Genomic Medicine/Dysmorphology

Question 1

Karyotyping

Answer 1

G-banding
5-10 Mb resolution
Detects aneuploidy, large insertions/deletions, translocations, inversions
Whole genome, low resolution
* good for detecting balanced translocations

Question 2

FISH

Answer 2

• targeted detection of deletions, duplications, and translocations on chromosomes
• does NOT detect small insertions, deletions, or inversions

Question 3

SKY

Answer 3

spectral karyotyping
FISH probes to lots of parts of every chromosome
great to detect interchromosomal aberrations

Question 4

aCGH

Answer 4

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

Question 5

CMA

Answer 5

1. aCGH: copy number variation
2. 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

Question 6

Exome/targeted sequencing and whole genome sequencing

Answer 6

best resolution, but lots of unusable data, high data storage demand

Question 7

genetic individuality

Answer 7

genetic variability between individuals that underlies phenotypic variation

Question 8

sequence coverage

Answer 8

average number of sequencing reads that align to each base within the sample DNA

Question 9

analytic validity

Answer 9

how accurately and reliably test measures genotype of interest

Question 10

clinical validity

Answer 10

how consistently and accurately the test detects or predicts the intermediate or final outcomes of interest

Question 11

clinical utility

Answer 11

how likely the test is to significantly improve patient outcomes

Question 12

variation of normal

Answer 12

> 4% population, no medical concern

Question 13

minor malformation

Answer 13

<4% population, no medical concern

Question 14

major malformation

Answer 14

functional or cosmetic significance

Question 15

malformation

Answer 15

intrinsic defect in development

Question 16

disruption

Answer 16

formed normal, then something destroys it

Question 17

deformation

Answer 17

formed normal, then something deforms it

Question 18

malformation syndrome

Answer 18

predictable pattern

i.e. Down Syndrome

Question 19

malformation sequence

Answer 19

primary malformation causes several secondary malformations (not related pathogenically)

Robin malformation sequence

Question 20

association

Answer 20

• 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)

Question 21

pathognomonic

Answer 21

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

Question 22

common finding in triploidy

Answer 22

fused 3rd and 4th fingers

Question 23

Age 35 and advanced maternal age

Answer 23

risk of detecting DS by amniocentesis or chorionic villus sampling is greater than procedure-related risk of miscarriage

Question 24

Causes of spontaneous abortions

Answer 24

1. trisomies 60%
2. monosomies 15% (Turner, X0)
3. triploidy 15%

• trisomy 16 most common
  *

Question 25

Balanced translocation gametes

Answer 25

Alternate: two balanced
Adjacent I: two unbalanced and smaller loss of material
Adjacent II: two unbalanced and large loss of material

Question 26

Robertsonian translocation gametes

Answer 26

1 balanced and normal
1 balanced but abnormal

one trisomy and one monosomy (in two different ways)

Question 27

Age 35 risk of any chromosomal abnormality

Answer 27

1/200

Question 28

Risk of trisomy 21 for 35 and 20 year old

Answer 28

1/250, 1/1660

Question 29

6 structural congenital anomalies seen with US and association with chromosomal abnormality

Answer 29

1. cystic hygroma 60-75%
2. non-immune hydrops: 30-80%
3. holoprosencephaly 40-60%
4. cadiac defects 5-75%
5. omphalocoele 30-50%
6. diaphragmatic hernia 20-25%

Question 30

Detection for chromosome abnormalities with US

Answer 30

Trisomy 13 and 18: 90%

Down Syndrome: 60-80%

Question 31

First trimester screening tests

Answer 31

hCG, PAPP-A
US measure of nuchal translucency

Detection for DS is 79-85%

Question 32

Second trimester screening tests

Answer 32

AFP, UE3, inhibin A (DIA), hCG

Detection for DS is 76-81%

Question 33

NO/weak association with chromosome abnormality when seen on US

Answer 33

hydranencephaly, gastroschisis

Question 34

background risk for major congenital anomalies

Answer 34

2-3%

Question 35

Maternal medical problems that cause fetal abnormalities

Answer 35

diabetes, seizure disorder, congenital adrenal hyperplasia

Question 36

amniocentesis

Answer 36

15-20 weeks gestation
1/200 risk loss rate

2.5% pregnancy loss after early amniocentesis
incidence of clubbed feet higher, membrane rupture

Question 37

CVS

Answer 37

after 9 weeks gestation

Question 38

screening test

Answer 38

gives risk percentage, not yes or no

Question 39

Commonly seen on US with high sensitivity but not necessarily correlated with chromosomal abnormalities

Answer 39

Open neural tube defects: 95%
congenital heart disease: 90%
renal abnormalities: 90%