Genetics Flashcards
(127 cards)
1
Q
Post zygotic, mitotic nondisjunction results in what?
A
Mosaicism
2
Q
When to suspect a chromosomal abnormality?
A
Growth restriction/retardation
Structural abnormalities (especially more than one)
Developmental delay or mental retardation
3
Q
Causes of trisomies
A
nondysjunction (advanced maternal age)
Translocation
4
Q
For the following maternal ages, give the risk of Down syndrome at birth and the risk of all chromosomal abnormalities: 20, 35, 40, 49
A
20: 1/1667, 1/526
35: 1/385, 1/204
40: 1/106, 1/65
49: 1/11, 1/7
5
Q
Recurrence risk of Down Syndrome
A
If trisomy 21: 1% until age 40, then age related risk
If 14,21 robertsonian translocation: di novo, not significantly higher; maternal carrier: 10-15%; paternal carrier: 3-5%
6
Q
Down syndrome causes
A
95% due to trisomy 21: 47, XX (or XY), +21
4% due to translocation: 46, XX (or XY), der(14;21)(q10;q10)
1-2% mosaic trisomy: 46,XX/ 47, XX, +21
7
Q
Down Syndrome Abnormalities
A
Hypotonia, open mouth, protruding tongue, poor reflexes, short stature, flat face (can be seen in ultrasound)
Mental Retardation
Mild microcephaly, upslanting palpebral fissures, epicanthal folds, small nose, hydrocephalis
Clinodactyly of the 5th finger, transverse palmar crease (35%)
Eyes: speckled iris (Brushfield spot) with peripheral hypoplasia
Intestinal obstructions (duodenal atresia)
Cardiac Anomalies (40%)
- atrio-ventricular canal
- VSD
- patent ductus arteriosus
Wide gap between 1st and 2nd toe
Skin: loose posterior neck, cutis marmorata (reddish-purple skin in cold)
Genitalia: hypogonadism (infertile)
Recurrent infections Hypothyroidism Delay in milestones Poor coordination Increased risk of Leukemia Increased risk of cataracts Alzheimer’s development in adulthood
Most die from congenital heart disease
8
Q
When does a Robertsonian translocation cause Down Syndrome? What happens to the other cells?
A
It must be passed from a carrier mother’s germ cells to a progeny’s autosomal cells
If a cell is a balanced translocation, no trisomy
If a cell has trisomy or monosomy, it will abort, HOWEVER some trisomy 21 translocation cells remain viable and cause trisomy 21
9
Q
Edwards Syndrome: characteristics and survival rate
A
Trisomy 18– 1 in 10,000 live births
Pre and post natal growth deficiencies (low birth weight despite full term) including microcephaly, prominent occiput, low set ears
Clenched hands (with index finger over 3rd finger)
Congenital heart diseases more severe than Down syndrome (90%)
- anomalous coronary arteries
- transposition of great vessels
- tetralogy of Fallot
- coarctation of the aorta
Only 10% survive to age 1 with severe retardation and poor growth. Very few survive past 1
10
Q
Patau syndrome: characteristics, survival
A
Trisomy 13: 1 in 15,000
Holoprosencephaly, severe mental deficiency, cleft palate (usually midline; 70%; this is the biggest signal of brain malformation), abnormal ears, scalp defects (aplasia cutis; cigarette burns), postaxial polydactyly (after pinky)
Congenital heart abnormality (80%)
- VSD
- patent ductus arteriosus
- ASD
Single Umbilical artery
Omphalocele
About 15% survive beyond first year but with severe mental/physical abnormalities
11
Q
What is the prevalence of autosomal monosomies?
A
None; these result in miscarriages in first trimester unless they are mosaic with a normal cell line
12
Q
What is the prevalence of Triploidy births? What happens if it comes from the mother vs. the father?
A
1 in 50,000 liveborns
This is an example of imprinting
Maternal origin: digyny, small placenta, growth restricted fetus
Paternal origin: dispermy (two sperm fertilize one egg; most common triploidy), or paternal nondisjunction; large hydropic placenta (incomplete mole); 3,4 syndactyly, macrocephaly, deformed face
13
Q
If you really wanna know what’s going on genetically (besides translocations), what test should you do? When does it work best?
A
Microarray
When you know what you are looking for
14
Q
What are the only viable trisomies?
