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101 Cards in this Set
- Front
- Back
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Resolution of karyotype versus aCGH?
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Karyotype: 5-10 million bp
aCGH: 10-50 thousand bp |
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Benefits/detriments of aCGH
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Can run on stillbirth samples since don't need dividing cells
Can identify marker chromosomes Can't detect trisomy, inversions, or balanced translocations Can't detect mosaicism <20% Microdeletions and duplications <15% of the genetic disease burden |
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Risks associated with a balanced translocation in the mother?
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35% miscarriage
23-27% abnormal liveborn Smaller translocations more dangerous since can survive the extra or missing bits of DNA |
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Microdeletions and duplications at 16p11.2?
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Some susceptibility to autism
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Risks associated with a de novo marker chromosome?
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15-20% risk for congenital anomaly or developmental delay
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Percentage of stillbirths due to chromosome abnormalities
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30%
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Translocation:
Alternate segregation |
Homologous centromeres separate (as they should) at Meiosis I
Occurs with equal frequency to Adjacent I Get either a balanced translocation product or normal chromosomes |
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Translocation:
Adjacent 1 segregation (6 possible gametes from 3 options) |
Homologous centromeres separate (as they should) at Meiosis I
Occurs with equal frequency to Alternate Products contain duplications and deletions |
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Translocation:
Adjacent 2 segregation (6 possible gametes from 3 options) |
LEAST COMMON
Homologous centromeres don't split. They go to the same cell. Breakpoint so close to the centromere the cell can't distinguish which is which Get duplications and deletions |
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3:1 segregation is a nondisjunction event
(6 possible gametes from 3 options) |
Typically one derivative chromosome is very small
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Which are the acrocentric chromosomes? (can have Robertsonian translocations)
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13, 14, 15
21, 22 (21 smallest) |
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Incidence of reciprocal translocations in the population?
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0.1-0.5%
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When do homologous chromosomes pair?
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Pachytene
(Prophase I of meiosis) |
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What is the size of a microdeletion?
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Too small to visualize at the microscope
< 5Mb |
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Balanced and unbalanced nomenclature
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t(3;11)(q12;p15.4)
der(3)t(3;11)(q12;p15.4) deletion of 3q12 to q terminus duplication of 11p15.4 to terminus (and vice versa in other gamete) der(11)t(3;11)(q12;p15.4) deletion 11p15.4 to terminus dupl 3q12 to terminus If adjacent 1 segregation |
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Small pericentric inversions produce what?
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Large duplications and deletions when crossing over occurs
What's distal to the breakpoint is a large amount of genetic material Probably not viable |
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Large pericentric inversions produce what?
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Small duplications and deletions when crossing-over occurs
(at ends of arms distal to the breakpoints is duplicated material from SAME chromosome on both ends like shoelace caps) MORE DANGEROUS SINCE A BABY CAN BE BORN |
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Paracentric inversions
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Involve only one arm of the chromosome
Dicentric or acentric products when cross-over 1/2 of the gametes viable (for sperm) (Cross-over involves 2 of the 4 strands) Non viable and lost at mitosis |
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Pericentric inversions
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Surround the centromere, involving both arms of the chromosome
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Isochromosome
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Identical material duplicated on both sides of the centromere
i(12)(p10) |
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Ring chromosome
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r(14)(p11.2q32)
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Nomenclature for adding material from chromosome 4 (q12q25) to chromosome 20 at location q13.1
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ins(20;4)(q13.1;q12q25)
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Prader-Willi and Angelman location
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15q11.2
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Unbalanced product of this mother's inversion:
46,XX,inv(6)(p22.2q25.2) No semicolon since is on same chromosome |
46,XY,rec(6)dup(6p)inv(6)(p22.2q25.2)
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Prader-Willi
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Incidence 1/10,000 livebirths
SNRPN 75% deletion 25% maternal UPD (older mothers more prone) Very low recurrence risk unless imprinting control center mutation Failure to thrive, hypotonia Later: Obesity, hyperphagia MR Small hands + feet Hypogonadism Autistic-like features Short stature Fair complexion/hair |
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How can you detect uniparental disomy?
