment?

A

The chromosome set has additional or missing material

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72
Q

What are some of the outcomes of unbalanced rearrangement?

A

Duplication of genetic material can lead to partial trisomies.

Deletions of genetic material can lead to monosomies.

Phenotypically ABNORMAL

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73
Q

What are the two most common chromosomes involved in Robertsonian translocation?

A

Chromosomes 13 and 14.

Can occur in chromosome 21

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74
Q

Which chromosomes are acrocentric?

A

13, 14, 15, 21, and 22

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75
Q

Which acrocentric chromosomes are most commonly fused together?

A

13 and 14

14 and 21

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76
Q

What are the benign pericentric inversions?

A

9 qh, 16 qh, 1 qh, and Yqh

These are within the heterochromatic region

Does NOT result in spontaneous abortions, infertility, or recombinant offspring

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77
Q

What is the risk of a balanced translocation carrier having an unbalanced progeny?

A

0-30%

maternal carriers are morel likely to have a progeny with a phenotype

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78
Q

Incidence of Inversion structural rearrangements?

A

1%

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79
Q

What percentage of meiotic recombinations for inversion carriers lead to a normal progeny or balanced progeny?

A

50%

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80
Q

Numerical abnormalities vs. structural abnormalities?

A

Numerical abnormalities are more common than structural abnormalities

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81
Q

Define Epigenetic

A

Mitotically and meiotically heritable variations in gene expression that are not caused by changes in DNA sequence

EX: post-translational modifications of histones and DNA methylation.

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82
Q

Name a couple of proteins that recognize methylated DNA and play a role in gene silencing

A

HDAC

MeCP2

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83
Q

Where does methylation of DNA take place?

A

CpG islands

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84
Q

What is the function of DNA methylation?

A

Usually gene silencer BUT in some cases acts as a gene activator!

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85
Q

What is genetic imprinting?

A

Sex-Dependent epigenetic modulation of regulatory regions such as promoter sequences

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86
Q

What percent of the human genome is imprinted?

A

Less than 10%

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87
Q

What enzyme is responsible for the propagation of methylated marks?

A

Maintenance methyltransferase

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88
Q

Describe Epigenetic Reprogramming

A

In primordial germ cells demethylation occurs. If you produce oocytes, the specific corresponding region is methylated. If you produce sperm, then the male corresponding region is methylated.

Somehow the cell KNOWS. So that you pass on the correct methylation pattern to your progeny.

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89
Q

What causes Prader Willi Syndrome?

A

Deletion of paternal 15q 11- 13

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90
Q

What percentage of Prader Willi Syndrome is due to deletion of paternal chromsome 15?

A

70%

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91
Q

What percentage of PWS is caused by maternal uniparental disomy?

A

28%

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92
Q

Percent of PWS caused by imprinting centre mutation on paternal allele?

A
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93
Q

What is the major cause of Angelman Syndrome?

A

Deletion of maternal chromosome 15 q 11- 13

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94
Q

What percent of Angel Syndrome is caused by deletion of maternal chromosome 15?

A

70%

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95
Q

What percent of AS is caused by paternal uniparental disomy?

A

4%

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96
Q

What percent of AS is caused by imprinting center mutation on maternal allele?

A

8%

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97
Q

What percet of AS is caused by mutation of UBE3A on maternal allele?

A

8%

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98
Q

Which cells undergo universal demethylations?

A

Primordial cells

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99
Q

What is the outcome of maternal uniparental disomy of chromosome 15?

A

Prader Willi Syndrome

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100
Q

What is the outcome of paternal uniparental disomy of chromsome 15?

A

Angelman syndrome

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101
Q

What leads to the deletion of PWS And AS genes?

A

misalignment and homologous recombination

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102
Q

Significance of gene HERC2

A

generates repeats that flank the 15q 11 -13 region on chromosome 15

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103
Q

Prader-Willi Syndromes

A

short stature
excessive eating
hypogonadism
some degree of intellectual disability

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104
Q

Angelman Syndrome

A

Severe intellectual disability
Spasticity
Seizures
Short stature

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105
Q

Cancer Cytogenetics is important for what two diseases?

A

Leukemia and lymphomas

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106
Q

What test is used for the diagnosis of children with developmental delays?

A

Chromosomal Microarray (CMA) AKA Array CGH

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107
Q

What two tests do you use to investigate leukemia and lymphoma?

A

Chromosome analysis and FISH

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108
Q

Name the specimens used in cancer diagnostics

A 
Bone Marrow
Unstimulated Blood
Lymph node tissue
Solid tumor tissue
Cerebrospinal fluid
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109
Q

What are the uses of FISH?