A
13, 18, and 21 (and RARELY 22)
15
Q
What is better for determining a duplication/deletion: metaphase or prometaphase spread?
A
Prometaphase because the chromosomes are more spread out and elongated which means better band resolution
16
Q
Crit du chat
A
1 in 50,000 live births
5p- (p arm of chromosome 5 is missing genetic material)
Characteristic cry of cat as a newborn (goes away eventually)
Failure to thrive, developmental delay
Hypotonia
Small face, large nose, large mouth
17
Q
What candidate gene on the p arm of the Y chromosome initiates the cascade that leads to male genitalia formation? How does it initiate the cascade?
A
SRY gene
Causes secretion of testosterone from Leydig cells which stimulates male genitalia formation from mesonephric ducts
Causes secretion of Mullerian inhibiting factor from Sertoli cells which stimulates regression of paramesonephric ducts
18
Q
Give an example of autosomal genes that also influence the cascade of sexual differentiation.
A
If 3-a-hydroxytestosterone is not present (absence of 5 alpha reductase), then external male sex characteristics are absent
If the gene for cholesterol biosynthesis is absent, sexual differentiation is incomplete (because we need cholesterol to make testosterone)
19
Q
How does Lyonization work? Give an example of the effect on an X linked disease like hemophilia (factor 8 production).
A
Around 2 weeks post conception, half of the X chromosomes in a female are silenced (15% of the genes are not silenced; silenced X become Barr bodies). Theoretically, half of the cells silence the paternal X and half silence the maternal X.
Hemophilia— X linked; men symptomatic; only 1% of women symptomatic because they have enough active X’s that produce normal levels of factor 8. If symptomatic, that female will have about half the amount of Factor 8 that a normal person has because mostly mutated X’s are activated
20
Q
Gonadal dysgenesis
A
Poorly developed or streak gonads
21
Q
Male pseudo hermaphrodite
A
Genotype of male; mixed phenotype
22
Q
Female pseudo hermaphroditism
A
Genotype of female; mixed phenotype
23
Q
True hermaphrodite
A
Pathological presence of ovarian and testicular tissue
24
Q
45, X Turner Syndrome
A
Missing a sex chromosome
Short stature and infertility
Karyotype: 45, X (53%) or mosaic with 45, X
Cause: paternal nondisjunction (therefore risk does not increase with MATERNAL age)
Incidence: 1 in 5,000 live births; about 95% end in miscarriages; 20% of first trimester miscarriages are due to Turner syndrome.
Physical characteristics: Prenatal— cystic hygroma (lymph fluid trapped in sac around the neck), hydrops, cardiac malformations, renal malformations, or NO FINDINGS
Birth— webbed neck, low set ears, broad chest, wide spaced nipples, low posterior hair line, edema, cardio and renal abnormalities, cubitus valgus
25
What happens to genitalia in Turner syndrome?
Gonadal dysplasia— no gonads
In puberty, there is pulsatile secretion of FSH but no end organ to be stimulated. Total follicular atresia during development. Because there are no sex organs to release sex hormones (estrogen/estradiol), external female characteristics do not develop. Ex) no breast tissue development.
26
Management of Turner Syndrome
Look for cardiac and renal malformations
HGH injections (to increase height)
Hormonal replacement (estrogen/progesterone)— can’t do it too early though because estrogen closes the growth plates. She will have external genitalia with vagina, Fallopian tubes, but no ovaries.
Reproductions support
Mosaic Turners can have a baby but may not go through the whole reproductive cycle (age wise)
27
Klinefelter Syndrome
Karyotype: 47, XXY
Maternal nondisjunction
1 in 1,000 live births
50% lost in miscarriage
Birth: normal male
Extra X, maternal nondisjunction, infertile (azospermia)
Not limited sperm, there is NO sperm production (hylanized tubules)
Puberty: tall, thin; small testis, hypogonadism, gynecomastia
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Trisomy X
Karyotype: 47, XXX
Infertile
Usually look like a normal female
Slight mental delay possible
29
How does counting Barr bodies work?
Extra X’s will be turned off.
