Genomic Medicine/Dysmorphology Flashcards
Karyotyping
G-banding
5-10 Mb resolution
Detects aneuploidy, large insertions/deletions, translocations, inversions
Whole genome, low resolution
* good for detecting balanced translocations
FISH
- targeted detection of deletions, duplications, and translocations on chromosomes
- does NOT detect small insertions, deletions, or inversions
SKY
spectral karyotyping
FISH probes to lots of parts of every chromosome
great to detect interchromosomal aberrations
aCGH
analytical sample vs reference
hybridize to see amplification or deletion (won’t overlap)
- number of DNA elements determines resolution
- can’t detect structural chromosomal aberrations that don’t have a copy number change
- Copy number variation
CMA
- aCGH: copy number variation
- oligo/SNP: copy number and genotype info
- strength determined by amount of targets sample binding to probes
- resolution determined by number of probes used and their distribution through genome
- SNP arrays: perfect matches for each one of possible alleles
- UPD, LOH, consanguinity
Exome/targeted sequencing and whole genome sequencing
best resolution, but lots of unusable data, high data storage demand
genetic individuality
genetic variability between individuals that underlies phenotypic variation
sequence coverage
average number of sequencing reads that align to each base within the sample DNA
analytic validity
how accurately and reliably test measures genotype of interest
clinical validity
how consistently and accurately the test detects or predicts the intermediate or final outcomes of interest
clinical utility
how likely the test is to significantly improve patient outcomes
variation of normal
> 4% population, no medical concern
minor malformation
<4% population, no medical concern
major malformation
functional or cosmetic significance
malformation
intrinsic defect in development
disruption
formed normal, then something destroys it
deformation
formed normal, then something deforms it
malformation syndrome
predictable pattern
i.e. Down Syndrome
malformation sequence
primary malformation causes several secondary malformations (not related pathogenically)
Robin malformation sequence
association
- abnormalities that occur together but are not obviously related in terms of pathogenesis, no known genetic cause
(VACTERL association: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities)
pathognomonic
sign or symptom is so characteristic of a disease that it makes the diagnosis
- there is virtually no clinical finding that is pathognomonic for chromosome abnormalities, much variation
common finding in triploidy
fused 3rd and 4th fingers
Age 35 and advanced maternal age
risk of detecting DS by amniocentesis or chorionic villus sampling is greater than procedure-related risk of miscarriage
Causes of spontaneous abortions
- trisomies 60%
- monosomies 15% (Turner, X0)
- triploidy 15%
- trisomy 16 most common
*
Balanced translocation gametes
Alternate: two balanced
Adjacent I: two unbalanced and smaller loss of material
Adjacent II: two unbalanced and large loss of material
Robertsonian translocation gametes
1 balanced and normal
1 balanced but abnormal
one trisomy and one monosomy (in two different ways)
Age 35 risk of any chromosomal abnormality
1/200
Risk of trisomy 21 for 35 and 20 year old
1/250, 1/1660
6 structural congenital anomalies seen with US and association with chromosomal abnormality
- cystic hygroma 60-75%
- non-immune hydrops: 30-80%
- holoprosencephaly 40-60%
- cadiac defects 5-75%
- omphalocoele 30-50%
- diaphragmatic hernia 20-25%
Detection for chromosome abnormalities with US
Trisomy 13 and 18: 90%
Down Syndrome: 60-80%
First trimester screening tests
hCG, PAPP-A
US measure of nuchal translucency
Detection for DS is 79-85%
Second trimester screening tests
AFP, UE3, inhibin A (DIA), hCG
Detection for DS is 76-81%
NO/weak association with chromosome abnormality when seen on US
hydranencephaly, gastroschisis
background risk for major congenital anomalies
2-3%
Maternal medical problems that cause fetal abnormalities
diabetes, seizure disorder, congenital adrenal hyperplasia
amniocentesis
15-20 weeks gestation
1/200 risk loss rate
2.5% pregnancy loss after early amniocentesis
incidence of clubbed feet higher, membrane rupture
CVS
after 9 weeks gestation
screening test
gives risk percentage, not yes or no
Commonly seen on US with high sensitivity but not necessarily correlated with chromosomal abnormalities
Open neural tube defects: 95%
congenital heart disease: 90%
renal abnormalities: 90%