A

INITIAL differential diagnosis

monitor treatments or disease progression

110
Q

Auer Rod

A

Suggests Myelogenous Leukemia

111
Q

What are some of the key differences of MicroArray vs. regular Cytogenetics techniques?

A

Chromosomal Microarray detects gains and losses ONLY

It uses interphase DNA instead of mitotic cells

Analyzes ALL CELLS

Technology Dependent

Detects runs of homozygosity

112
Q

What is the threshold for CMA detecting runs of homozygosit

A

can evaluate greater than or equal to 5 Mb with a 10 Mb threshold

113
Q

Limitation of CMA

A

Cannot detect very low level mosaicism, heterodisomy, or balanced chromosome rearrangement

114
Q

Protocol for child with developmental delays

A
  1. If deletion or duplication is detected by CMA consult Database of Genomic Variance
  2. Parental FISH studies will be offered to determine if this finding is a rare,
    normal, familial variant.
  3. If a deletion or duplication is found in one or both parents, other family
    members may be tested by FISH. Often extensive consultation between
    the clinical geneticist, genetic counselors and cytogeneticist are required.
  4. If the deletion or duplication is not found in either parent, and it is not found in
    the genomic variants Database, further data-base mining, literature
    searches are performed. Often a gene or genes mapped in the region of
    deletion or duplication reveals a syndromic association.
115
Q

Pharmacogenetics

A

Variable response due to individual genes

116
Q

Pharmacogenomics

A

Variable response due to multiple loci across the genome

117
Q

Pharmacokinetics

A

the rate at which the body absorbs, transports, metabolizes, or excretes drugs or their metabolites

“What the body does to the drug”

118
Q

Pharmacodynamics

A

The differences in the way the body responds to the drug.

“What the drug does to the body”

119
Q

Phase I drug metabolism

A

the introduction of a more polar group to a compound that allows a side group to be more readily attached

The hydroxyl group attached in phase I
provides a site for a sugar or acetyl group to be attached to the drug to detoxify it and make it much easier to excrete in what is referred to as phase II of drug metabolism

120
Q

Mutation that causes cytochrome P450 to have no activity

A

splicing or frameshift mutations

121
Q

Mutation that causes REDUCED activity in cytochrome P450

A

missense mutation

122
Q

Where are are the gene products of CYP450 most active?

A

Mostly in the liver.

Also, intestinal epithelium

123
Q

What are the three main families of the CYP450 gene?

A

CYP1, CYP2, CYP3

124
Q

Significance of CYP3A4

A

takes part in metabolism of 40% of all drugs

125
Q

Drugs that CYP3A metabolizes

A

Felodipine (CA channel blocker that can be used for hypertension) and Cyclosporine (immunosuppressant)

126
Q

CYP3A inhibitors

A

grapefruit juice and ketoconazole (an antifungal agent)

need to reduce drug dosage so that patient does not suffer from drug toxicity

127
Q

CYP3A inducers

A

rifampicin.

Need to increase drug dosage

128
Q

important difference of CYP2D6 gene?

A

It ACTIVATES codeine into morphine

129
Q

Drugs that the NAT gene metabolizes?

A

Isonizad for tuberculosis

130
Q

Drug that the TMPT gene metabolizes?

A

6-mercaptopurine and 6-thioguanine

131
Q

clinical relevance of the TMPT gene?

A

6-mercaptopurine is a drug used to treat ALL but in .5% of children the TPMT activity is so low (due to a mutation) that drug toxicity can occur and the child will die. Only 10% of standard drug dose is needed for these children.

TPMT is an enzyme transcribed from the TMPT gene and detoxifies the 6-mercaptopurine drug.

132
Q

What drugs does the VKORC gene metabolize/

A

Warfarin which is a blood thinner that is always started at 5 mg/day and then adjusted from there

133
Q

Define Heritability of a trait

A

The proportion of total variance in a trait the at is due to variation in genes

134
Q

Heterogeneity in Cystic Fibrosis

A

Different alleles at same location can cause CF

135
Q

Heterogeneity in Alzheimers

A

Alleles at different location or Loci can cause AD

136
Q

Example of diesease that demonstrate multifactorial inheritance

A 
Some cancers
diabetes I and II
Alzheimers
Inflammatory bowel disease
Asthma
Schizophrenia
Hypertension
Cleft lip / palate
Rheumatoid arthritis
137
Q

Odds ratio

A

Risk of disease if carrying a given gene variant/ risk of disease if not carrying a given gene variant

138
Q

How do we find diseases today?

