Topics A34-38 Genetic Disorders/Developmental Abnormalities: Diagnosis, Autosominal Dominant, Recessive, Cytogenic, Single Gene - Atypical Inheritance

Question 1

What “conventional” genetic disorder diagnostic method is older, but still used for copy number abnormalities (like Downs syndrome, trisomy 21)?

How does it work?

Answer 1

Cytogenic karyotype analysis with “G banding”

Giema stains chromosomes with bands during metaphase, then the chromosomes are organized based on alternating light/dark patterns to see if there are any chromosomal abnormalities like deletions.

[FISH and comparative genomic hybridization (CGH) have become popular for focused analysis of chromosomal regions]

Question 2

What are 3 ways to categorize a chromosome, based on the position of the centromere in the middle or closer to one side, or just short chromosome with no clear centromere?

Answer 2

Metacentric: centromere is in the middle

Submetacentric: centromere closer to one side

Really short chromosome, no clear centromere: acrocentric

(helps identify which chromosome is which during G banding)

Question 3

What letter is assigned for a short arm in a chromosome?

What about the long arm?

Answer 3

short arm is “p” for “petite”

long arm is “q” for “qlong”

(jk its just the next letter)

Question 4

What are the possible numerical alterations in chromosomes?

Answer 4

1. Polypoidity: 3n, 4n, etc. Entire chromosome series (all 46 of them) have extra copies. A fetus with this will die before developing, but this can still occur in cancer cells.
2. Aneupoloidy: only certain chromosomes have less or extra copies. Monosomy, trisomy, etc. As in Down’s syndrome, trisomy 21 - have extra copy of 21. Not immediately lethal but many health problems

Question 5

How do numerical alterations like monosomy or trisomy develop? (2 ways)

Answer 5

1. Meiotic non-dysjunction at meiosis I: Failure of two members of a chromosome pair to separate from one another, causing both chromosomes to go to a single daughter cell.
2. Failure of sister chromatids to separate during meiosis II.

Results in some gametes with too many chromosomes, others with not enough.

Question 6

Which two chromosomes tolerate aneuploidy (usually meaning monosomy or trisomy) better than others?

Answer 6

Sex chromosomes: don’t need a Y chromosome to survive, and can also live with only one X (Turner syndrome). X is more commonly affected.

In general, loss of a chromosome produces more severe effects than gain

Question 7

What are 3 major numerical chromosomal disorders involving autosomal chromosomes (not XY)?

Answer 7

All are trisomy:

1. Down syndrome: +21 (most common cause)
2. Patau syndrome +13
3. Edwards syndrome +18

(Edwards and Patau are very severe defects, usually die within one year. Not going to ask any more about them but Down Syndrome will come up later)

Question 8

What are 3 major disorders involving numerical chromosomal differences in sex chromosomes?

Answer 8

1. Klinefelter’s Syndrome (47, XXY)
2. Turner syndrome (45, X0)
3. Triple X syndrome (47, XXX) aka Vin Diesel Syndrome

Question 9

What is a Barr body?

How does this relate to genetic abnormalities?

Answer 9

Inactivated X chromosome that is rendered inactive by “lyonization.” Can be visualized (darker bc of heterochromatin) and used for diagnosis. Normal in females because they have two X chromosomes, and one must be inactivated. XY people have no Barr bodies.

Turner syndrome: no Barr bodies because only 1 X.

If they have 3 X’s, then they will have 2 Barr bodies, 4 X’s -> 3 Barr bodies, and so on.

Question 10

What is the short way that you write the karyotype of translocations in chromosomal abnormalities, as in translocation from 2 to 5, and from the long 31 arm to short 14 arm?

Answer 10

For example for a woman it would be:

46, XX, t(2;5)(q31;p14)

Question 11

What are the two types of translocations?

Answer 11

1. Balanced Reciprocal: exchange. No information is lost, it’s just moved from one area to another
2. Central Fusion / Robertsonian: some genetic information is lost in translocation. May also be a cause of Down’s syndrome, (t21;14) instead of trisomy 21

Question 12

What are isochromosomes?

Answer 12

When sister chromatids (identical) separate horizontally rather than vertically, you get one chromosome of only short arms, and another of only long arms

[If this is your first time hearing about this and you’re confused, just look up a picture because it’s much simpler to visualize than explain]

Question 13

What do frameshift mutations cause at a chromosomal level?

Answer 13

Deletion type of structural chromosomal abnormalities

Very harmful..