1 Barr body with female phenotype is normal female
2 Barr bodies with male phenotype is male kleinfelter 48, XXXY
3 Barr bodies with female phenotype is 48, XXXX
3 Barr bodies with male kleinfelter is 49, XXXXY
4 Barr bodies with female phenotype is 49, XXXXX
30
47, XYY
Paternal nondisjunction
1 in 1000 live births
Hardly any abnormalities
Tall, may have behavior problems
Normal fertility: not at risk for aneuploidy children
31
Androgen insensitivity
46, XY
No androgen receptor in target cells (has testes, produces testosterone but it doesn’t signal anything; MIH still works however so Müllerian ducts degenerate— no uterus, no ovaries, no Fallopian tubes)
X-linked
1 in 20,000
Small clitoris/labia; only lower 2/3 of vagina is present
Increased risk of gonadal neoplasia due to undescended testes
32
Gonadal Carcinoma
Any individual with XY cell lines (mosaic or not) and gonadal dysgenesis should have their gonads removed
33
Fragile X (characteristics and mutation, etc.)
X-linked mental retardation
-dominant with incomplete penetrance
1 in 125 males
1 in 2500 females
Perinatal— normal
Prepubertal— Developmental delay; tantrums, hyperactivity, autism
Postpubertal— intellectual incapacity, large ears long face, macroorchidism
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Mutation: Located at Xq27.3
Trinucleotide repeats (CGG)
-normal: 10 to 50 repeats
-permutation (carrier) 51 to 200 repeats
- Full mutation: >200 repeats (causes hypermethylation and silencing of the FMR1 gene)
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The end of the X chromosome has little break points where the FMR1 gene is.
34
Anticipation
Seen in genetic diseases that pass through generations
Subsequent generations are more severely affected by a disease
Mechanism: increased number of triplet repeats in the fragile area of the X chromosome through generations (example, Fragile X)
35
Sherman Paradox
Unique to Fragile X
Expansion of the trinucleotide repeat occurs more readily when the premutation is passed from the female to her son
Occurs less readily when a male passes it to his daughter
36
Infertility
Inability to achieve conception or sustain a pregnancy
Only a fraction of infertility is related to chromosomal abnormality
37
Which sex chromosome abnormalities are related to infertility?
Klinefelter— 47, XXY—> azoospermia or oligospermia (low sperm concentration)
Turner syndrome— 45,X
38
Infertility related to autosomal abnormalities
Very infrequent
Reciprocal translocations and inversions are related to oligospermia
Robertsonian translocations
Translocations between autosomes and sex chromosomes
39
Causes of female infertility
Four causes:
```
Fallopian tube obstruction
Anatomic abnormalities of the genital tract
Endometriosis
Ovulation disorders (most cytogenic causes in this category)
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40
Gene mutations that cause infertility
Mutations resulting in premature ovarian failure/insufficiency (loss of ovarian function before age 40): FMR1, SRY, FSHR, LHCGR, CYP17A1, CYP19A1, AIRE, NR5A1, GALT
Chromosomal causes are usually X chromosome deletions or translocations
41
When can monosomy X still be fertile?
When mosaic (some pregnancies have been reported in monosomy X mosaics but none in women with 45,X/46,XY)
42
X;autosome translocations— which X gets inactivated?
Balanced X; autosome translocation— the NORMAL X is inactivated
Unbalanced X;autosome translocation— the ABNORMAL X is inactivated
Body is trying to compensate for the imbalance
43
What can be said of an infertile man with a normal semen analysis? What about a man with normal sperm count but doesn’t fertilize?
Less likely to have a cytogenetic or molecular cytogenetic basis for infertility
Have an increased risk of chromosome abnormality
44
Chromosomal causes of male infertility
Klinefelter syndrome: 1 in 1000 live born; 7-13% of azoospermic males; small firm testes; gynecomastia; azoospermia; 90% have 47,XXY karyotype while 10% are mosaic 46,XY/47,XXY
Sperm retrieval is possible
45
Microdeletions of Y
One of the most commonly identified molecular genetic causes of male infertility (genes necessary for sperm production are on Yq).
8-15% of men with azoospermia or oligospermia
46
Genomic Imprinting
Epigenetic phenomenon that causes genes to be expressed in a parent-of-origin specific manner (remember these are GENES, not full chromosomes)
Gene becomes “imprinted” in either the sperm or the egg. Depending on the gene it may always be imprinted from the mother or father.