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SNP array
A form of loss of heterozgosity |
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Common pericentric inversions
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2, 9, 10, Y
inv(2)(p11.2q13) inv(9)(p11q13) inv(10)(p11.2q21.2) inv(Y)(p11.2q11.2) No phenotype. No unbalanced offspring. Too close to the centromere to get crossing over that will be detrimental. |
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Definition of a variant versus a polymorphism
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>1% of the pop is a polymorphism
(variants are <1%) |
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Microdeletion syndromes
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Velocardiofacial/DiGeorge
(22q11.2) Prader-Willi/Angelman (15q11.2) Smith-Magenis (17p11.2) Miller-Dieker (17p13.3) Cri du Chat or 5p- syndrome 5p15) Wolf-Hirschorn or 4p- syndrome (4p16) Williams syndrome (7q11.23) Langer-Giedion (8q24) 1p36 deletion syndrome (not strong phenotype) |
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How does UPD occur?
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MOST COMMON: Trisomic rescue
(mitotic error produces two copies of a male or female chromosome in the cell, accidentally kicks out the non-UPD of the trisomy) Monosomic rescue (doubles) Very rare |
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What should you think if see trisomy in the placenta?
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Could be UPD in the fetus after trisomic rescue
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Which chromosomes are imprinted, so it matters if there is UPD?
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6 (neonatal hyperinsulinism)
7 (growth restriction if maternal UPD) 11 (BW/Russell Silver) 14 15 (PW/Angelman) |
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What tissue do you get with CVS?
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Villi are derived from trophoblast (outside of blastocyst)
Cytotrophoblast with an outer layer of Syncytiotrophoblast (invaded uterine lining) =Direct preparation Mesenchymal core =Long-term culture (some labs only do this) |
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Why do both directs and long-term CVS culture?
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2 different cell types
Look for mosaicism Look for maternal cell contamination |
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Number of metaphases look at in CVS (don't get colonies)
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Direct: 5 (less reliable)
Sat o/n in colcemid Disaggregate with collagenase and trypsin Long-Term 20 metaphases from at least 2 independent cultures (pieces of villi) |
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Pseudomosaicism
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Artifact of culture.
Just a single cell or colony |
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Confined placental mosaicism
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Part of placenta mosaic
Fetus is not 2-3% of pregnancies? |
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Percentage of pregnancies miscarry in first trimester
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15-20%
50% of them chromosomally abnormal |
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Most common chromosome abnormalities in early miscarriage?
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Turner's syndrome
Trisomy 16 Triploidy |
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Complete mole
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HI LEVEL OF HCG
46,XX Chromosomes completely paternal Doubled up after fertilize empty egg Abnormal placenta grows/little or no fetus "Cluster of grapes" Risk of choriocarcinoma (X required for survival never see YY) |
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What's going on in light G-bands?
Dark G-bands? |
Light:
Gene-rich GC-rich Early replicating Dark: Low concentration of genes AT-rich Late replicating |
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Partial moles
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Triploid w/69 chromosomes
Typically due to dispermy (2 sperm fertilize) Abnormal cystic placenta/will have a fetus |
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Ovarian teratoma
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46,XX (like complete moles)
Maternal contribution only No placental development Mass contains hair, teeth, bone, etc. |
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Stats for the HAPLOID genome
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~20,000 genes
~3 billion base pairs of DNA 400 G-bands at metaphase 850 bands at prophase |
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Satellites
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Acrocentric chromosomes have small masses of chromatin attached to their short arms by narrow stalks
18S and 28S ribosomal RNA |
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Telomeres
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(TTAGGG)n
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Chance of chromosome abnormality in someone with MR and 3 or more birth defects?
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5.5%
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Chance of chromosome abnormality in couple with two or more first trimester miscarriages?
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2-5%
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Chance of chromosome abnormality in male with azoospermia?
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15%
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When do you do chromosome breakage analysis?
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Fanconi anemia
Ataxia Telangiectasia |
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What stage of cell cycle can you do FISH?
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Metaphase
Interphase |
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What color blood tube used for karyotyping?
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Green top
Sodium-heparin tube |
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What are the chromosomal breakage syndromes?
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Autosomal recessive
Defects in DNA repair mechanisms Increased risk for cancer Fanconi anemia Ataxia telangiectasia Bloom syndrome Xeroderma pigmentosum |
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Fanconi anemia
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Genes in FA-BRCA network
13 complementation groups A 66% B, C 10% Increased chromosome breakage Radial formations TKTK |
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Ataxia telangiectasia
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ATM gene
Increased spontaneous chromosome rearrangements Particularly chrom 7, 14 Leukemia in 9% Myelodysplastic syndrome 7% Solid tumor risk: Head, neck, skin, GI tract, genital tract |
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Bloom syndrome
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Mutations in BLM gene
Increased sister chromatid exchange rates |
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Xeroderma pigmentosum
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Cellular UV hypersensitivity
Unscheduled DNA synthesis |
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How do you write trisomy 21?