Question 14

What are inversions, regarding structural chromosomal abnormalities?

What are the 2 kinds?

Answer 14

Orientation of genes and genetic material changes.

1. Paracentric inversion: centromere not affected
   2: Pericentric inversion: inversion occurs around the centromere

Question 15

What are ring chromosomes?

Answer 15

Very rare structural chromosomal abnormality. After a deletion of terminal segments of the chromosome, the chromosome has “sticky ends” that end up looping around to connect to each other, forming a ring shape

Question 16

What is the FISH method of diagnostics?

What are the advantages?

Answer 16

Fluorescent In Situ Hybridization: analyzes structural or numerical chromosomal alterations. Compared to conventional G banding, it’s more expensive, higher resolution, don’t need dividing cells for chromosome to be visible, software figures out problems automatically.

Major disadvantage: No “genome-wide picture” - need to have an idea what chromosomal regions to test for, and need specific probes for whatever you’re looking for (i.e. 5p probe if you’re looking for 5p deletion).

Question 17

What is the array CGH method of molecular diagnostics of genetic diseases?

Answer 17

Array Comparative Genome Hybridization: most modern method, has both high resolution and genome-wide picture. Very expensive.

A sample of patient’s DNA is dyed red and compared against reference “healthy’ DNA that’s dyed green. Combine the samples to get a “heat map.” The two should combine to make a yellowish color, but if it’s more red, then the patient’s sample is amplified. If it’s more green, then the patient’s sample is under-represented.

Question 18

What is the GWAS diagnostic method?

Answer 18

GWAS: Genome-Wide Association Studies.

This is used to analyze SNPs. Take a patient group (i.e. alcoholics), then compare their SNPs against a general population of non-alcoholics, making heat maps with CGH. From these, you see if there are any SNPs that are more common in the patient group vs the non-patient group.

Very popular research recently.

Question 19

How does Sanger sequencing work to test for genetic mutations?

Answer 19

PCR sequencing of DNA. “Chain terminating method” - keep adding nucleotides that terminates a chain (e.g. ACGTCA-stop). Add 4 different fluorescent dyes (one for each stop nucleotide). Read the fluorescence as it goes through capillary electrophoresis (separates by size, short DNA strands go through first) and you can get the sequence.

Mutation may look like 2 peaks of different color in same region. Used for identification of point mutations, genetic diseases, oncology diagnosis, etc..

Question 20

What are two invasive techniques to check for genetic fetal abnormalities?

Answer 20

1. Amniocentesis: amniotic fluid contains some fetal cells. Can also detect α-fetoprotein (AFP) levels that give a wide-array of diagnostic information, including things like neural tube defects
2. Chorionic villus sampling: Transcervically or transabdominally between 10th and 12th week. Results are available sooner than with amniocentesis.

Question 21

What are two non-invasive tests to check for fetal genetic abnormalities?

Answer 21

1. Ultrasound. Can see some morphologies indicative of things like Down or Turner syndromes.
2. Maternal Triple Marker Screening. Can also see α-fetoprotein (AFP) levels in maternal serum, levels drop in Down syndrome. Low hCG levels and decrease in urine unconjugated estradiol are both indicators or Down syndrome.

Question 22

What are two important non-coding RNAs? (only bringing it up because they spent a while on it in lecture)

Answer 22

1. MicroRNAs: short, regulate protein expression. Can be used in therapy: design small, interfering miRNA and target mRNA with it
2. Long non-coding RNAs (lncRNA): regulates transcription and translation. Can bind to DNA, RNA, etc… diverse functions. Has involvement in some disorders.

Question 23

How are germline and somatic mutations different?

Answer 23

Germline: inherited, present in every cell (spread down through family line, may be nothing, may be pathological, or could be evolutionary advantage)

Somatic: acquired mutations, only present in somatic cells (like cancers)

Question 24

What are the 4 main types of genetic mutation classifications that alter protein synthesis? (from lecture)

Answer 24

1. Missense: “point mutations” - change of just one nucleotide, can lead to change of just one amino acid that it codes for (example: Sickle Cell Anemia)
2. Nonsense: amino acid codon changes to a stop codon. Get truncated, shorter proteins that may decay faster.
3. Frameshift: Insertion or deletion of some nucleotides, but not of 3 of them and so the type of amino acid coded for is changed the entire way down the rest of the protein construction line
4. Trinucleotide Repeat: too many trinucleotide repeats makes the gene unstable. Seen in Fragile X Syndrome and Huntington’s disease.