A

Start with disease –> MAP genome –> find gene –> figure out its functio

139
Q

Linkage Diequilibrium tends to occur within..

A

haplotype blocks because they are so close together that recombination does not typically occur

140
Q

Candidate Gene DNA sequencing

A

Hypothesis driven

“I think this disease is caused by this gene”

Leads to FALSE POSITIVES 97% of the time

141
Q

What are the two fatal flaws in Gene-by-Gene Case control design?

A

Stratification - no such thing as a homozygous population

Publication bias - the only studies that get published are the ones with positive confirming results

142
Q

Describe what a Genetic Linkage Study is

A

Using patterns of inheritance to guess whats going on in a rare disorder

143
Q

When should you use Genetic Linkage Study?

A

For UNCOMMON Mendelian traits

144
Q

Define CentiMorgan

A

unit of genetic distance/recombination

145
Q

LOD

A

“Log of Odds”

statistical measure of likelihood that loci are linked together given the inheritance/disease pattern

146
Q

Level of LOD that confirms loci are linked?

A

> 3

147
Q

Name the hypothesis-free approach to finding a disease,

A

Genetic Linkage

Genome-Wide Association Study

148
Q

Describe Genome Wide Association Study (GWAS)

A

Tests ALL parts of the genome simultaneously between individuals for patterns of SNPs associated with diseases

149
Q

Pros of GWAS

A

can accurately measure and correct for population stratification

You know the number of tests performed genome-wide (don’t care about other studies)

150
Q

When is GWAS most useful?

A

For COMMON alleles with small to moderate effect size

Can discover NEW genes as well

151
Q

Benefits of Exome/Genome Sequencing

A

You sequence the coding region oof the genome and can combine result with other affected family members to narrow down the cause of disease.

Will eventually be replaced BY GENOME SEQUENCING

152
Q

Cons of Exon/Genome Sequencing

A

Data interpretation can be difficult due to Variant of Unkown Significance.

Creates a lot of “noise”

153
Q

What are the most commonly used types of DNA polymorphisms for finding genes?

A
  1. Microsatellites
  2. Single-Nucleotide-Polymorphisms (SNPs)
  3. Copy-Number-Variants (CNVs)
154
Q

What is allelic heterogeneity?

A

The existance of multiple mutant alleles of a single gene

155
Q

Define compound heterozygote?

A

One who carries two different mutant alleles of the same gene

156
Q

Phenylketonuria phenotypes

A 
High phenylalanine level in the blood
hyperactivity
epilepsy
mental disability
microcephaly
157
Q

What type of disorder is Phenylketonuria?

A

Autosomal Recessive

158
Q

Biochemical cause of Phenylketonuria?

A

mutation in PAH that encodes phenylalanine hydroxylase (PAH) in 98% of case.

PAH converts phenylalanine to tyrosine

159
Q

Biochemical cause of Phenylketonuria in 1-2% of cases

A

Defects in the PAH cofactor BH4 that disrupts production of tyrosine, dopamine, and serotonin

160
Q

Where is the PAH gene located?

A

12q22-24

161
Q

What type of heterozygote are PKU patients?

A

compound heterozygotes

162
Q

How to manage PKU in patients?

A

Low phenylalanine diet.

Phenylalanine is an essential amino acid so you need some

163
Q

Describe maternal PKU

A

Not dictated by the child’s gene. Mom who is not on a restricted diet will lead to an increase in F in the maternal circulation leading to MISCARRIAGE and DEVELOPMENTAL ABNORMALITIES

164
Q

Timing for newborn PKU screening

A

newborn won’t have elevated F because mom’s enzyme was working. Need to wait a couple days after birth to compare.

165
Q

How to test of newborn PKU?

A

Mass spectroscopy

166
Q

Guthrie test

A

The old way to test for PKU.

thienalalnin inhibits growth of bacteria. This can be inhibited by high level of phenylalanine causing bacteria to grow = + test

167
Q

Clinical features of alpha 1-antitrypsin deficiency (ATD)

A

emphysema (shortness of breath)
increased risk for liver cirrhosis
LATE ONSET

168
Q

Population most affected by ATD?

A

Northern Europeans

169
Q

Biochemical defect in ATD?

