Exam 2: Lecture 31 Flashcards
(22 cards)
What is aneuploidy?
2N+1–> Trisomy
2N-1 –> monosomy
What are causes of aneuploidy?
-non-disjunction: failure of homologous chromosomes or sister chromatids to separate during meiosis
- Mosaicism–> post-zygomatic mitotic nondisjunction leads to 2 or more cell lines with different karyotypes; clinical severity depends on proportion of abnormal cells and which tissue its in
What etiology can lead to structural chromosome variants?
DNA repair mechanism
1) Non-allelic homologous recombination–> happens during recombination; misalignment can happen and undergo recombination leading to deletions
- translocations can happen on NAHR
2) Nonhomologous end joining–> repairs double strand breaks by putting it together without a template; mistake prone; can lead to deletions at the site
- can generate translocations if 2 chromosomes have a break at the same time –. can mistakenly joining ends from diff chromosomes together
Describe the types of chromosome structural variants
- deletion
- duplications
- inversion
- insertion
- translocation
Describe the type of translocations one can have
- structural rearrangements
- reciprocal translocation: involves any chromosomes
- Robertsonian translocation: involves acrocentric chromosomes (have centromere at the top), 13. 14. 15. 21. 22 –> p arm is loss of both acrocentric chromosomes and both q arms fuse, forming a single chromosome composed of both acrocentric chromosomes
Common aneuploidies compatible with life
1) 47, XY, +21 (Down syndrome)
2) 47, XX, +13 (Patau Syndrome)
3) 47, XY, +18 (Edwards Syndrome)
4) 47, XXY (Klinefelter Syndrome)
5) 45, X (Turner Syndrome)
- gene dosage effect:
- most extra chromosomes are smaller in size
- X inactivation affects expression
- variability exist with other genes playing into their phenotype
Trisomy 21, Down syndrome clinical features
- intellectually disability (mild to moderate)
- characteristic facies:
single palmar crease, clinodactyly, wide space 1st and 2nd toe - hypotonia (decreased muscle tone)
- congenial heat defects (AV septal defect, VSD)
- duodenal atresia (blockage od duodenum- small intestines)
- female may reproduce; males typically are infertile
- increased risk for leukemia and early onset of Alzheimer
- median age for death 47
Trisomy 18, Edward’s syndrome clinical features
- clinched fingers with overlapping fingers
- prominent occiput (back part of the skull), micrognathia (lower jaw is smaller than usual)
- curl to the heel that looks like a rocker (Rocker- bottom feet)
- severe intellectual disability
- shield chest- barrel chest with wide set nipples or short prominent sternum
- Kidney abnormalities: horseshoe kidney
- congenial heart defects
- life expectancy: typically, a few days; most < one yr
Trisomy 13, Patau syndrome
- severe CNS defects (midline defect)
- severe intellectual disability
- microphthalmia (small eyes), cleft/lip. polydactyly (extra finger)
- congenial heart defects
-renal defects - scalp defects (cutis aplasia)–> missing skin and lack of hair growth
What etiology is common with trisomy syndromes?
- mosaicism
- meiotic non-disjunction
- translocation with down syndrome and Patau
Which trisomies usually end in miscarriage?
- Edwards syndrome
- Patau syndrome
Maternal age is a risk of down syndrome
Segregation of Robertsonian Translocation
Sex Chromosome Aneuploidy
- phenotypes are typically less severe than autosomal aneuploidy due to X inactivation and low gene content on the Y chromosome
- common Sex chromosome trisomy and monosomy –> XXY, XXX, XYY, X
Klinefelter syndrome (XXY)
- extra X chromosome
- common cause of primary testicular failure
- tall stature, long limbs
- hypogonadism: low testosterone and infertility (azoospermia–> no sperm produced)
- gynecomastia ( breast development, wide hips, female type pubic hair pattern)
- learning and psychosocial difficulties
- Lab findings: decreased testosterone and inhibin B, increase FSH, LH, and estrogen
- management: testosterone replacement, fertility counseling
Turner Syndrome, 45, X
- short stature
- transient congenital lymphedema (causes puffy hands/ feet, webbed neck)
- cystic hygroma webbed neck (fluid filled sac on the back of neck.. causing webbed neck appearance)
- low posterior hairline
- cubitus vulgus (abnormal bending of the elbow)
- cardiac anomalies
thyroid disease - normal IQ
- gonadal dysgenesis, ovary (streak gonads)
- gonadal dysgenesis; amenorrhea, delayed maturation, infertility
- reduced estrogen levels with compensatory elevation on LH and FSH
- treated with estrogen replacement to undergo menses and can possible get pregnant with reproductive technologies
Why is the recurrence risk for Turner lower than 1%
- father is the one who didn’t give X chromosome (nondisjunction and missing sex chromosome is paternal in nature)
- nondisjunction
Turner syndrome: mosaicism and 46 XY
- you can have a Y chromosome and have turners, those who have it are at risk of getting gonadoblastoma
- female sex organs are produced, but may get a gonadoblastoma
- tumor with different type of gonadal tissue
- patient should be screened
Microdeletions/ duplication syndromes
- deletion or duplication of multiple genes at closely linked loci
- may be visible cytogenetically, but are only visible using FISH or aCGH
- 2 common microdeletions syndromes” 22q11.2 deletion syndrome ( DiGeorge Syndrome or Velocardiofacial syndrome)) and Cri du Chat syndrome (5p-_
22q11.2 deletion - DiGeorge’s Syndrome
- clinical heterogeneity –> not all individuals will exhibit conditions in the same way
- 22q11.2 deletions (involves 50 genes)
- includes cardiac anomolies
- cleft palate
- congenial heart defects (conotruncal anomolies)
- nasal sounding speech pattern
- mild facial
- fullness of eye-lids–> looks hooded
- broad nasal bridge with tubular nose
- round ears with thick over folded helixes and low set
- parathyroid hypoplasia–> hypocalcemia
- developmental delay, psychiatric disorders
CATCH -22
C –> cardiac
A –> atypical facies
T –> thymic hypoplasia
C–> cleft palate
H–> hypocalcemia
Cri du chat (5p-) hint: picture a cat with the tip of their tail clipped
- deletion of lower tip of chromosome 5–>not all individuals have the same size of the deletion, so different severities
involes up to 100 genes - high pitched, cat- like cry in infancy
- microcephaly, round face, hypertelorism
- severe intellectual disability
- hypotonia, failure to thrive
Describe the recurrence risk of microdeletion
- typically de novo
- 22q11. 2 deletion can be inherited ( 50% autosomal dominant)
- inherited from balance translocation carrier parent ( 10-15% if parent has balanced location–> Cri du chat