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47,XX,+21
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Down syndrome mechanism
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1/800-1/900 livebirths
85% spontaneously abort 95% extra chromosome: Majority nondisjunction at maternal meiosis I 4% due to unbalanced translocation (Robertsonian) 1% mosaic |
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Down syndrome features
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MR
Heart defects Hypotonia Flat nasal bridge Lowset ears, overfolded helix Epicanthal folds Transverse palmar crease Fifth finger clinodactyly Transient myeloproliferative disorder as a newborn Leukemia risk 15x |
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How many gametes can form from a Robertsonian translocation?
How many are viable? |
6 gametes
Half not viable 1 normal 1 balanced (the Robertsonian) 1 Trisomy 21 3 not viable |
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Translocation Down syndrome nomenclature
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46,XY,der(14;21)(q10;q10),+21
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Mother with a balanced Robertsonian translocation
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45,XX,der(14;21)(q10;q10)
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Chromosome Nomenclature
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t = translocation
der = Robertsonian translocation der(#)t(#;#)(breakpoint;breakpoint) Derivative chromosome named by origin of the centromere del = deletion dup = duplication inv = inversion i = isochromosome r = ring mar = unknown origin add = unknown material past a breakpoint |
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Down syndrome due to Robertsonian translocations
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Incidence 1/1000
60% involve chroms 13, 14, 15, +21 1/4 inherited 40% involve chroms 21 or 22, +21 90% of these are der(21;21) MOSTLY DE NOVO If inherited, all children will have Down syndrome |
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Recurrence risk for Robertsonian Down syndrome
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Maternal: 10-15%
Paternal: 1% |
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Trisomy 18 (Edwards syndrome)
47,XX,+18 |
1/7500 births
95% spontaneously abort 3:1 females Petite features MR Failure to thrive Heart malformations Prominent occiput, receding jaw, short sternum Malformed, lowset ears Short palpebral fissures Hypertonia Clenched fists 2/5 fingers overlap 3/4 Rocker-bottom feet Single palmar creases Hypoplastic nails |
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Trisomy 13 (Patau syndrome)
47,XX,+13 |
1/20,000-1/25,000
20% caused by unbalanced translocation Nondisjunction in maternal meiosis I MR, holoprosencephally Omphalocele Postaxial polydactyly Growth retardation Malformed ears, microphthalmia Cleft lip and palate Postaxial polydactyly Clenched fists Rocker-bottom feet Heart defects Polycystic kidneys Scalp defects Cryptorchidism |
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Mosaic trisomies
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Trisomy 8
Trisomy 9 Trisomy 22 mosaicisms can live |
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Turner syndrome 45,X cytogenetics
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1/5000 to 1/2500 female births
99% miscarry MOST COMMON abnormality in SABs 45,X = 50% 15% are mosaic with 46,XX 15% are 46,X,i(X)(q10) 5% are mosaic with 46,X,i(X)(q10) Xp is therefore important!!! Small r(X) lacking XIST have association with MR |
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Features of Turner syndrome
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Short stature, webbed neck
Low posterior hairline Streak gonads Broad chest, widely-spaced nipples Kidney and Heart anomalies Edema of hands and feet as newborn Shortened 4th metacarpal Normal intelligence: Verbal>Nonverbal |
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Klinefelter syndrome 47,XXY
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1/1000 male births
Hypogonadism at puberty Need testosterone treatments Gynecomastia, infertility Normal intelligence 1/2 result from nondisjunction error in PATERNAL meiosis I 15% mosaic 47,XXY/46,XY |
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Which syndrome results from PATERNAL nondisjunction at meiosis I?
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Klinefelter syndrome 47,XXY
(XY go into same sperm) |
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Which syndrome results from PATERNAL nondisjunction at meiosis II?
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47,XYY
(YY go into the same sperm) |
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47,XYY
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1/1000 male births
Paternal nondisjunction at meiosis II (YY sperm) Fertility normal Tall Increased risk of school and behavior problems No increased risk for chrom abnormalities in children |
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47,XXX
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1/1000 female births
Tall Normal intelligence Some learning difficulties Increased risk for chrom abnormal offspring Normal fertility |
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X-inactivation: When?
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Lyonization
Late blastocyst Random Nearly complete Permanent and clonal Inactive X: Barr body, late-replicating Differential methylation |
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Mechanism of X-inactivation
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X Inactivation Center (XIC)
Xq13.2 XIST expressed by INACTIVE chromosome Untranslated RNA Associated with macroH2A histone modification in heterochromatin |
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If X translocation with an autosome, what happens to X-inactivation?
