Cytogenetics: Lect 20 and 21 Flashcards
Classifying chromosomes:
- total length of chrom
- position of centromere
- presence of satellites
Chromosomal abnormalities:
2 types?
-account for a large number of spontaneous abortions.
- numerical
- structural
Numerical chrom abnormalities:
- Euploidy (polyploidy): no. of chrom is in multiples of 23
- Triploidy: 3 copies of each chrom (69) incompatible w/ life
- Tetraploidy: 4 copies of each chrom (92) lethal
- Aneuploidy:
- monosomy: loss of a chrom. Incompatible w/ life except Turner synd/monosomy X
- trisomy: presence of additional chrom
Chromosomal aneuploidy:
Autosomal trisomy
- trisomy 21 (Down synd)
- trisomy 18 (Edward synd)
- trisomy 13 (Patau synd)
Sex chrom aneuploidy:
- Turner synd (45,X)
- Klinefelter synd (47,XXY)
Trisomy 21: Down syndrome
- 47, XY+21
- most common liveborn autosomal trisomy
- risk factor: incr. maternal age, incr risk of meiotic nondisjunction during oogenesis (Meiosis I)
- intellectual disability, short stature, depressed nasal bridge, upslanting palpebral fissures, epicanthal folds, congenital heart defects, changes similar to Alz disease at young age (gene factors for Alz is on chrom 21)
- seen in FISH and Karyotype
Trisomy 18: Edward syndrome
- 47,XY,+18
- nondisjunction during oogenesis
- clenched fist, overlapping fingers, rocker bottom fee, congenital heart defects, low set ears, small lower jaw, microcephaly and intellectual disability.
Trisomy 13: Patau syndrome
- 47,XX,+13
- nondisjunction during oogenesis.
- polydactyly, cleft lip/palate, microphthalmia, microcephaly, intellectual disability, cardiac anomalies.
Sex Chromosme Aneuploidy:
- Turner Syndrome:
- 45,X = no Barr body
- nondisjunction during meiosis
- X chrom monosomy, short stature, webbed neck, cystic hygroma at birth(neck swelling), primary amenorrhea, gonadal dysgenesis, streak ovaries.
- some cells are 45,X and others are 46XX and 47XXX (mitotic nondisj during embryogenesis)
- Klinefelter syndrome:
- 47,XXY; presence of Barr body
- nondisj during meiosis
- testicular atrophy, gynecomastia, female distribution of hair, infertility.
- may be caused by nondisjuc during meiosis I or II in mom or meiosis I in dad.
Nondisjunction:
- most common in meiosis I females.
- indivs w/ Downs have 2 maternal chrom 21 and 1 paternal chrom 21.
XYY fetus result of?
-meiosis II nondisjunc in dad
XXX females result of?
-meiosis I or II in moms or meiosis II in dad.
non-disjunction during embryonic development?
-occurs as a post-zygotic event.
Structural chromosomal abnormalities:
- Balanced: no gain/loss of genetic material
- Unbalanced: gain/loss of genetic material.
- Translocations (reciprocal or Robertsonian)
- Deletions
- Inversions
- Ring chromosome
- Isochromosome
Reciprocal translocation:
- exchange of genetic material between non-homologous chrom.
- in somatic cells, effects may transform to cancer and incr growth rate of cells or may be silent.
- –ex: activation of an oncogene. Phil chrom t(9:22)>activation of ABl = chronic ML. Burkitt’s lymphoma= T(8:14).
-in germ line cells; higher incidence of spontaneous abortions in carrier.
Robertsonian translocation:
- occurs btwn acrocentric chrom
- chrom 13, 14, 15, 21, 22
- loss of the short arms of the two chroms and fusion of the long arms.
- Alternate segregation: balanced chrom material (1 nl gamete and 1 carrier)
- Adjacent segregation: unbal chrom material (parital trisomy) on fertilization. (trisomy 14 “incompatible w/ life = spont abortion” and trisomy 21 ‘Down synd”).
- accounts for 2-3% of Down syndrome
Microdeletion Syndromes:
- large deletions >4Mb; Wolf-Hirschhorn and cri du chat (detected by cytogenetic studies)
- small deletions
Indications for Cytogenomic testing:
- deletion or duplication syndrome.
- Unexplained developmental delay or autism
- congenital anomalies/dysmorphic features.
-array CGH or SNP does not detect balanced rearrangements.
Cri-du-Chat syndrome:
- deletion of chrom 5p
- high pitched cat-like cry, severe intellectual disability, speech problems, microcephaly.
- FISH and CGH for diagnosis
22q11 Deletion syndrome
- Velocardiofacial/DiGeorge syndrome
- most common microdeletion disorder in humans
- microdeletion of chrom 22q
- congenital heart defects, absence of thymus, cleft lip/palate, prominent nasal root, learning disability, incr. risk for schizophrenia.
Wolf-Hirschhorn syndrome:
- deletion of chrom 4p
- facial anomalies: widely spaced eyes, prominent nose, abnormal iris, cardiac anomalies, intellectual/development delay.
WAGR syndrome:
- small-microdeletions;
- Wilms’ tumor, aniridia, GU malformations and retardation of growth and development.
Deletions in chrom 15:
- Angelman: deletion of maternal chrom 15q11
- Prader-Willi: deletion of paternal chrom 15q11
Inversions:
- may be pericentric (involves the centromere) or paracentric (does not involve the centromere).
- usually balanced & no clinical probs in carriers.
- result in change in banding pattern of chrom seen via Karyotype analysis.
- gametes w/ acentric and dicentric chrom are not viable.
- carriers of inversions may be asymptomatic but w/ high risk of spont abortions.
Isochromosomes:
- loss of one arm of a chrom and duplication of the other arm
- results in chromosomal and gene dosage imbalance.
- in some children w/ Turner synd; w/ inactivated X isochrom.
Ring chromosomes:
-forms when a chrom loses genetic material at the terminal portions and the ends fuse to form a ring like structure.