Imprinting is extrinsic to changes in the nucleotide sequence; rather, it is due to DNA methylation, Histone modification, or non-coding RNAs
Reset during gametogenesis; sperm gets paternal pattern of imprinting and eggs get maternal pattern
47
Uniparental Disomy (UPD)
The inheritance of a pair of chromosomes from one parent with no copy of that chromosome from the other parent (NOT trisomy; still only two chromosomes present)
48
What are the two types of UPD for an entire chromosome?
Isodisomy: two copies of one homolog from one parent (this can more easily result in recessive disorders or make dominant disorders worse)
Heterodisomy: one copy of each homolog from one parent
49
Trisomy Rescue
One of the three chromosomes from a trisomic conceptus is lost (during mitosis)
UPD results if both salvaged chromosomes are from the same parent
50
Monosomy Rescue
Mechanism of UPD
Chromosome in a monosomic zygote duplicates itself to create isodisomy
51
Nondisjunction resulting in UPD
One daughter cell has 3 copies while the other has 1
3 copy cell does trisomy rescue and might end up with uniparental disomy
1 copy cell might do monosomy rescue
52
Gamete Complimentation
UPD resulting when one gamete has two copies of a chromosome and the other gamete has none
53
What are phenotypic consequences of UPD?
AR diseases to homozygosity of single chromosome
Transmission of X-linked genes from father to son
Imprinted gene effects for some chromosome regions
54
Prader-Willi Syndrome
Discovered in 1956
Affects 1 in 10,000 to 20,000
Due to imprinting on the paternal chromosome 15
Characterized by Hypotonia, hyperplasia, hypogonadism, and Obesity (because they can’t stop eating; they don’t know that they are feel). Skin picking, cognitive delay as well
55
What causes Prader-Willi Syndrome?
70-75% deletion of paternal chromosome 15 (or imprinting of normally expressed genes); associated with hypopigmentation and skin picking
20-25% maternal disomy for chromosome 15 (trisomy rescue); no paternal genes; these have higher verbal IQ and better memory than others.
1-5% imprinting center defect (families with recurrent cases of PWS have abnormality of imprinting process)
56
Angelman Syndrome
Deletion/imprinting of the same region as PWS (15q) but on the MATERNAL chromosome
Severe intellectual impairment, seizures, ataxic movements, incessant hand clapping, excessive drooling and laughter, wide mouth, protruding tongue, absence of speech, acquired microcephaly by age 3
57
Causes of Angelman syndrome
Four types of abnormalities that disrupt UBE3A gene
70% maternally derived deletion on 15
6% paternal UPD for chromosome 15
3-6% imprinting defect
10% UBE3A gene mutation
58
How does PWS/AS methylation study work?
Detects 100% of PWS and 80% of AS
If normal, rule out PWS. Do UBE3A mutation analysis. If normal, probably not AS. If abnormal, AS diagnosed due to mutation
If methylation abnormal, move to FISH analysis. If abnormal, PWS/AS diagnosis due to microdeletion.
If FISH normal, move to UPD study. If normal, PWS/AS diagnosis due to Imprinting center defect (methylation). If abnormal, PWS/AS diagnosis due to UPD
59
What is the recurrence risk of PWS/AS due to various etiologies?
Deletion— happens by chance (<1%)
UPD— chance (<1%)
IC abnormality— 50%
Gene mutation (AS only)— 50%
60
Pertinent Genetic Screening questions
Maternal age
Family History
Ethnic background- some disorders higher in certain backgrounds
Specific directed questions- ever had a child with specific risks; alcohol, etc.
61
Types of Genetic Fetal Disorders
Chromosomal
Mendelian (single gene)
- AD
- AR
- X-linked
Multifactorial
Uniparental Disomy
62
Chromosomal Abnormalities are the cause of... (percentages)
- 50% of first trimester losses (increases with advancing maternal age)
- 3% of couples with recurrent miscarriage (one miscarriage isn’t usually investigated, but multiple miscarriages ARE likely due to this); usually due to a balanced translocation.
- 7% of stillborns
- 0.5% of liveborns
63
Maternal Serum alpha fetoprotein (screening test)
Draw mother’s blood and look for alpha fetoprotein- unique in fetuses; like albumin
Noted to leak into amniotic fluid when fetus had an OPEN neural tube defect
Also leaked into amniotic fluid when fetus had other defects
Higher levels in amniotic fluid leads to higher levels in maternal serum
64
Will alpha fetoprotein be found in the mother under normal circumstances? (MSAFP)
Yes. The baby excretes some in the urine which crosses the placenta, but it will only be a little bit.