Question 25

What is meant by Mendellian inheritance Disorders?

What are some modifying factors? (2 are listed)

Answer 25

Inheritance pattern involves classic dominant/ recessive alleles. “Autosomal” if not on an X or Y chromosome.

Mendellian genetics is true but too simple, so some modying factors:

1. Pleiotropy: one gene has many phenotypic effects (e.g. Cystic fibrosis is one mutation with many effects)
2. Genetic heterogeneity: different mutations lead to same trait (e.g. deafness can be caused by many different mutations)

Question 26

What is characteristic in the family tree of people with autosomal dominant disorders?

Answer 26

There is an infected individual in every generation, and males and females are affected equally often.

It’s enough to have 1 mutant allele (heterozygous) to have the disease.

Question 27

With genetic disease inheritance, what do “penetrance” and “expressivity” mean?

Answer 27

Penetrance: not everyone with autosomal dominant gene is affected (they are phenotypically normal). for example if 10 patients have mutation but only 8 have the disease, the penetrance is 80%

Expressivity: Within patients that show the trait, this refers to the severity. Not everyone who inherits a disease has it equally severe (“variable expressivity”).

Question 28

What are two methods that epigenetic regulation occurs?

Answer 28

1. DNA methylation (cytosine residues methylated, made inaccessible to RNA polymerase, becomes silent)
2. Histone acetylation and methylation for either suppression or activation

Question 29

What is a dominant negative allele?

Answer 29

A mutant allele that can impair the function of a normal allele

Question 30

If two parents are both heterozygous for an autosomal recessive allele, what is the chance that each of their children will get it?

Answer 30

25%, 1 in 4

Autosomal recessive diseases are the most common Mendellian inheritance diseases, probably because so few people in the family are likely to be affected and so more offspring will survive unaffected as carriers.

Question 31

Which chromosome are sex-linked genetically inherited disorders always on?

Answer 31

The X chromosome.

Worst thing known of the Y chromosome is to cause the disfigurement of having hairy ears.

Heterozygous X linked disorders are carried by females and normally transmitted only to sons

Question 32

Marfan syndrome:

Type of inheritance What gene is affected?
Common changes / health problems?

Most important cause of death?

Answer 32

Autosomal dominant inheritance

Connective tissue disorder: mutation affecting fibrillin gene (FBN1), makes microfibrils. Microfibrils affected in aorta, ligaments. Get skeletal abnormalities, overgrowth of bones, lens dislocation. Heart: “Floppy valve syndrome”.

Important cause of death: aortic rupture

Question 33

Ehlers-Danlos Syndrome

Type of inheritance?
Genes affecting what protein is affected?

Major health risks?

Answer 33

Group of diseases, some are autosomal dominant and others are recessive

Mutation of various genes related to collagen production.

Tissues lack collagen, so skin is hyperextensible and joints are hypermobile

Major health risks are impaired wound healing, ruptures of large arteries and colon

Question 34

Familial hypercholesterolemia:

Type of inheritance? Which gene affected? Prevalence?

Major health risk?

Answer 34

Autosomal dominant inheritance, LDLR gene (for LDL receptor). 1 in 500 people are heterozygous for this.

Heterozygotes have higher rates of atherosclerosis and early AMI but won’t have them until adulthood, while homozygotes basically guaranteed to have AMI and die before the age of 20.

Review cholesterol metabolism: LDL receptor binds to ApoB-100 and E, taking in cholesterol from both IDL and LDL

Question 35

What is the most common lethal genetic disease in white people?

What type of inheritance does it follow? On which gene?

Answer 35

Cystic Fibrosis (1 in 3200 live births in the US) - not common in people who are not of European descent

Follows autosomal recessive inheritance. Usually mutation is CFTR gene change F508
[more on CF in next deck, has whole topic]

Question 36

Phenylketonuria (PKU):

Type of inheritance? What enzyme is deficient?

Health problems?

Answer 36

Autosomal recessive. Phenylalanine hydroxylase (PAH) deficiency. Converts phenylalanine to tyrosine (using tetrahydrobiopterin). Without the enzyme, get hyperphenylalaninemia.

Causes severe mental retardation, seizures, decreased pigment (melanin is from tyrosine). Low phenylalanine diet treatment is fairly successful, can also get enzyme supplements.