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If BALANCED
Skewed to preserve those autosomal genes as active If UNBALANCED Shuts down the X with the extra or missing material |
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Williams syndrome and its "opposite"
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Williams syndrome
Deletion (7q11.23) Chatty, cocktail-party personality Duplication 7q11.23 Severe expressive language delay |
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What does every kid with a heart defect get tested for?
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FISH for 22q11.2 deletion
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Where do microdeletions come from?
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Nonallelic homologous recombination
At low copy number repeats flanking the genes Produces duplications and deletions |
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22q11.2 deletion syndrome
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1/4000
USUALLY SPORADIC (14% of parents have it) 3 Mb deletion typical del(22)(q11.2q11.2) 5% of all congenital heart disease Abnormal development of 3rd and 4th pharyngeal pouches (thumus and parathyroids) Abnormal 4th branchial arch (great vessels of the heart) |
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Features of 22q11.2 deletion syndrome
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Long face
Lateral buildup on nose Long TAPERING fingers Anxiety Psychiatric issues (schizophrenia) |
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Williams syndrome and its "opposite"
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Williams syndrome
Deletion (7q11.23) Chatty, cocktail-party personality Duplication 7q11.23 Severe expressive language delay |
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What does every kid with a heart defect get tested for?
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FISH for 22q11.2 deletion
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Where do microdeletions come from?
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Nonallelic homologous recombination
At low copy number repeats flanking the genes Produces duplications and deletions |
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22q11.2 deletion syndrome
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1/4000
USUALLY SPORADIC (14% of parents have it) 3 Mb deletion typical del(22)(q11.2q11.2) 5% of all congenital heart disease Abnormal development of 3rd and 4th pharyngeal pouches (thumus and parathyroids) Abnormal 4th branchial arch (great vessels of the heart) |
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Features of 22q11.2 deletion syndrome
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Long face
Lateral buildup on nose Long TAPERING fingers Anxiety Psychiatric issues (schizophrenia) |
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FISH nomenclature
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Metaphase:
46,XX.ish 22q11.2(TUPLE1x2) 46,XX.ish del(22)(q11.2q11.2)(TUPLE1-) If only looked at this, not all chroms: ish 22q11.2(TUPLE1x2) If interphase: nuc ish(TUPLE1)x2 If can see by eye: 46,XX,del(22)(q11.2q11.2) |
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Subtelomeric FISH
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Ends of chromosomes gene-rich
Look similar on G-banding, hard to see deletions ~1% MR has cryptic rearrangement |
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What size deletions/duplications do labs report on aCGH?
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~200-500 Kb
Competition between patient and control DNA |
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What do you do if see an abnormality on aCGH?
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Go to genome browser, see if any genes there
Check databases of known CNVs Check the parents to see if they share it |
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Isodicentric chromosome nomenclature
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idic
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Charcot-Marie-Tooth neuropathy type I (CMT1)
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1/2500
Autosomal dominant Can be a PMP gene duplication at 17p12 80% of CMT1 have PMP duplication Distal muscle weakness and atrophy Sensory loss Slow nerve conduction Pes cavus deformity Bilateral foot drop (5-25 years of age) |
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Hereditary Neuropathy with liability to pressure palsies (HNPP)
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Autosomal dominant
PMP gene deletion at 17p12 Pressure neuropathies Carpal tunnel syndrome Mild Presents in 2nd or 3rd decade of life Unequal crossing-over between flanking low copy number repeats creates this and CMT1 |
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First trimester spontaneous abortions
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15-20% pregnancies miscarry
>50% are chromosomally abnormal Mostly aneupoloidies Turner syndrome most common Trisomy 16 Triploidy |
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What if CVS is trisomic for chromosome 15?
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Offer an amnio with:
Chromosome studies UPD studies |
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Can you do fragile X testing on CVS?
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Methylation studies are not reliable on CVS
Better to do an amnio |
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What if see trisomy 16 in the placenta?
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Is confined mosaicism
Risk of IUGR Preeclampsia |
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Microsatellites
Minisatellintes VNTR's |
Microsatellites: 2-5 bp repeats
=Short tandem repeat polymorphisms (STRPs) Can change when polymerase stutters Hairpin loop forms Or through unequal recombination Minisatellites: 10-100 bp repeats =Variable number of tandem repeats (VNTRs) |