65
What allows MSAFP false positives and false negatives?
There is some cross over between healthy levels of MSAFP and spina bifida/anencephaly levels
66
Prevention of Neural Tube Defects (NTD)
All women should receive 400ug of folic acid one month prior to pregnancy and at least first trimester
Neural tube closes at 6 menstrual weeks
If prior affected child, refer for counseling prior to counseling
Larger doses of folic acid used (2-4mg/day); risk of masking a B12 anemia
67
Quadruple Screen
Four maternal serum metabolites
- AFP
- Estriols
- bHCG
- Inhibin A
Values are predictive at 15 to 20 weeks of gestation
Accurate gestational age is essential (because the values between week 16 and week 18 (for example) change normally)
68
What are the most common reasons (in order) that quad screen results are irregular?
1) got the dates wrong
| 2) there are twins
69
Quad screens results for: Down syndrome, Trisomy 18, and open NTD
Down Syndrome:
- AFP decreased
- Estriols decreased
- Beta hCG increased
- Inhibin A increased
Trisomy 18:
- AFP decr
- Estriols decr.
- Beta hCG decr
- Inhibin A unchanged
Open NTD
- AFP increased
- other tests don’t apply
70
Quad screening capabilities?
False positives— around 4%
Positive Predictive values— 1.5-2.5%
What does that mean? It means that more positives are false than real
Quad screen and detailed ultrasound detects about 85% of Down syndrome
71
Fetal DNA in Maternal Blood (cell free DNA test)
Normally, there are fragments of fetal DNA mixed with maternal DNA in maternal blood. It will be elevated if the fetus has a trisomy of some sort. Very sensitive test.
High detection rate— trisomy 21,18 (sensitivity about 99%)
Adequate detection of trisomy 13
Low false positive rate (.5-1%)
False negative— extremely low (residual risk)
Done after 10 weeks of gestation
Still considered a screening test
Some inadequate samples
72
When is cff DNA test recommended?
Prior trisomy
Abnormal biochemical screening
Advanced maternal age
Ultrasound abnormality
73
What can cause a false positive cffDNA?
Maternal/placental mosaicism
Maternal tumor
Vanishing twin
74
Techniques to obtain fetal samples
Chorionic villus sampling (CVS)
Amniocentesis
Fetal Blood sampling
75
Genetic amniocentesis (give a clinical example)
Cells taken from the amniotic fluid can be separated/grown and tested:
```
Direct assay DNA
Chromosomal analysis
Enzyme analysis
AFP concentration
etc.
Example: cells harvested and electrophoresis performed showed a defect in acetylcholinesterase enzyme from the brain (neural tube defect)
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Performed after 15 weeks gestation
Most commonly between 15 and 22 weeks
Procedure related loss rate: 1 in 500
Few contraindications
- Anhydramnios (no fluid)
- Certain infections (HIV)
76
Chorionic Villus Sampling
Trying to get a piece of the placenta
Performed at 10-13 weeks gestation
Procedure related loss rate: 1 in 200
Few contraindications
- Cervical Infections
77
Ultrasound Screening for Fetal Abnormalities
Best done at 18-20 weeks
Combined use of the triple screen and detailed ultrasound detects about 75% of Down syndrome
THE GENETIC ULTRASOUND
78
What is the double bubble? What do you need to rule out?
