Genetic mechanisms in disease

Question 1

Trisomy 21

Answer 1

Downs syndrome

Question 2

Trisomy

Answer 2

Extra chromosome. Possible in the smaller chromosomes with no critical genes but not seen in larger ones.

Question 3

Monosomy

Answer 3

Only 2 known examples: 1. Monosomy 21 and Monosomy 22

Question 4

Klinefelter syndrome

Answer 4

XXY or XXYY

Question 5

Turner syndrome

Answer 5

Missing a sex chromosome. XO genotype (not possible to be YO)

Question 6

Barr body

Answer 6

Inactive X chromosome

Question 7

Mosaicism in women

Answer 7

Some cells in the body have one X activated and some have the other

Question 8

Microdeletion

Answer 8

Small deletion spanning several genes which can’t be seen in a chromosome test

Question 9

Microduplication

Answer 9

Small duplication which can’t be seen in a chromosome test. Less problematic than deletions.

Question 10

Balanced translocation

Answer 10

No missing, extra genetic material, often doesn’t cause disease unless right through important gene

Question 11

Unbalanced translocation

Answer 11

Can see missing/extra piece. Like having a deletion or duplication. Can happen in children of parent with balanced translocation.

Question 12

Contiguous gene syndrome

Answer 12

Microdeletion that spans 2 or more genes adjacent to each other

Question 13

Routine chromosome tests

Answer 13

Karyotyping or cytogenic analysis. Can detect 1. Monosomy 2. Trisomy 3. Big deletions 4. Duplications 5. Rearrangements

Question 14

Fluorescent in situ hybridization (FISH)

Answer 14

Will detect microdeletions and duplications, but need to know what you are looking for.

Question 15

Subtelomeric FISH

Answer 15

Detects microdeletions and subtle rearrangements that disrupt genes near ends of chromosomes which can cause mental retardation.

Question 16

Microarray (CMA, CGH)

Answer 16

Also called genomic array. First line test used-multiple probes and don’t need to know what you’re looking for. Results can be known disease (diagnosis), “variant of unknown significance,” parents have/don’t have (diagnosis) it, benign normal CNVs (copy normal variants). Used for detecting intellectual deficiencies with unknown cause, multiple congenital anomalies, seizures, microcephaly. Costs $2600

Question 17

Pathogenic CNVs

Answer 17

Usually bigger, deletions/amplifications, genes in CNS

Question 18

Benign CNVs

Answer 18

Usually smaller, gene-poor, present in healthy relative, duplications better than deletions

Question 19

Risk CNVs

Answer 19

Inherited, variable penetrance but occur in disease state more often than normal, deletions/duplications, genes in CNS. Genetic counseling difficult.

Question 20

Williams syndrome

Answer 20

Neurodevelopmental disorder form deletion in 26 genes on chromosome 7

Question 21

Dominant negative effect

Answer 21

When defective protein inhibits function of normal one in dimer/multimer

Question 22

Neurophakomatoses

Answer 22

Loss of functionn in tumor suppressor genes-second hit gives cancer

Question 23

X-linked lethal

Answer 23

Only females get this X-linked disease because males die before birth

Question 24

Exome sequencing (NextGen)

Answer 24

Looks for homozygous rare variants in affected individuals/families with patterns of dominant or recessive disease. Successful, but sometimes find other risk variants.

Question 25

Families with recurring recessive disease (inbred)

Answer 25

Homozygosity mapping followed by focused Sanger or focused/whole exome sequencing

Question 26

Families with recurring dominant disease

Answer 26

Linkage followed by Sanger sequence of candidate genes or focused/whole exome sequencing