Genetics/Repro
Terms
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copy deck
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Sample types for prenatal cytogenetic testing
Give:
1. risk of pregnancy loss
2. weeks -
Chorionic villi
(1) 1% (2)10-12 weeks
Amniotic fluid (most common; can pick up more DNA)
(1) 0.5% (2) 15-18 weeks
Percutaneous umbilical cord
(1) 2% (2) later in pregnancy
Products of conception-->amnion, chorion, villi, and fetal tissue *presence of maternal tissue can cause errors - tissues commonly used for postnatal cytogenetic testing
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1. peripheral blood
2. tissue: skin, pericardium, tendon
3. BM/core, LN, tumors
DO NOT FREEZE -
Define:
1. Euploidy
2. aneuoploidy -
1. Euploidy=loss or gain of entire chormosome set (46, 23, 69, etc)
2. aneuoploidy=loss or gain of less than an entire chromo set (tri or monosomy) - Aneuplody and live birth
- Types and proportions of aneuoploidies found between live and spontaneous birth are different. High degree of lethality even if compatible with birth.
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At what phases of meiosis does:
1. recombination occur?
2. independant assortment of homologues occur? -
1. recombination= prophase I
2. independant assortment= anaphase - Nondysjunction in meiosis I and II both end up with mono and trisomies, but how can you tell them apart?
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M I-->tri of three different chromos
M II-->tri of two same chromos and one from other parent - Mitotic nondysjunction: Mosaicism
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Three differnet cells lines: normal, trisomy, monosomy.
In many cases, monosomy does not survive. would have only two cells lines therefore: normal and trisomy.
At times, trisomy may not survive either. one cell line that is normal.
Extent is infuenced by survivability and timing. - Mosacism phenotypes: name two
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Gonadal=only in gonads; pheno normal but increased repro risk
Generalized=distributed thorugh body or confined to particular tissue. Pheno can range from normal to non-mosaic pheno if almost all cells. - anaphase lag
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Anaphase lag=one chromosome fails to migrate and is lost from the cell. Gametes are null and normal.
If occurs during meiosis II, will get mostly normal with one null.
If M I: two normal, two null. - anuploidy
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Loss or gain of less than an entire set of chormosomes (eu=23, 46, 69, etc)
Nondisjunction (gain and loss)
Anaphase lag (loss only)
Meiosis (all cells affected) vs Mitosis (mosaicism possible) - Most trisomies occur secondary to what?
- maternal meiosis I errors
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Abnormal recombination and its contribution to trisomies.
Monosomies are usally... -
Among pregnancies with trisomy 16, 21, or a sex chromosome trisomy:
--the number of recombination events is decreased and sometimes completely absent
--the placement or distribution of recombination events is altered.
Monosomies are usually paternal. NO AGE ASSN. -
Polyploidy
1. Tetraploidy
2. Failed cytokinesis
3. orgins of triploidy -
1. tetraploidy--very lethal; less than 10 liveborn
2. 46 chr-->fertilization-->triploid pregenancy with 69 chr.
3. most common orgin of triploidy is two sperm in normal egg - Relative risk for common trisomies.
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FOR COMMON TRISOMIES, RISK IS RELATED TO AGE
<35 years old = 1% (germline mosaicism?)
>35 years old = age related risk
Offer prenatal dx for all future pregnancies - FISH
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used to detect common aneuploidies
20-35% of chr. abnormalities go undetected - Structural chromosomal abnormalities
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--less common than numerical abnormalities
--more likely to occur during male meiosis
--more variable, many rearrangements are particular to a family or indiv.
--occur secondary to recombination between shared DNA sequences in nonallelic regions; high copy #, etc. - Parental karyotypes are always requested when a structural rearrangement is observed. Why?
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--Given an inherited mutation no increased risk.
--Given a new mutation risk is minimally 6-7%.
--May actually be unbalanced and they canÂ’t pick it up.
--Malsegregation
--counseling: emperic risk is 10% but changes with size, region, family history -
Clinical:
Floppy baby, eyes are slanting, white spots in periphery of iris = brush field spots, Ear is overfolded, Excess nucal syndrome, Single transverse crease, = sandal gap. Also can be seen if normal. - Down's syndrome
- Where did the extra chr 21 come from?
