Exam 5: Single Gene Disorders

Question 1

allele heterogeneity

Answer 1

different mutations in same gene cause different phenotypes; gain or loss of function
Ex: cystic fibrosis - mutations in different domains of same gene have different impact on function of gene production

Question 2

anticipation

Answer 2

severity of disease increases when transmitted through a pedigree
frequently observed in triplet expansion mutations

Question 3

autosomal recessive

Answer 3

both alleles of gene are defective
Affected children usually have normal parents
Both sexes are equally affected
Consanguinity is often present

Question 4

carrier of recessive genetic disease

Answer 4

Person carries only one defective allele - don’t suffer from disease but have 50% chance of passing defective allele to child

Question 5

coefficient of inbreeding

Answer 5

degree of homozygosity of child
Siblings share 50% of genes, if they have a child, child will be homozygous for 25% of genes
Coefficient for inbreeding for children of siblings is 1/4

Question 6

compound heterozygote

Answer 6

2 recessive alleles for same gene, but with those two alleles being different from each other (both alleles mutated but at different locations)

Question 7

Recessive inheritence is mostly observed in defects of

Answer 7

Enzymes

Proteins involved in transport and storage

Question 8

consanguineous mating

Answer 8

Matings of closely related individuals

Increases risk for development of recessive disease - more likely to carry same recessive mutant allele

Question 9

delayed age of onset

Answer 9

disorders appear later in life
People do not know if they are carriers of disease by time they have children - do not know if they are at risk of passing it on

Question 10

dominant negative effect

Answer 10

Affects mostly structural proteins
If mutation produces an abnormal protein, mutant protein may compete with wildtype form. If protein is part of large complex, mutant proteins may destabilize
structure
Dominant inheritance

Question 11

expressivity

Answer 11

how strong a disease phenotype shows

Question 12

gain of function

Answer 12

mutation that alters the proteins activity, can give new function
mutation function different from wildtype - can see effect of mutation no matter how many wildtype versions are present
Seen in signal transduction proteins
Dominant inheritance

Question 13

genetic fitness

Answer 13

chance of person to reproduce

fitness of zero = can’t reproduce at all

Question 14

haploinsufficiency

Answer 14

half of gene dosage is not sufficient for cell to carry out its function
Many structural proteins needed in quantities too large to be supplied by just one allele
Dominant inheritance

Question 15

heteroplasmy

Answer 15

presence of a mixture of more than one type of organellar genome within a cell
cells contain varying fractions of defective mitochondrial DNA molecules

Question 16

lifetime risk for single gene genetic disease

Answer 16

2%

Question 17

single gene disorders

Answer 17

one or both alleles of one gene is defective

Question 18

loss of function

Answer 18

mutation that may reduce the protein’s activity

Question 19

modifier genes

Answer 19

genes that have small quantitative effects on the level of expression of another gene

Question 20

mutation hotspot

Answer 20

a chromosomal region where mutations occur frequently

typically a CG dinucleotide repeat

Question 21

null mutation

Answer 21

underlying mutation completely destroys a protein

Question 22

penetrance

Answer 22

the extent to which a particular gene or set of genes is expressed in the phenotypes of individuals carrying it, measured by the proportion of carriers showing the characteristic phenotype

Question 23

premutation

Answer 23

change in gene that proceeds a mutation; does not alter function of gene
In Huntington’s Disease above 40 repeats in triplet expansion, disease develops. Close to 35 repeats may not develop HD, but chance of them producing gametes with pathogenic number of repeats is high
Likely to have several offspring with penetrant new mutations

Question 24

pseudoautosomal region of Y

Answer 24

area of Y chromosome that has extensive homology to X chromosome, required for alignment with X-chromosome in meiosis
Only a few genes on Y chromosome

Question 25

sex determining region of Y (SRY)

Answer 25

area of Y chromosome that contains the genetic information for male development of an embryo

Question 26

recurrence risk

Answer 26

chance of parents having another affected child after having one risk of having child affected with single-gene disorder remains same because conceptions are statistically independent events

Question 27

sweat chloride test

Answer 27

measurement of electric conductivity of skin surface | tests for cystic fibrosis (defect in chloride channel causes sweat to be salty & high electric conductivity)

Question 28

two hit model

Answer 28

need to inactivate both alleles for disease to be seen If a person already lacks one of copies (born with mutated allele) they are very sensitive to mutations in other allele & more likely to develop disease - predisposition

Question 29

X-chromosome inactivation

Answer 29

one of female X chromosomes are inactivated early in embryonal development in random, but fixed manner some cells use maternal and other cells use paternal X chromosome (mosaic)

Question 30

Achondroplasia

Answer 30

Defect in bone growth Autosomal Dominant New mutations, fitness, dominant negative allele, mutation hotspot

Question 31

Cystic Fibrosis (CF)

Answer 31

Defective chloride channel Autosomal Recessive Allele heterogeneity, modifier loci

Question 32

Duchenne Muscular Dystrophy (DMD)

Answer 32

Defect in dystrophin (necessary for attachment of smooth, cardiac, and skeletal muscle cells to extracellular matrix) X-recessive new mutations, large target

Question 33

Ehlers-Danlos Syndrome

Answer 33

Collagen disorder | Autosomal Dominant and Recessive

Question 34

Familial Hypercholesterolemia

Answer 34

Defective LDL receptor Autosomal Dominant Allele heterogeneity - heterozygotes have elevated serum levels of lipoproteins (2x) and homozygotes have lipoprotein levels 4x as high (gene dosage)