A

Deficiency in protease inhibitor alpha1-antitrypsin (SERPINA1, AAT) which inhibits elastase

170
Q

Function of elastase

A

breaks down elastin in CT

171
Q

Function of Z allele in ATD

A

Glu342Lys and the Z allele protein is not folded properly and accumulates in liver cells leading to liver damage

ZZ genotype = 15% normal alpha1-antitrypsin function

172
Q

Function of S alleles in ATD

A

Glu264Val makes unstable SERPINA1 protein

50-60% of normal SERPINA1 level

173
Q

What environmental factor aggravates ATD?

A

smoking

174
Q

Treatment for ATD

A

intravenous infusion and aerosol inhalation of SERPINA1

175
Q

Tay-Sachs Disease Phenotype

A

progressive destruction of the central nervous system

neurological deterioration 3-6 months

Die by 2-4 years

176
Q

First signs of Tay-Sachs Disease?

A

muscle weakness and startle response at sudden sound

177
Q

Who is at most risk for Tay-Sachs disease?

A

Ashkenazi Jews

178
Q

Biochemical defect in Tay-Sachs disease?

A

Inability to degrade GM2 ganglioside which leads to a build up within lysosomes in neurons found in the CNS

Defective Hexoaminidase A enzyme

179
Q

What gene causes Tay-Sachs?

A

HEXA

180
Q

What mutation causes Sanhoff Disease?

A

HEXB gene and affects HexA and HexB enzyme activity

181
Q

AB variant Tay Sachs disease

A

rare form that does not affect Hex A or Hex B activity. Instead mutation on the GM2 activator protein which leads to build up of GM2 ganglioside

182
Q

What is Turner’s Syndrome?

A

Sex chromosome disorder. Women missing an X chromosome 45X

183
Q

Turner Syndrom CVS abnormalities

A

aortic coarctation
bicuspid aortic valve
systemic hypertension
conduction difficulties

184
Q

Turner Syndrome Abnormalities of the eye

A

inner epicanthal folds
ptosis (drooping of the eye)
Blue Sclera

185
Q

Turner syndrome abnormalities of Skeletal System

A

Short 4th metacarpal

short stature

186
Q

Turner syndrome abnormalities of the Neck

A

Web neck
low hairline
cystic hygroma

187
Q

Turner syndrome learning abnormalities

A

difficulty in math
visual spatial skills
low non-verbal skills

188
Q

Turner syndrome abnormalities of chest

A

widely spaced nipples

189
Q

Trisomy 21

A

95% of patients with Down Syndrome

due to nondisjunction in maternal meiosis I

190
Q

Unbalanced Translocation Trisomy 21

A

3-4% of patients with Down Syndrome

Due to a Robertsonian Translocation leading to the fusion of chromosome 21 and 14

191
Q

Mosaic Trisomy 21

A

1-2% of patients with Down syndrome
mixture of normal and abnormal cells
milder symptoms

192
Q

DS phenotypes

A 
upslanting palpebral fissure
epicanthal folds 
midfacial hypoplasia 
small ears
large appearing tongue
low muscle tone
193
Q

CVS problems with DS

A 
congenital heart disease
atrioventricular canal (hole between all four heart chambers)
194
Q

GI problems with DS

A

esophageal atresia - leads to blind pouch rather than stomach

195
Q

What is the significance of polyhydramnios

A

Child is unable to swallow amniotic fluid

196
Q

What chromosome defect causes Prader-Willi?

A

15q11-13

197
Q

Chorionic villus sampling

A

a prenatal test that is used to detect birth defects, genetic diseases, and other problems during pregnancy. Sample taken from the placenta where it attaches to the wall of the uterus.

198
Q

What test is used to test DS?

A

FISH

199
Q

What test is used to test for Prader Willi?

A

FISH or microarray

II. Methylation testing

200
Q

Physical features Prader Willi?

A

hypotonia
undescended testes
lighter pigmentation
feeding issues

201
Q

Toddler Prader Willi features?

A

Increase appetite

persistant hunger

202
Q

Eye medical problems with Prader Willi

A

strabismus - lazy eye

nystagmus - jiggly eye

203
Q

Developmental abnormalities Prader Willi

A

mild-moderate developmental delays

behavioral issues

204
Q

What chromosomal abnormalities are linked to autism?

A

IDIC 15

Maternally inherited interstitial duplication

205
Q

What is the Cause of Kleinfelter Disease?

