Patterns of inheritance

Question 1

Compound Heterozygote

Answer 1

Both alleles are mutant but the mutations within those alleles are different.

Question 2

Hemizygous

Answer 2

1. Abnormal gene is located on X-chromosome in male patient

Question 3

Allelic Heterogeneity

Answer 3

Different mutations can occur in the same gene

Question 4

Phenotypic Heterogeneity

Answer 4

Different mutations in the same gene can produce very different phenotypes ranging from normal, moderate, to severe.

Question 5

Locus heterogeneity

Answer 5

Mutations at different loci or different genes all together can produce the same phenotype

i.e. Long QT syndrome

• Phenotype: In EKG, QT segment is longer than it should be due to taking a longer amount of time for heart to repolarize.
• Genotype: this phenotype can result from mutations in genes encoding sodium and potassium channels, and structural proteins.

Question 6

Autosomal Recessive Disease Genetic and Key features

Answer 6

1. I.e. Cystic Fibrosis
2. Genetic Features
   
   1. Affected: has 2 mutant alleles
   2. Can be compound heterozygote in which the mutations in each allele are different.
   3. Carrier: has 1 mutant allele
   4. Mutant alleles for AR disorders:
      
      1. Reduce or eliminate function of the gene product
      2. Affect the function of enzymes
3. Key Features
   
   1. Parents are unaffected, asymptomatic carriers so there is skipping of generations
   2. Males and Females equally affected
   3. The risk of an unborn sibling of an affected individual having disease does not change and stays as ¼.
   4. Phenotype is found in siblings.
   5. If we are looking for other members of the kindred who are affected, we are more likely to find them among the siblings, not among the parents or the kids of the people affected.
   6. If trait is rare, there is likelihood of cosanguious mating

Question 7

Autosomal Dominant Key and Genetic Features

Answer 7

1. I.e. Familial Hypercholesterolemia
2. Genetic Featuers
   
   1. Affected: needs 1 mutated allele in order to be affected. There are no BB alleles because BB genotype is lethal.
   2. Carrier: there are no carriers because if you have mutant allele, you are affected.
   3. Unaffected: no mutated alleles or bb
3. Key features
   
   1. Every affected individual has an affected parent; there is no skipping of generations
4. Usually occur in genes coding multimers
5. 1. Males and Females are equally affected
   2. About ½ of the offspring of an affected individual are affected
   3. Normal siblings of affected individuals have all normal offspring because if someone is normal, they do not have mutation and there is no change that they will pass that mutation on to their children

Question 8

Incomplete dominance

Answer 8

1. Implies that an individual that is homozygous for the AD mutation will be more severely affected than an individual who is heterozygous
2. The BB homozygous mutation in AD disorders is very uncommon because it causes early lethality. Exceptions to this are:
   
   1. Achondroplasia-defect in long bone growth. Individuals have extreme short stature
   2. Familial hypercholesterolemia
      
      1. Affected are both BB and Bb
      2. BB is severely affected whereas Bb is affected to a milder degree

Question 9

X-linked Recessive

Answer 9

1. Genetic Features
   
   1. Cross between unaffected male and a carrier female
      1. 1:2 risk that females will be carrier of the disorder
      2. 1:2 that male will be affected by the disorder
   2. Cross between affected male and unaffected female
      1. All females are obligate carriers
      2. All males are normal
      3. No male to male transmission occurs
2. Key Features
   
   1. There are more males affected than females
   2. Gene is transmitted from affected male to all daughters who then become obligate carriers.
   3. Heterozygous females are usually unaffected depending on X-inactivation.
      
      1. X inactivation or dosage compensation
      2. Normal individuals only should have 1 functioning X-chromosome
      3. In women, one of the X-chromosomes is selectively inactivated and it occurs in balanced fashion such that 50% of the time, the paternal X is inactivated and the other 50%, the maternal is inactivated.
      4. Therefore, females are somatic mosaics for the X-chromosome.
      5. In recessive disorder, sometimes when inactivation is imbalanced such that mutated chromosome is expressed at a higher ratio than non-mutated, women can express phenotype.
   4. Mutant allele may be transmitted through a series of carrier females.
   5. No male to male transmission.

3.

