OBJ - Medical Genetics II: Modes of Inheritance of Single Gene Disorders

Question 1

Pedigree Symbols

Answer 1

Males = Square
Females = Circle
Unknown sex = Diamond
Shaded = affected
Siblings = single line

Deceased = slash through

heterozygous = 1/2 shaded

Twins:
Dizygotic = 1 point of origin with angled lines
Monozygotic = line between the angle

Spontaneous abortion/miscarriage = small triangle

When drawing:

• start in very middle of space
• list kids left to right, oldest to youngest

Question 2

Mode of inheritance

Answer 2

1) Horizontal/vertical
2) X linked or autosomal (ratio females/males or male -> male transmission)
3) Go back & check it makes sense or try to prove other 3 wrong

Question 3

Single Gene Disorders

Answer 3

result of a single mutated gene

X linked Dominant/Recessive
Autosomal Dominant/Recessive

Question 4

Autosomal Dominant Inheritance

Answer 4

• vertical transmission
• both males and females are affected
• example of male to male transmission
———————————————————

• Have to be HETEROzygous for mutation to be expressed

Assume Heterozygote (homozygotes are typically unviable)

• Vertical transmission (every level of tree)
• ~ same ratio of male & female

Affected individuals

• Have affected parents
• Will have 50% of affected children

Unaffected family members:
- Will have no affected children

Types of dominant mutations:

1) Haploinsufficiency - 1/2 normal amount of protein
2) Dominant negative Effect - mutant protein interferes with normal protein function
3) Gain of function - new or encahnced property of the protein

Examples:

• Familial hypercholesterolemia
• Osteogenesis imperfecta
• Achondroplasia (short-limbed dwarfism)
• Huntington disease

Question 5

Autosomal Recessive Inheritance

Answer 5

• horizontal transmission
• both sexes are affected
• consanguineous mating (inbreeding - double line)
———————————————————

• have to be homozygous for mutation to be expressed
• Horizontal transmission (looks horizontal in-law is carrier & sibling is carrier & skips generation)
• ~ same ratio of male & female

Both parents are affected = all kids
One parent is affected = all kids carriers
One parent is affected and one is a carrier
= ½ affected, ½ carrier

**often enzyme defects, usually rare

Examples:
• Sickle cell anemia
• Cystic fibrosis
• Tay-Sachs disease
• Phenylketonuria
• alpha & beta Thalassemia
• Bloom's Syndrome

Question 6

X linked Recessive Inheritance

Answer 6

• horizontal transmission
• only males affected
• no male to male transmission
———————————————————

• Mostly shows up in males, often carriers
• Fathers never transmits to son (-> y)
• Daughters of affected females = all carriers
• Carrier Male = 1/2 affected & 1/2 not
• Affected Females = affected father & carrier/affected mother

Examples:
• Duchenne muscular dystrophy
• Hemophilia (A and B)
• Red-green color blindness

Question 7

Obligate heterozygote

Answer 7

Have to be heterozygotes based on parental homozygote recessive affected

Question 8

Compound heterozygotes

Answer 8

having two heterogeneous recessive alleles at a particular locus that can cause genetic disease in a heterozygous state

i.e. a1 & a2 for A, a1, a2

Question 9

X Linked Dominant Interitance

Answer 9

• vertical transmission
• no examples of male to male transmission
• all affected males passed the condition to their daughters (makes X linked most likely)
(could also be autosomal dominant)
———————————————————

• Vertical Transmission
• Females more affected than males
• Fathers never transmits to son (-> y)

-Affected males
Transmits to all daughters, no sons
- Affected Females
Trasnmits to 50% daughters & 50% sons

Examples:

Both sexes affected:
• Fragile X syndrome
• Vitamin D resistant rickets

Lethal in males:
• Aicardi syndrome
• Incontinentia pigmenti
• Rett syndrome

Question 10

Allelic heterogeneity

Answer 10

Different mutations/ALLELES in the same gene/locus/location

Different alleles may lead to:

a) clinically indistinguishable phenotypes
b) different severity and/or extent of symptoms
c) different clinical presentations (rare)

Compound heterozygotes - adds more complexity to clinical manifestation

Question 11

Locus (genetic) heterogeneity

Answer 11

Mutation in 2 different genes cause the same disease

Mutations in different LOCATION/genes/loci, cause the same disease

Question 12

Penetrance

Answer 12

the likelihood that the disease allele will result in the disease

Incomplete/Reduced penetrance:
clinical symptoms are not always present in individuals who have the disease-causing mutation

Question 13

Delayed onset

Answer 13

An individual may pass the allele on to offspring, but die of unrelated causes prior to showing the disease

13 on House

Question 14

Germline/gonadal mosaicism

Answer 14

mutation in the germ stem cell

2 offspring with new mutations

Question 15

Pleiotropy

Answer 15

diverse effects of a single gene on several organs

I.e. Marfan’s syndrome (heart, skeleton, eye problems)

Question 16

Expressivity/Variable expressivity

Answer 16

the degree of clinical manifestation of the same mutant allele in different individuals

Question 17

Differences in Penetrance & Expressivity

& their clinical manifestations

Answer 17

• Modifier genes
• Environmental factors
• Complex genetic and environmental interactions