Question 37

Galactosemia:

Type of inheritance? Which gene mutation and enzyme deficiency?

Health problems

Answer 37

Autosomal recessive, gene and enzyme both called GALT: Galactose-1-phosphate uridyltransferase. Galactose metabolism impaired, leads to buildup of galactose-1-phosphate and other intermediates.

Accumulates in liver (hepatomegaly, jaundice, cirrhosis), kidney (aminoaciduria), brain (edema, loss of nerve cells)

Other effects: vomiting and diarrhea after milk ingestion, E. coli sepsis, cataracts

Treat with low galatcose diet.

Question 38

Lysosomal storage diseases:

• Type of inheritance?
• What are 3 examples of lysosomal storage diseases? Which one do we have a histo slide for?
• Which one is also a glycogen storage disease?

Answer 38

Autosomal recessive inheritance

• Gaucher disease (has histo slide, PAS stain)
• Tay-Sachs disease
• Neimann-Pick Disease types A, B, and C

Pompe disease is a lysosomal disease that is also a glycogen storage disease

Question 39

What are 3 common health-related consequences of lysosomal storage diseases?

Answer 39

1. Storage of insoluble intermediates in the mononuclear phagocyte system, creating hepatosplenomegaly
2. Neuron damage, CNS impairment
3. Cellular dysfunctions, caused by storage of undigested material and secondary events like macrophage activation and release of cytokines

Question 40

Tay Sachs disease:

• What enzyme is deficient?
• Which organ is mainly affected?
• Clinical course?

Answer 40

Enzyme: hexosaminidase A. Degrades GM2 (a ganglioside). Without it, GM2 accumulates in lysosomes.

Brain is principally affected: neurons and glial cells store GM2, and affected cells appear swollen and foamy.

Appear normal at birth, motor weakness begins within 6 months. Neurologic impairment progresses, blindness develops. Dies within 2-3 years old. 1 in 30 Ashkenazi Jews are carriers.

Question 41

Neimann-Pick Diseases types A, B, and C:
-What is deficient/mutated?
-Major clinical symptoms?
[this card may not be too important for now, wasn’t big in lecture]

Answer 41

A and B: deficient in acid sphingomyelinase, accumulate sphingomyelin, cannot break it down into ceramide. Macrophages stuffed with droplets of complex lipids. Concentric lamellated myelin figures called “zebra bodies” may appear. Mostly affects spleen, liver, bone marrow, lymph nodes, and lungs. Massive visceromegaly. Type A has neurologic deterioration and worse prognosis (death by 3 years age), type B does not have neurologic problems, less severe.

Type C: Distinct. Mutations of NPC1 and NPC2 genes, defect in lipid transport. Affected cells accumulate cholesterol and gangliosides in cytosol. May have ataxia, dystonia, dysarthria, and the easy-to-remember “vertical supranuclear gaze palsy”

Question 42

What is the major defect with Gaucher disease?

Answer 42

Lysosomal storage disease: Mutation of gene that encodes for glucocerebrosidase, which breaks down ceramide by cleaving glucose from it (part of cell membrane). Ceremide normally broken down by macrophages, and so macrophages accumulate the glucocerebroside intermediate and become giant cells: Gaucher cells. These can be >100 microns and have “wrinkled tissue paper” appearance

These macrophages also become active and secrete TNF alpha, IL-1, and IL-6, leading to fibrosis of the organ..

Question 43

What are the three kinds of Gaucher disease?

Answer 43

1. Chronic Non-neuropathic form: 99% of cases. Osteopenia, no CNS symptoms occur, but hepatosplenomegaly is very characteristic. Spleen becomes massive. Gaucher cells found in liver, spleen, lymph nodes and bone marrow.
2. Acute Infantile Neuropathic: have the other symptoms but also CNS involvement. Die when they are babies.
3. Chronic neuropathic form: Slowr progression of neurological symptoms, die in teenage years.

Question 44

What are the 3 main inherited glycogen storage diseases to know? Type of inheritance? What enzyme is deficient in each and what are the most important health complications?

Answer 44

All autosomal recessive inheritance

1. Hepatic types: von Gierke is the most important. Glucose-6-phosphatase deficient. Hepatomegaly and hypoglycemia
2. Myopathic types: McArdle is most important one. Muscle glycogen phosphorylase is deficient. Muscle cramps during exercise, myoglobuinuria result
3. Pompe disease: lysosomal acid maltase deficient (lysosomal storage disease that affects glycogen). Glycogen deposits in virtually every organ, cardiomegaly is major problem. Usually die within 2 years of age from cardiorespiratory failure

Question 45

What is the definition for “polymorphism?”