A

47 XXY

206
Q

Kleinfelter behavioral childhood presentation

A

childhood- learning disability
delayed speech and language
tendency to be quiet

207
Q

Kleinfelter phenotype

A 
tall stature
small testes
reduced facial hair
infertility
hypospadia - urethra is underside of penis
gynecomastia - enlarged breasts in males
208
Q

What is the genomic abnormality Jacobs Syndrome

A

47 XYY

209
Q

Signs of Jacob’s disease

A 
learning disabilities
speech delays
developmental delays 
behavioral and emotional difficulties
autism spectrum 
tall stature
210
Q

Signs of Triple X syndrome

A 
learning disabilities 
delayed speech 
delayed motor
seizure
kidney abnormalities
211
Q

5 alpha reductase deficiency

A

can’t convert testosterone to dihydrotestosterone

under virilized male then increased during puberty

212
Q

Gene involved in Digeorge Syndrome?

A

22q11.2

213
Q

Presentation of Digeorge Syndrome?

A

Cleft lip / palate
congenital heart disoders
Thymus defect
parathyroid defect

214
Q

What percentage of babies with Down syndrome also have congenital heart defects?

A

40-50%

215
Q

If a pregnant 40-year-old woman presents to your office at 16 weeks of gestation, what standard test are you likely to perform to rule out Down syndrome?

A

amniocentesis and FISH

216
Q

What is the Karyotype for Patau syndrome?

A

Trisomy 13

217
Q

How are imprinting patterns maintained in offspring?

A

Maintenance methylation

218
Q

Prader-Willi and Angelman’s syndromes result from genetic aberrations to the same region of chromosome 15. Which of the following correctly explains why the resulting phenotypes differ from each other?

A

Phenotype depends on whether the mutation is maternal or paternal in origin.

Their effects are dependent on sex-specific methylation patterns that silence the only good copy of a gene.

219
Q

essential characteristic for normal epigenetic marking to be successful?

A
  1. Modification must be established in gametes
  2. Must be stably maintained after fertilization
  3. Must be reversible so appropriate sex-specific imprint is passed on
220
Q

What is the purpose of a whole chromosome paint using FISH?

A

identification of markers and translocations

221
Q

What is the recurrence risk for DS?

A

1/100 (1%) plus maternal age risk

222
Q

Single Palmer crease and wide space between 1st and 2nd toe are phenotypes of what disease?

A

Down Syndrome

223
Q

Define Pseudogene

A

They are non-functional genes that can be synthesized through reverse transcription

224
Q

What is the karyotype for Edward’s syndrome?

A

Trisomy 18

225
Q

What are the phenotypes associated with Edward’s syndrome?

A 
small for gestational age
microcephaly
clenched hands/overlapping fingers
Rocker bottom feet 
Heart/brain abnormalities 
90% perinatal lethality
226
Q

What are the phenotypes associated with Patau syndrome?

A 
Characteristic facies
severe intellectual disabilities
Congenital malformations (fusion of brain lobes, facial clefts, polydactyly, renal defects)
227
Q

Describe the alpha cluster in the alpha globin gene

A

zeta - alpha 2 - alpha 1 on CHROMOSOME 16

228
Q

Describe the beta cluster

A

epsilon - gammaG - gammaA - delta - beta on CHROMOSOME 11

229
Q

HBA

A

Majority of hemoglobin made up of alpha2 and beta2

230
Q

Hb Gower I

A

zeta2 and epsilon2

231
Q

Hb Gower 2

A

alpha 2 and epsilon2

232
Q

Hb Portland

A

zeta2 gamma 2

233
Q

Globin Switching part I

A

turn off zeta and epsilon, turn on alpha and gamma during early embryogenesis

234
Q

Globin Switching part II

A

turn off gamma and turn on delta and beta at time of birth

235
Q

HBF

A

Fetal Hemoglobin alpha2-gamma2

Has higher affinity for O2 at low pO2 than HbA

236
Q

Hispanic Thalassemia

A

Caused by the deletion of the Locus Control Region (LCR) on the beta like cluster

237
Q

Example of Qualitative Hemoglobinpathies

A

Hb^Kemsey (binds oxygen too tight)

Hb^Kansas (bind too weak)

238
Q

HBSS

A

mutation glutamate –> valine at codon 6

Hemoglobin is now 80% less soluble when not bound to O1 and polymerizes into long fibers

239
Q

HbCC

A

Milder form of hemolytic anemia

mutation glutamate –> lysine at codon #6

forms crystals

240
Q

Sickle Cell trait

A

HbS trait

heterozygous HbS/HbA

clinically normal except when under severe low pO2

241
Q

Restriction enzyme used to distinguish sickle cell from wild type?

A

MstII

cannot distinguish Hemoglobin C disease!