Double bubble on ultrasound is duodenal atresia, need to rule out trisomy 21
79
Increased Nuchal translucency
Trisomy 21, 18, 13
Turner Syndrome
Isolated Complex congenital heart disease
80
First trimester screening
Nuchal Translucency
PAPP A
B hCG
81
Newborn findings in Fetal Infections
- microcephaly
- microphthalmia
- midfacial hypoplasia (smaller midface)
- Growth restriction
- deafness
- valvular congenital heart disease
- skin scarring/lesions
- hydrops fetalis (extrafluid in fetal compartments)
- brain calcifications
- pneumonia
- hepatosplenomegaly
- Thrombocytopenia
- Petechiae
- hyperbilirubinemia
82
TORCH
Causes of newborn infections:
- Toxoplasmosis
- Other (syphilis, varicella, Zika)
- Rubella
- CMV
- Herpes
83
Toxoplasmosis
```
Increased spontaneous abortions
Mircrocephaly
Chrioretinitis
Growth Restriction
Hepatosplenomegaly
BRAIN CALCIFICATIONS
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If infected early (first trimester) more likely to miscarry but born with more symptoms
If infected later (third trimester) most babies are asymptomatic. 60% of infections occur here
84
Syphilis
Most newborns asymptomatic
Others: chorioretinitis, deformed nails, alopecia, maculopapular rash
Hydrops fetalis
Growth restriction
Hepatosplenomegaly, jaundice, lymphadenopathy, fever
Clinical:
Hutchinson’s teeth (blunted upper incisors)
Severe hydrops fetalis and stillborn
85
CMV
Cytomegalovirus
-1-2% of newborns have CMV infection
90% are asymptomatic
10% have hearing loss
Some have mental retardation
86
Cytomegalovirus Inclusion Disease
Advanced form of CMV (this severe form probably started during first trimester while most CMV occurs in the third trimester)
- Microphthalmia
- Microcephaly
- Hydrocephalus
- Chrioretinitis
- Hernia
- Hearing loss
- Mental Retardation
- Brain calcifications
87
Herpes
Specific structural abnormalities rare (microcephaly, growth restriction)
Primary herpes in the first and second trimester: miscarriage, rare cases of disseminated disease
Third trimester: disseminated disease, skin lesions
Baby can also contract herpes on the way out of womb
88
Zika virus
First case in 1952
Flavivirus- transmitted by infected mosquitos
Associated with microcephaly if infection in uterus— also calcifications and other brain normalities
89
Non-teratogenic infections
Hep B,C
Measles
Flu
Rhinovirus
Enterovirus
HIV
90
Considerations in evaluation of non-infectious teratogenic exposure
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Timing of exposure
Duration of exposure
Quantity (dose) of exposure
Teratogenicity of exposure
Maternal modulation
Access to embryo
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91
When is the worst time for a teratogenic exposure (in weeks post conception)?
Embryonic period (2-8 weeks post conception)
92
Fetal Alcohol Syndrome
CNS: mental retardation, microcephaly, poor coordination, hypotonia, irritability, hyperactivity
Growth Deficiency: prenatal and postnatal
Facial Characteristics: short palpebral fissures, upturned nose, hypoplasia philtrum, smooth, thin upper vermillion, hypoplasia maxilla, retr/microagnathia
Also: ptosis of eyelids, strabismus, ASD, low set ears, hypospadias, labial hypoplasia
93
Risk categories for Prescription Drugs
Category A: controlled human studies have demonstrated no fetal risk
Category B: either animal studies indicated no fetal risk and no human studies available, or adverse effects noted in animals but not in humans
Category C: no adequate studies are available but same drugs are the same as category A or B
Category D: evidence of fetal risk, but benefit may outweigh risk
Category X: proven fetal risk and contraindicated in pregnancy
94
Coumarin derivative (Warfarin)
Fetal warfarin syndrome if used in first trimester
Nasal hypoplasia, stipples epiphysis of bones (extra calcifications all over the place)
95
Thalidomide
Sedative given to pregnant women
Malformations: limb reduction (phocomelia)/ limb defects (only affects mesodermal origins)
96
Diethylstilbestrol
Synth estrogen to prevent pregnancy loss
Uterine anomalies (t-shaped uterus)
97
Androgens
-Masculinization of female fetuses
Not actually a problem because the mother can metabolize it well
98
Phenytoin (Dilantin)
Anti-epileptic medications
Fetal hydrantoin syndrome
Nail agenesis or hypoplasia
99
Valproic Acid
Anti-epileptic
Lumbosacral meningomyelocele (neural tube defect) 2-3%
100
Carbamazepine (tegretol)
Anti-epileptic
NTD (about 1%)
Similar findings as fetal hydantoin syndrome but not as common or severe
101
Isotretinoin (Retin A)
Used against severe acne
CNS: hydrocephalus, microcephaly, Dandy Walker cyst
SMALL OR NO EARS, microstoma, micrognathia, depressed nasal bridge, cleft palate
transposition of vessels, VSD, ASD, tetralogy
102
Lithium
First trimester use: malformations especially cardiovascular
Epstein anomaly
-poor development of the tricuspid valve
103
Ionizing Radiation during pregnancy
No risk of abnormalities until you hit a total dose of 10-20 RADs
Excess of 50 RAD significant risk
Most common abnormalities are microcephaly and growth restriction. Worse effects if exposure is earlier (2-8 weeks)
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Metabolic Abnormalities
Uncontrolled diabetes: cardiac malformations, NTDs, sacral agenesis
Maternal PKU: microcephaly, growth restriction, cleft lip/palate, mental retardation
105
Congenital Rubella Syndrome
Eyes: cataracts, glaucoma, microphthalmia, salt and pepper retinopathy
Heart: peripheral pulmonic stenosis, PDA, VSD, myocarditis
Head: microcephaly, encephalitis, mental retardation
Ears: deafness
BONES: radiolucencies of long bones (CALCIFICATIONS)
Other findings: hepatosplenomegaly, jaundice, pneumonia, hydrops fetalis
106
Should confidentiality be kept even when it affects other members of the family (example, mother tests positive for BRCA1 gene and daughter comes in)?