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3-4% are due to unbalanced Robertsonian translocations
Approx. 40% of which are inherited from a carrier parent. BUT carrier parent would have 100% recurrence risk Robersonian.
about 1-2% are mosaic with a normal cell line: mos 46,XX/47,XX,+21
Either post-zygotic non-disjunction event or trisomy rescue
In general a milder phenotype but cannot predict on an individual basis -
Clinical:
Growth retardation. Microcephaly. REMEMBER HAND FORMATION. CLENCHED HAND. Pointed ear and posteriorly rotated ears. -
Trisomy 18
--mean life expectancy is 4d
--most males die in utero, most long term survivors are female
--from maternal meiotic nondysjunction, 85% -
Clinical:
Growth retardation. Microcephaly. REMEMBER HAND FORMATION. CLENCHED HAND. Pointed ear and posteriorly rotated ears.
What are the other problems? -
Trisomy 18
Growth deficiency
VSD, ASD, TOGV, TOF, coarctation, pulmonic stenosis; _complex heart defects_,
Hydronephrosis, Wilms tumor, polycystic kidneys, ectopic kidney; _renal probl._
Thyroid and adrenal hypoplasia
Meckels diverticulum, hernias, omphlalocele -
Clinical:
Microcephaly, scalp defects, clefts, _microphthalmia_, _polydactyly_, cardiac defects, renal anomalies -
Trisomy 13
86% due in first year; MLifeExpectancy 130d
75% trisomy 13 from nondisjunction
20% translocations can be roberstonian
13;14 balanced carrier has 1% risk of unbalanced offspring
The 13;14 Robertsonian translocation!!!!!! is the most common ranslocation - THE MOST COMMON AUTOSOMAL TRISOMY IN HUMANS.
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Trisomy 16
do NOT survive to be liveborn -
Clinical:
Short stature, Lymphedema- puffiness, Gonadal dysgenesis,Coarctation of the aorta-more common genearlly in males, Nuchal webbing, Short 4th metacarpals
Intelligence normal, but often problems with spatial perception
Infertility a -
Turner's Syndrome
50% are 45, X
ther remainder have other abnormalities
risk of gonadoblastoma if has Y cell line
remove ovaries. -
Clinical:
Tall stature
Hypogonadism, Infertility-can present, 50% have Learning disabilities but normal IQ, Problems with socialization, Require testost supplem - Clinefelter syndrome 47, XXY
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Clinical: female, Above average stature,
Normal phenotype, Most have learning disabilities, Behavior problems common - Trisomy X; 47 XXX
- Clinical: Severe growth and mental retardation, Ocular hypertelorism-wide space btwn eyes, Cleft lip and palate, Cardiac anomalies
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4p minus syndrome
Wolf-Hirschhorn syndrome -
Clinical: High-pitched cry in infancy, Severe somatic and mental retardation
Microcephaly, increased inner canthal distance, downslanting palpebral fissures, epicanthal folds, ear anomalies, micrognathia-small jaw, round face, Congenital heart -
5p deletion syndrome
cri-du-chat syndrome - Microdeletion syndrome
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Average band size: approximately 3.5-5 Mb
Many deletions are submicroscopic
FISH techniques enable diagnosis
Most of these are multiple congenital anomaly syndromes caused by deletion of several genes - Velo-Cardio-Facial syndrome
- cleft palate, dysmorphic faces, slender hyperextensible fingers, cardiac abnormalities, learning disabilites, hypocalcemia,
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Prader-Willi syndrome--inherited from DAD!
chr 15
Short stature
Small hands and feet
Hypogonadism
Mental retardation, usually mild -
hypotonia
_feeding problems_
microdeletion syndrome
_in later childhood, onset of excessive appetite and obesity_ -
Angelman Syndrome--inherited from MOM!
chr 15 -
Supravalvular aortic stenosis
Pulmonary artery stenosis
Mental retardation, friendly personality
Microcephaly
Short stature
Seizures
Frequent unprovoked laughter
Severe mental retardation
Ataxia