242
Q

Hb Kempsey leads to

A

Over production of blood cells - Polycythemia

243
Q

Hb Kansas

A

Cyanosis

244
Q

alpha thalassemia

A

caused by deletion of one or both copies of the alpha-globin gene in the alpha cluster.

gamma and beta globin now in excess

245
Q

alpha thalassemeias most common in Southeast asia

A

Hydrops Fetalis - - / - - ton of gamma 4
HbH disease a - / - - beta 4
mild anemia aa / - - alpha thalassemia - 1 trait

246
Q

alpha thalassemias most common in Africa, Mediterranean, and Asia

A

mild anemia a - / a - alpha thalassemia - 2 trait

247
Q

alpha thalassemeias most common in Southeast asia

A

Hydrops Fetalis - - / - - ton of gamma 4
HbH disease a - / - - beta 4
mild anemia aa / - - alpha thalassemia - 1 trait

248
Q

alpha thalassemias most common in Africa, Mediterranean, and Asia

A

mild anemia a - / a - alpha thalassemia - 2 trait

249
Q

As an adult how much HbA2 do you have?

A
250
Q

What gene is mutated in Achondroplasia?

A

Fibroblast Growth Factor Receptor 3

FGFR3

251
Q

Molecular basis of Achondroplasia?

A

Chromosome 4p16.3 nucleotide 1138
missense mutation Gly380Arg
Mutation increases the activity of the protein interfering with skeletal development

252
Q

Mutation rate for Achondroplasia?

A

80%

253
Q

Gonadal/germline mosaicism

A

The likely explanation of the rare situations where a person without a dominant condition can have two children with the same autosomal dominant condition

254
Q

What is Retinoblastoma?

A

Malignant tumor of the retina

255
Q

What is Neurofibromatosis Type 1

A

Mutation in the NF1 gene in Chromosome 17q11.2

Loss of function of a tumor suppressor gene NF1

256
Q

Neurofibromatosis phenotype?

A

6 or more café-au-lait spots
2 or more neurofibromas
1 plexiform neurofibroma
2 or more Lisch Nodules

257
Q

What is Neurofibromatosis Type 1

A

Mutation in the NF1 gene in Chromosome 17q11.2

Loss of function of a tumor suppressor gene NF1

258
Q

Neurofibromatosis mutation rate?

A

50%

259
Q

Osteogenesis Imperfecta Type 1 clinical manifestation

A

Multiple fractures
Mild short stature
Adult onset hearing loss
Blue sclera

260
Q

Mutation that causes Osteogenesis Imperfecta Type 1

A

Collagen type 1 alpha 1 COL1A1 on Chromosome 7q21.3

Reduced production of pro-alpha 1 chains that reduces the type 1 collagen production by half

261
Q

What is Marfan’s Disease?

A

Systemic disorder of connective tissue, musculoskeletal and cardiovascular problems.

Aortic Root enlargement seen!

262
Q

Things to look for to diagnose Marfan’s Disease?

A

Thumb and wrist sign
scoliosis
ectopia lentis
pectus excavatum

263
Q

What is the mutation involved in Marfan’s Disease?

A

Fibrillin gene FBN1 on Chromosome 15q21.1

264
Q

What causes Huntington’s disease?

A

CAG repeats >39

265
Q

Clinical manifestations of Huntington’s Disease

A

Progressive neuronal degeneration causing motor, cognitive and psychiatric disturbances
Age of onset 35-44
Death approximately 15 years after onset

266
Q

Clinical manifestations of Huntington’s Disease

A

Progressive neuronal degeneration causing motor, cognitive and psychiatric disturbances
Age of onset 35-44
Death approximately 15 years after onset

267
Q

What causes early Huntingtons onset?

A

Paternal transmission

268
Q

Clinical manifestations of Myotonic Dystrophy Type 1

A 
Adult onset muscular dystrophy
Progressive muscle wasting and weakness
Myotonia
Cataracts
Cardiac conduction defects
269
Q

What causes Myotonic Dystrophy Type 1?

A

CTG repeat >50

Myotonic dystrophy protein kinase (DMPK) gene on Chromosome 19q13.3

270
Q

How is Myotonic Dystrophy Type 1 transmitted?

A

Maternally!

271
Q

What type of inheritance do metabolic diseases have?

A

Typically autosomal recessive

ex: PKU and Gaucher’s disease

272
Q

Important use of DNA sequencing?

A

Ideal for looking at the sequence of a known disease gene

Can detect NOVEL mutations

M2M Unit II (1 decks)

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