What is the common disease-common variant hypothesis?
[The wording on the answer is awkward because it’s directly from the lecture and I’m not sure I fully understand it]

Answer 45

Polymorphism: genetic variant that has at least 2 alleles and occurs in at least 1% of the population

Common disease-common variant hypothesis: Complex multigenic disorders occur when many mild polymorphisms (modest effects and low penetrance) are co-inherited

These would be alleles related to more mild and complex diseases with many environmental factors like diabetes mellitus type II

Question 46

What is chromosomal mosaicism?

Answer 46

Because Barr body formation (inactivation of one X chromosome in females and others with more than one X), parts of the body will have different X chromosomes and thus a slightly different genetic code.

It uncommonly can occur with autosomal disorders that are not sex-linked as well.

Question 47

What are the two possible causes of Down syndrome?

Answer 47

1. Trisomy 21: most common cause (95%), occurs via meiotic nondysjunction mentioned earlier. Sporadic mutation, non-inherited. Women over the age of 45 have strong chance of producing Down syndrome baby this way (1 in 25). May have chromosomal mosaicism, with some 46 chromosome cells and others with 47.
2. 4% cases are translocation of long arm of chromosome 21 to chromosome 22 or 14. This type can be inherited.

Question 48

What are the most important characteristic features and health complications of Down syndrome?

Answer 48

Features: epicanthic folds, low IQ (25 to 50), flat face. Highly mosaic Down syndrome may have mild symptoms, decent intelligence.

Health complications: susceptible to acute leukemia, heart defects (normally of endocardial cushions. major cause of death)

Question 49

22q11.2 Deletion Syndrome: What two disorders were formerly thought to be caused by different things, but are both from this same deletion?

What are the major health consequences?

Answer 49

[Deletion of 11.2 region of long arm of chromosome 22]
Used to be divided into DiGeorge Syndrome and Velocardiofacial syndrome (more severe)

DiGeorge Syndrome: T cell immunodeficiency and hypocalcemia are dominant symptoms

Velocardiofacial syndrome: mild immunodeficiency, but pronounced dysmorphology and cardiac defects (of the outflow tracts)

Both at risk for schizophrenia and bipolar disorder

Question 50

What causes Cri du Chat Syndrome? What is characteristic for it?

Answer 50

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

Get characteristic “moon face,” may also have some growth retardation, microcephaly, cardiac defects, etc.

Question 51

What is the most common karyotype of Klinefelter syndrome? What is the genetic cause?

What are the symptoms?

Answer 51

Most are 47XXY, but may have mosaicism with some 46XY cells and then they have milder symptoms. Results from meiotic nondysjunction.

Male but has hypogonadism, “eunichoid” features. Gynecomastia, testicular atrophy, infertility. May be mildly mentally retarded.

Question 52

What is the karyotype of people with Turner syndrome?

What are the major signs/symptoms?

Answer 52

Usually 45, X0. May also just have loss of part of the second X chromosome (more mild). Will not have any Barr bodies.

Signs/Symptoms: webbed neck, hypogonadism, primary amenorrhea (no menstruation), growth retardation (short stature, normally the SHOX gene regulating height is active in both X chromosomes), cardiovascular abnormalities, horseshoe kidney

Question 53

What are 3 conditions known to be associated with trinucleotide repeat sequences?

Answer 53

1. Fragile X syndrome: second-most common genetic cause of mental retardation after Down syndrome. X-linked, so primary affects males. (this one was spoken about more in lecture and the book, not gonna elaborate on the others)
2. Huntington’s Disease
3. Myotonic dystrophy (a type of muscular dystrophy)

Question 54

What is “genomic imprinting?” What are the two related diseases associated with genomic imprinting?

Answer 54

Because we have both maternal and paternal alleles, one will often be suppressed epigenetically. So, you have silencing via maternal imprinting vs paternal imprinting,

Prader Willi and Angelman Syndromes: both result from deletion of part of chromosome 15, but Prader-Willi has deletions of the paternal one, while Angelman is of the maternal chromosome. On top of the deletion, the other chromosome is also silenced via imprinting.

Both have characteristic mental retardation, obesity, and hypogonadism. Angelman also has ataxic gait, seizures, and inappropriate laughter (“happy puppet syndrome”)