Yes; confidentiality even in this case is of the utmost importance
107
Beneficence/Non-maleficence
Beneficence (the greater good)— Help/act in the best interest of our patients and/or their families; put the interests of patients ahead of your own interests or that of third parties (insurers, managed care, etc.)
Non-maleficence (Do no harm)— Refrain from providing ineffective or inferior care (by act or by omission); refrain from acting with malice towards the patient
108
What is the ASHG’s position on breach of confidentiality?
Confidentiality may be breached and information shared with family members at risk for a genetic condition when:
- attempts to encourage disclosure on the part of the patient have failed
- the harm is likely to occur and is serious and foreseeable
- the at-risk relative is identifiable
- the disease is preventable, treatable, or medically accepted standards indicate that early monitoring will reduce the genetic risk
- precautions are taken to ensure that only the genetic info needed for diagnosis or treatment of aforementioned condition is disclosed
109
A man has adult onset muscle disorder. Did not seek prenatal testing but after birth asks for genetic testing to see if child will have it. How could this violate autonomy?
The condition is not onset until adulthood, so like the BRCA1 gene we do not usually test until the patient is of adult age. If we go ahead and do the test, we are in a way breaching the autonomy of the patient by forcing knowledge upon them via their parents.
Let the baby grow up and decide if they want to know.
“The right not to know”
110
Autonomy
Self-determination— making medical decisions free from controlling interferences by others
How do physicians demonstrate their respect for patient autonomy?
- Providing informed consent
- following patient wishes
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What are the challenges with informed consent?
- Complexity of genetic information
- complicated nature of clinical options such as pregnancy termination or prophylactic surgery
- The social and psychological implication of testing
- Unforseen information uncovered by testing such as non-paternity, results of unknown significance, incidental findings
- informed CONSENT vs. ASSENT
- appropriate age of consent?
112
Case: parents have a child with a recessive autosomal defect. Both parents agree to blood testing to see what the odds of having another affected child are. Turns out the husband is actually the father. What do you do? What does justice have to do with this?
The risk is definitely lower (the father is most likely not a barrier).
If you don’t tell them, then they will seek expensive genetic testing during each pregnancy
Telling only the mother might be considered a breach of Justice because the husband is being treated unequally (1983 case)
On the flip side, non-maleficence would say that families should not be broken up by genetic testing (1994 case)
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Genetic Information Nondiscrimination Act of 2008 (GINA) and Affordable Care Act (Obamacare)
If you get genetic testing and have a predisposition your premium can’t go up
If you are diagnosed with a condition, your premiums CAN go up
114
Who should undergo carrier screening?
