Single Gene Disorders

Question 1

Compound heterozygote means that _______________ but mutations are ____________

Answer 1

Compound heterozygote means that BOTH ALLELES ARE MUTANT but mutations are AT DIFFERENT LOCATIONS IN THE GENE

Question 2

Hemizygous means that abnormal gene is located on _ chromosome in ____ patient

Answer 2

Hemizygous means that abnormal gene is located on X chromosome in MALE patient

Question 3

Allelic heterogeneity means that you can have the ____ disease but the type of mutation leading up to it can be _______, i.e at _____ ______

Answer 3

Allelic heterogeneity means that you can have the SAME disease but the type of mutation leading up to it can be VERY DIFFERENT, i.e at DIFFERENT AREAS OF THE GENE

In other words: distinct mutations in the same gene that produce the same phenotype

Question 4

Phenotypic heterogeneity means that you can have mutations in same gene but different _____ _______

Answer 4

Phenotypic heterogeneity means that you can have mutations in same gene but different CLINICAL SEVERITY

In other words: distinct mutations in the same gene producing very different phenotypes

Question 5

Locus heterogeneity is when a phenotype can be caused my mutations in ___________

Example: _________

Answer 5

Locus heterogeneity is when a phenotype can be caused my mutations in MORE THAN ONE GENE

Example: LONG QT SYNDROME, MUTATION IN K CHANNELS, NA CHANNELS, AND STRUCTURAL PROTEINS (ANKYRIN)

In other words, mutations at different loci that produce the same phenotype.

Question 6

Pleiotropy is _______ that affects ____________

Example: _____

Answer 6

Pleiotropy is ONE GENE that affects MULTIPLE TRAITS

Example: VHL disease, RNA binding proteins

Question 7

Polygenic disease is when _____ is affected by ______

Answer 7

Polygenic disease is when ONE TRAIT is affected by MULTIPLE GENES

Question 8

Factors that can confound pedigree interpretation:

1. ____ lethality of disorder
2. ____ family size
3. _____ age of onset; _____ penetrance or _____ expressivity.
4. ______ inheritance

Answer 8

Factors that can confound pedigree interpretation:

1. EARLY lethality of disorder
2. SMALL family size
3. VARIABLE age of onset; DECREASED penetrance or VARIABLE expressivity.
4. NON-MENDELIAN inheritance

Question 9

Features of an AD pedigree:

1. Every individual has an ____ parent.
2. Males can have ________.
3. About _____ of the offspring of an affected individual are affected.
4. _____ siblings of affected individuals all have _____ offspring.

Answer 9

Features of an AD pedigree:

1. Every individual has an AFFECTED parent.
2. Males can have UNAFFECTED DAUGHTERS.
3. About ONE HALF of the offspring of an affected individual are affected.
4. NORMAL siblings of affected individuals all have NORMAL offspring.

Question 10

Incomplete dominance implies that an individual that is _____ for the AD mutation will be ________ affected than an individual who is ______.

Examples: ______ and _______

Answer 10

Incomplete dominance implies that an individual that is HOMOZYGOUS for the AD mutation will be MORE SEVERELY affected than an individual who is HETEROZYGOUS.

Examples: ACHONDROPLASIA and HYPERCHOLESTEROLEMIA

Question 11

Reduced penetrance is the probability that the gene will ______________.

If the probability is _______, then the gene has reduced penetrance.

Answer 11

Reduced penetrance is the probability that the gene will HAVE ANY PHENOTYPIC EXPRESSION AT ALL.

If the probability is LESS THAN 100%, then the gene has reduced penetrance.

Phenotype can have age-dependent penetrance.

Question 12

Variable expressivity is the _________ of the expression of the ______ among individuals with the same disease-expressing _____.

Answer 12

Variable expressivity is the SEVERITY of the expression of the PHENOTYPE among individuals with the same disease-expressing GENOTYPE.

Question 13

Sex limited traits occur on ______ chromosomes but phenotype is evident only in ______

Example:

Answer 13

Sex limited traits occur on AUTOSOMAL chromosomes but phenotype is evident only in ONE SEX

Examples: MALE-LIMITED PRECOCIOUS PUBERTY

• mutation in LH receptor gene (LHR)
• constitutive activation of LHR
• phenotype is expressed in males only

Question 14

AR Sex Limited Phenotype Example

Answer 14

Hemochromatosis; Fe overload. More common in males who have no physiologic process to reduce excess Fe.

-In women, pregnancy and menstruation reduce Fe levels.

Question 15

X-Linked Recessive Inheritance pattern

Answer 15

• Skips generation
• males are more affected
• depends on phenotype of Het woman (usually unaffected due to X-inactivation)
• no male-male transmission
• all daughters of affected males are obligate heterozygotes

Question 16

Hemophilia A:

• Factor _____ is a co-factor for clotting
• Phenotype depends on _________
• Severe is

Answer 16

Hemophilia A:

• Factor 8 is a co-factor for clotting
• Phenotype depends on AMOUNT OF FACTOR 8
• Severe is <1%
• Moderate is 1-5% normal activity
• Mild is 5-40% of normal activity (ONLY OCCURS IN SOME HET FEMALES)

Question 17

X-Linked Dominance Inheritance Pattern

Answer 17

• No male-male transmission of trait
• 2x more females affected than males
• Expected outcome bw affected male and normal female: all daughters are affected and all sons are normal.

Question 18

Mosaicism is the presence in an individual of at least 2 ______ that differ genetically but are ____________.

Can have either _______ or _____ mosaicism.

Answer 18

Mosaicism is the presence in an individual of at least 2 CELL LINES that differ genetically but are DERIVED FROM A SINGLE ZYGOTE.

Can have either SOMATIC or GERMLINE mosaicism.

Question 19

Pedigree clue of germline mosaicism:

Parents who are ________ normal and who test ______ for being a carrier have more than 1 child affected with a ________ or ______ disorder.

Answer 19

Pedigree clue of germline mosaicism:

Parents who are PHENOTYPICALLY normal and who test NEGATIVE for being a carrier have more than 1 child affected with a HIGHLY PENETRANT AD or XLR disorder.

Examples: osteogenesis imperfecta, hemophilia A and B, Duchenne muscular dystrophy

Question 20

New mutations in gametes have probability of 10^ ___ - 10^ ___ per gamete. Affected child will share alleles for all other genes with both parents.

• Rare in _____ diseases
• Can cause genetic ____ diseases which cause parents to not want kids.

Answer 20

New mutations in gametes have probability of 10^ -5 - 10^ -6 per gamete. Affected child will share alleles for all other genes with both parents.

• Rare in AUTOSOMAL RECESSIVE diseases
• Can cause genetic LETHAL diseases which cause parents to not want kids.