Patterns Of Single Gene Inheritance

Question 1

What are the exceptions to Mendelian patterns of inheritence?

Answer 1

Reduced penetrance
Variable Expressivity

Germ-line mosaicism
Genetic imprinting
New Mutations
Misattributed paternity

Mitochondrial gene disorders
TNR disorders (just special features)

Question 2

What is a compound heterozygote?

Answer 2

Both alleles are mutant, but mutations are at different locations on the gene

Question 3

What is hemizygous?

Answer 3

Abnormal gene is located on X chromosome, in male pt

Question 4

What is allelic heterogenity? Phenotypic heterogeneity?

Answer 4

Allelic: different mutations at same locus cause a similiar phenotype

Phenotypic: Disease appears different, but mutations are happening at same gene. Contributes to spectrum of a disorder

Question 5

What is locus heterogeneity?

Answer 5

Phenotype being caused by more than one gene mutations.

I.e. Long QT syndrome (potassium, sodium, and structural proteins can cause it)

Question 6

What is pleiotropy?

Answer 6

One gene that affects multiple traits

Question 7

What are the factors that could confound pedigree interpretation?

Answer 7

1. Early lethality of disorder
2. Small family size
3. Variable age of onset
4. Non-mendelian inheritance

Question 8

What are some features of Autosomal Recessive (AR) disease? What do these mutant alleles present as?

Answer 8

Must have 2 mutant alleles and no wt.
->type of mutation at each allele can be different (compound heterozygote)

Reduce or eliminate function of gene
Often affect function of enzymes
RARE

Unaffected child being carrier: 2/3
Either sex: 1/2 being carrier.

Question 9

What are key features of AR?

Answer 9

Parents are unaffected, asymptomatic carriers
Males at same risk of females
Phenotype found in sublings (not parents or kids of affected

Question 10

What factors can affects the risk of inheritance of an AR disorder?

Answer 10

1. Carrier frequency in a given pop.
2. Consanguinity
3. Inbreeding
4. Genetic isolated

Question 11

What are features of AD pedigree?

Answer 11

1.Every affected individual has an affected parent
->no skipping generations
(also BB homozygotes are rare)
2. Male=females, & there is M2M transmission

3. 1/2 offspring of an affected individual are affected
4. Normal siblings of affected individuals have normal offspring.
5. 2 affected parents (heterozygotes->75% offspring)

Question 12

What is incomplete dominance in terms of AD pedigrees? What are examples?

Answer 12

An individual who is homozygous for the AD mutation will be more severely affected than heterozygotes

Achondroplasia
Familial Hypercholesterolemia

Question 13

What is reduced penetrance? Variable expressivity?

Answer 13

Reduced penetrance: Probability a mutant gene will have any phenotypic expression at all
If that probability is less than 100 = reduced penetrance
I.e. AD form of Split-Hand Foot malformation

Variable expressivity:
Severity of the expression of the phenotype among indiv. With same disease-expressing genotype

Neurofibromatosis

Question 14

Sex-linked autosomal traits include:

Answer 14

1. Genes occur on autosomes and mutations present in both sexes
2. Phenotype only evident in one sex
3. Genes for the trait can be carried and transmitted by the opposite sex b/c anatomical or physiologic differences.

Question 15

What is an example of an sex-linked AD disorder?

Answer 15

Male-limited precocious puberty

• > mutation in luteinizing hormone receptor gene
• > constitutive active LHR
• > phenotype expressed in males only

Heterozygous females dont have phenotype but male child can be affected.

Transmited by affected males/unaffected females

Question 16

Sex-limited phenotype in AR disorders (examples):

Answer 16

1. Hemochromatosis
   - >most common single-gene inherited disease in the US

Males>Female (5-10X) w/p physiologic process to reduce excess iron.

Question 17

In X-linked recessive disorders, what are expected outcomes between unaffected male and carrier female?

Answer 17

1/2 Risk of Females carrying

1/2 risk male will be affected

Question 18

What is expected outcome of affected male and unaffected female in XLR?

Answer 18

All females are obligate carriers

All males are normal (no M2M transmission)

Skips geneation

Question 19

When does X-linked inactivation come into play?

Answer 19

XLR. Somatic mosaics. Unbalanced X-inactivation

Question 20

X-linked dominant patterns of inheritance?

Answer 20

No male to male transmission.

->Affected male and normal female =>
All daughters affected
All sons normal

Question 21

What is mosaicism?

Answer 21

Presence in an individual of at least two cell lines that differ genetically but are derived from single zygote.

Somatic: present in some tissues in embyro, but not germ cells

-Pure germline mosaicism

Question 22

What are clues in a pedigree that could unveil a germline mosaicism?

Answer 22

Parents that are phenotypically normal and who test negative for being a carrier AND have more than one child affected with a highly penetrant AD or XLR disorder

• > Osteogenesis imperfecta
• > Hemophilia A/B
• > Duchenne muscular dystrophy

Question 23

What is the probability of a new mutation forming in a gamete?

Answer 23

10^-5/6 per gamete

RARE

Diseases produced by dominant alleles with affects so severe persons with them do not have children.

Question 24

What is cause of Prader-Willi/Angelman syndrome?

Answer 24

Large deletions in gene, but gene that is present silenced thru epigenetics.

Prader-Will = 20 maternally imprinted genes affected

Angelman = 1 paternal gene