- Individual without any phenotype but may have one pathogenic variant within a gene associated with diagnosis (BRCA1)
- Couples identifying information related to their risk of having a child with a specific disorder
- For AR disorders within specific ethnic or racial groups
- Expanded (Pan-ethnic) carrier screening: population admixture makes ethnicity a less reliable criteria for carrier screening; NGS panel
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Diagnostic Testing: confirmation
-Can’t be done to just anyone; they must already have symptoms
Ex) Prader-William syndrome 15q11 deletion/UPD/imprinting defects
- To confirms suspected diagnosis or phenotype
- to confirm a pathogenic variant causing the disease symptoms observed in patients
Ex) Acute Promyelocytic Leukemia (APL) PML/RARA fusion all-trans-retinoic acid (ATRA)/Arsenic Trioxide (ATO)
-Professional guidelines provide clinical significance of the testing genes or variations in daises diagnosis, prognosis, as well as treatment
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Restriction Fragment Length Polymorphism (RFLP)
A polymorphic difference in DNA sequence between individuals that can be recognized by restriction endonucleases.
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Give a few examples of trinucleotide repeat diseases. Do these ever contract in size? What is the etiology of Fragile X?
Fragile X, Huntington, Muscular Dystrophy type I
CGG expansion mutation on FMR1 gene; methylation of extended repeats always inhibits FMR1
Normal: <45 repeats
Grey Zone: 45-55 repeats
Premutation: 55-200 repeats
Full-mutation: >200 repeats
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What are some associated risks with Fragile X syndrome?
Anticipation— expansion of CGG repeats from inherited maternal permutation
FXPOI— fragile X associated primary ovarian insufficiency in female premutation carrier
FXPAS— tremor/ataxia in male premutation carrier
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What are some sequencing methods (that could be used to catch fragile X, for example)? What is Sanger Sequencing best for?
Sanger Sequencing (dideoxy method)— it takes a long time to do
Sequencing by gel electrophoresis
Sequencing by capillary electrophoresis (using laser, gel, detector, and computer)
Sanger is best used for single nucleotide changes
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Genetic variation spectrum
Sequence variation— single nucleotide change
Structural variation— from 2-1000bp (the larger the difference, the more easily it can be seen cytogenetically; otherwise, it must be done molecularly)
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Epigenetics and imprinting. What can cause it? Give examples of some diseases. Where do the problems occur in these diseases?
DNA methylation— this can happen more readily as number of trinucleotide repeats increase
Histone modification and other changes in chromatin
Repressor proteins that bind to silencer regions of DNA
Examples:
- Prader-Willi/Angelman— both 15q11-13
- Beckwith-Weidmann syndrome
- Russel-Silver syndrome
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Bisulfite conversion
Test for DNA methylation
Normally, converts all cytosine residues to thymine but will not convert methylated Cs.
PCR will then be run followed by gel electrophoresis or sequencing to determine where the methylated Cs are.
123
Describe methylation specific PCR for PWS and Angelman syndrome
PCR run for wild type genes and compared to patient’s. WT will have two bands. PWS will have only one band representing defective, maternal methylated band. Angelman will have only one band representing defective, paternal methylated band.
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What are the disease-causing mutations for Prader-Willi Syndrome and Angelman Syndrome?
```
PWS:
-Pat. 15q11-13 deletion (70%)
-Mat. Uniparental Disomy (UPD) (25%)
-Imprinting defect, de novo, and Robertsonian translocation (5%)
Deletion + UPD = 95% of PWS
```
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AS:
-Mat. 15q11-13 Delection (70%)
-Mat. UBE3A mutation (11%)
-Pat. Uniparental Disomy (UPD) (5-7%)
-Imprinting defect, de novo, and robertsonian translocation (5%)
Deletion + UPD = 77% of AS
```
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What are the advantages and disadvantages of FISH, Microarray, and Methylation-specific PCR in testing for PWS/AS?
FISH— can detect 15q11-13 deletions; cannot distinguish between PWS/AS
Microarray— can detect 15q11-13 deletions and heterozygosity status (UDP) but cannot distinguish between PWS/AS
Methylation-specific PCR— can distinguish between PWS/AS; cannot clearly distinguish deletions/UPD
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How can CGH and SNP arrays help diagnose a disease like PWS or AS?
CGH uses hybridization and can tell if there is a deletion or duplication of genetic sequences within the 15q11-13 segment (uses the colorful plate thing)
SNP uses enzymes to cut DNA segments that don’t have a SNP. If it does have an SNP it will not be cut and it will register are large amplitude signal. If one side has a SNP, the enzyme will cut some of the gene and it will register a medium signal
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What is the example of NGS over FISH and Chr when looking at fusion genes?
FISH and Chr only work when you know the fusion partners
NGS works even when you don’t know them (because it’s basically sequencing)
