Cytogenetics, FISH and MCA Flashcards
Down Syndrome causes
-mostly meiotic errors (95%) \+increased risk with advanced maternal age -robertsonians (3-4%) -mitotic errors (1-2%) * ~1% recurrence risk
life expectancy in Down Syndrome
now about 60y, greatly increased from 9y
-can see early death in 10-20% affected individuals related to severe cardiac anomalies
complications associated with Down syndrome
-cardiac defects (40%) \+mostly A-V canal -GI anomalies (~5%) \+duodenal atresia/stenosis most common -increased leukemia risk (15-20 fold) -Alzheimer's disease for most affected adults
Down syndrome incidence
- 1 in 700 live births
- 75% of SABs
Trisomy 18 phenotype
- SGA
- overlapping clenched fists and rocker bottom feet
- micrognathia and severe ID
- hyper or hypotonia
- severe renal, GI or cardiac anomalies (95%)
Trisomy 18 incidence
- 1 in 5000-1 in 8000 live births
- 4:1 F:M sex ratio
- extremely low survival, 90% affected infants die within the first year of life, 95% result in SAB
Trisomy 13 phenotype
-FTT + hypotonia
-holoprosencephaly
+micro or anopthalmia
+severe ID
+clefting
-cardiac defects
-polydactly
Trisomy 13 incidence
- 1 in 10000-1 in 15000 live births
- 90% die within first year of life, 95% results in SAB
- 20% caused by robertsonian translocation
X inactivation
- reversible in germ cell development
- 15% of X-linked genes escape this
Turner syndrome incidence and causes
-incidence 1 in 1500-1 in 5000 live births-variable by study
+1 in 30-1 in 50 female conceptuses (3%) w/94% resulting in SAB
-extremely low recurrence risk & several chromosome and mutation arrangements that cause it (50% 45, X)
+2/3 retain maternal X chromosome
Klinefelter incidence
- 1 in 500- 1 in 600 newborns
- no recurrence risk
- 50% due to paternal meiosis I errors
48 XXYY
similar to Klinefelter but with more severe ID and 90% risk for dicentric chromosome w/Robertsonian
Klinefelter phenotype
- small testes after puberty, gynecomastia, sparse facial hair, low fertility d/t fibrosis of seminiferous tubes
- hypotonia
- scoliosis + “Euchenoid habitus”
- low to normal IQ, rarely ID, LD/reading disability related to language processing and verbal memory
Turner phenotype
-short stature, broad chest, webbed neck
-primary amenorrhea, gonadal dysgenesis (90%)
-cardiac anomalies (40-60%)
+coarctation of the aorta
-renal anomalies (greater than 60%)
-hand and foot edema
robertsonian translocations
- fusion between acrocentric chromosomes (13, 14, 15, 21, and 22)
- 90% dicentric, p arms usually not involved
- usually get homologous chromosomes from one parent-risk for UPD higher
- usually associated with trisomy
paracentric inversion
-no centromere involvement
-usually only in part of long arm or short arm
-usually only gives acentric or dicentric fragments
+lower risk to have unbalanced offspring
reciprocal translocation
- mutual exchange of material between two non-homologous chromosomes
- leads to increased risk for fetal loss and children with problems
- occurs in 1 in 500 individuals
pericentric inversion
-centromeric involvment
-involves material on both long arm and short arm
-can result in recombination and unbalanced offspring
+can result in duplication and deletion of material
meiotic segregation with reciprocal translocations
- not like normal homologous chromosome line-up
- all chromosomes interconnect and create a 4-way junction
alternate segregation
always results in normal outcome because two normal and two translocated chromosomes go together
-one of the most common types of segregation
adjacent 1 segregation
chromosomes on same side of horizontal axis pair
-another of the most common types of segregation, can result in normal outcomes depending on chiasma placement
adjacent 2 segregation
chromosomes on same side of vertical axis pair
-always gives abnormal outcomes
3:1 segregation
always causes abnormalities because 3 chromosomes pair together and one is alone
risk of unbalanced segregates
~11-12%, but depends upon the ascertainment of the translocation
- if a previous child is affected, recurrence risk is about 20%
- if multiple SABs, risk might be lower because affected babies can’t survive
robertsonian incidence
- relatively common-1 in 1000 individuals
- rate of inheritance depends on the translocation and the parent it was inherited from
rob(13q14q) and rob(14q21q)
most common robertsonian translocations
risk of unbalanced segregates in robertsonian carriers
based on empiric, not theoretical risk
female carrier of rob(14q21q)
15-20% empiric risk for unbalanced segregants
male carrier of rob(14q21q)
2% empiric risk for unbalanced segregants
female carrier of rob(13q14q)
1% empiric risk for unbalanced segregants
male carrier of rob(13q14q)
<1% empiric risk for unbalanced segregants
X-inactivation mechanisms
- altered chromatin structure by CpG island methylation
- X inactivation center at Xq13.2
XIST
RNA specifically produced by XIC from the initially inactivated X chromosome for initiation and continuation of X inactivation
de novo translocations
related to increased risk for ID and congenital anomalies
+20% newborns with these
+55% individuals with ID with these
+3 in 1000 individuals with ID have these
clinical effects of de novo translocations
- position effects; genes turned off or on
- breakage within a gene; ex: DMD
- del/dup requiring FISH or MCA
- UPD
risk of phenotypic abnormality in de novo translocation
6-8% of all fetuses based on empiric data
Fluorescent In-Situ Hybridization (FISH)
-metaphase cells, interphase nuclei
-prepared like karyotype, but tagged probes can hybridize to region of interest in interphase cells
+have to know what is being looked for
contiguous gene syndrome/segmental aneusomy/microdeletion syndromes
deletion of chunk of DNA, including multiple genes on a chromosome physically close to one another of unrelated function
detection of CGS
- if 5-10Mb del-400-500 band resolution
- if 2-5Mb del-1000 band resolution
- if <2Mb need array or FISH
3Mb deletion
equivalent to loss of 10-100 genes
percutaneous umbilical blood (PUBs)
sampling of fetal blood from umbilical cord
FISH limitations
- labor and time intensive to design multiple probes
- expensive to design new probes
- requires specified probe and knowledge of specific genome site of interest