Question 35

Fructose 1,6 bisphosphate deficiency

Answer 35

Fasting hypoglycemia | Autosomal recessive

Question 36

Glucose 6-phosphate dehydrogenase deficiency

Answer 36

Sensitivity to H2O2-generating agents and fava beans | X-recessive

Question 37

Glycogen storage disorders

Answer 37

Hypoglycemia, accumulation of glycogen | Autosomal recessive

Question 38

Huntington Disease (HD)

Answer 38

Neurological disorders Autosomal dominant New mutations, triplet expansion, anticipation

Question 39

Leber's Hereditary Optic Neuropathy (LHON)

Answer 39

Defect in mitochondrial DNA, leads to deterioration of optic nerve and blindness mitochondrial defect Heteroplasmy

Question 40

Neurofibromatosis (NF)

Answer 40

Multiple tumors Autosomal dominant new mutations, variable expressivity

Question 41

Osteogenesis Imperfecta I (OI-I)

Answer 41

Defective type I collagen Autosomal dominant Dominant negative alleles, allele heterogeneity

Question 42

Phenylketonuria (PKU)

Answer 42

tyrosine metabolism autosomal recessive newborn screening

Question 43

Sickle cell anemia

Answer 43

Hemolysis | Autosomal recessive

Question 44

Sucrase-Isomaltase deficiency

Answer 44

Sucrose/glucose polymer intolerance | autosomal recessive

Question 45

recessive mode of inheritance

Answer 45

loss of a functional copy can be compensated for by multiple regulatory mechanisms; needs loss of both alleles (two mutant alleles, homozygote)

Question 46

Dominant inheritance is mostly observed in defects of

Answer 46

structural proteins proteins involved in growth, differentiation, and development Receptor and signalling proteins

Question 47

Dominant inheritance

Answer 47

one mutant allele is enough to cause disease - heterozygosity

Question 48

X-chromosome mutations

Answer 48

dominant in males - have only one X chromosome in female, depends on if mutated X homolog is active or inactive and whether neighboring cells with normal copy can take over function of mutant cells X-linked diseases cannot be passed father to son

Question 49

Mitochondrial disorder inheritance

Answer 49

inherited from mother - does not follow Mendelian rules | many copies of mitochondrial chromosome - induces variable expression

Question 50

Using information from pedigree, one can

Answer 50

make accurate estimate of risk for a person to be a carrier of a recessive disease Estimate likelyhood couple will have an affected child

Question 51

Linkage analysis

Answer 51

Used to trace inheritance of a marker on chromosome linked to disease alleles

Question 52

Consanguineous matings

Answer 52

matings of closely related individuals | increases risk for developing recessive disease - good chance carry same mutant alleles

Question 53

Inborn Errors of Metabolism (IEM)

Answer 53

class of hundreds of autosomal recessive disorders caused by defects in metabolic enzymes Individually rare, but cumulatively occur 1/300 births typically screened for at birth can be acute or chronic

Question 54

characteristics of autosomal recessive pedigree

Answer 54

affected children usually have normal parents both sexes equally affected consanguinity often present

Question 55

characteristics of autosomal dominant pedigree

Answer 55

affected child has at least one affected parent both sexes equally affected disease can be transmitted father to son

Question 56

incomplete penetrance

Answer 56

people with disease genotype do not develop symptoms | leads to situation where dominant disease seems to "skip" generation

Question 57

variable expressivity

Answer 57

not all people with disease genotype will develop same set of symptoms at young age

Question 58

new mutation

Answer 58

``` occurs spontaneously (not passed on) would not see disease in parents & recurrence risk would be low ```

Question 59

triplet expansion

Answer 59

trinucleotide repeat expansion caused by slippage during DNA replication larger expansion, more likely to cause disease or increase severity of disease

Question 60

Haploinsufficiency vs. Dominant negative

Answer 60

Hap: reduced gene dosage not enough for cell to carry out function (structural proteins needed in too large quantities for only one allele - familial hypercholesterolemia) Dom: deformed mutant protein competes with wildtype form, may destabilize structure (collagen disorders, Ehlers-Danlos syndrome)

Question 61

OI-1 Type 1

Answer 61

Haploinsufficiency - all collagen made is normal, but amount is reduced by half (one copy of gene not enough) Brittle bones and blue sclerae

Question 62

OI-1 Type 2, 3, 4

Answer 62

Dominant negative - missense mutations in some of glycine codons cause abnormal collagen to be produced range from bone deformities/fractures to brittle bones, black sclerae and death

Question 63

Loss of function mutation in RET gene causes

Answer 63

Hirschsprung disease | destroy molecule's ability to respond to stimulus - impairs development of neurons that populate colon

Question 64

Gain of function mutation in RET gene causes

Answer 64

Multiple Endocrine Neoplasia (MEN) render signaling molecule constitutively active causes proliferation of neuroendocrine cells

Question 65

Characteristics of x-linked mutation pedigree

Answer 65

No father-son transmission Affected boys usually have unaffected parents Males are affected more than girls

Question 66

X-;linked dominant disease

Answer 66

affected male transmits disease to all of his daughters but none of his sons affected female transmits to half of her children

Question 67

Mitochondrial inheritance pedigree characteristics

Answer 67

passed from mothers to all of her children | fathers do not transmit disease