Question 10

X-linked dominant

Answer 10

1. Genetic Features
   
   1. Cross between affected male and unaffected female
      1. All daughters are affected
      2. All sons are normal.
   2. Cross between affected female and unaffected male
      1. 1:2 daughters will be affected
      2. 1:2 sons will be affected
2. Key Features
   
   1. No male to male transmission

Question 11

Reduced Penetrance

Answer 11

1. All or none
2. ONLY APPLIES TO AUTOSOMAL DOMINANT DISORDERS
   
   1. 100% of the people that have mutant gene should show phenotype
   2. If only 99% show the phenotype, there is reduced penetrance.
3. The probability that a mutant gene will have any phenotypic expression at all
4. If the probability of a mutant gene showing any phenotypic expression at all is less than 100%, the gene has reduced penetrance
5. This can depend on age such that people can express phenotype later on in age
6. I.e. Split hand foot malformation
   
   1. 70% of individuals who inherit mutant gene express phenotype
   2. 30% of other individuals are normal

Question 12

Variable Expressivity

Answer 12

1. Range
2. ONLY APPLIES TO AUTOSOMAL DOMINANT DISEASES
   
   1. Everyone with the mutant gene will express the phenotype
   2. The phenotype expressed can differ and have a range of severities
3. ALL individuals are affected but the severity of the disease phenotype differs in people who have the same genotype
4. I.e. Neurofibromatosis
   
   1. Individuals with the same mutation in neurofibromatosis gene can have spectrum of phenotypes that range from mild to severe
   2. Cafe Olay spots –> benign tumors

Question 13

Sex limited traits

Answer 13

1. This occurs in AUTOSOMAL DOMINANT genotypes
2. Transmitted in autosomal dominant pattern
3. Both sexes will inherit the gene and mutation
4. However, phenotype for the disorder is only seen in 1 sex throughout the pedigree
   
   1. Can be due to physiological, anatomical, or hormonal reasons
5. However, gene for the trait can be carried and transmitted by opposite sex although it is NOT displayed in that sex
   
   1. If you see male to male transmission, you know it is sex-limited
6. I.e. Male-Limited Precocious puberty
   
   1. Mutation in Leutenizing hormone receptor gene makes it consitutively active
   2. Phenotype
      
      1. Males develop secondary sexual characteristics like growth spurt earliers on

Question 14

Sex-influenced trait

Answer 14

1. This occurs in AUTOSOMAL RECESSIVE diseases
2. I.e. Hemochromatosis
   
   1. Mutation in HFE causes excessive body stores of iron
   2. Iron deposition occurs in liver, heart, and other organs
   3. Disease is only seen in males because women can reduce iron levels during pregnancy and menstruation

Question 15

Somatic Mosaicism

Answer 15

1. Present in some tissues in the embryo but not the germ cells
2. You have fertilized zygote, cell division occurs, and somewhere early in the process, a mutation occurs and all tissues derived from this cell contain the mutation but all the other tissues do not.

Question 16

Germline Mutation

Answer 16

1. Incidence of developing germ line mosaicism is higher than in other disorders
2. Mutation occurs in germ cells and a situation would arise where individual can be phenotypically normal but pass on the mutation through their germ line cells to their offspring.
3. Pedigree pattern
   
   1. Parents are phenotypically normal
   2. 1 or more child affected with highly penetrant AD or XLR disorder.
4. Disorders
   
   1. Osteogenesis imperfecta
   2. Hemophilia A
   3. Duchenne Muscular Dystrophy

Question 17

Permutations of mosaicism

1. Father has mutation in germline
2. Mutation occurs in zygote within first few cell divisons
3. Mutation occurs in post-zygotic development
4. Mutation occurs later in development

Answer 17

1. Child will be heterozygous for that mutation in every cell
2. Child will be heterozygous for that mutation in every cell
3. Child will have mutation in small percentage of cells
4. Child will have mutation in a very small percentage of his cells.

Question 18

New Mutations

Answer 18

1. Probability is 10^-5 to 10^-6 per gamete
2. Affected child will share alleles for other genes with both of the parents.
3. Diseases produced by dominant alleles with effects so severe that people with them do not have
   
   1. Osteogenesis imperfecta
   2. Duchenne muscular dystrophy

Question 19

Genomic Imprinting

Answer 19

1. Sex of transmitting parent plays a role in the expression of the phenotype in children
2. Only one of the two parental alleles of an imprinted gene is active.
3. Angelman syndrome (maternal gene is on)
   
   1. Paternal gene is imprinted
   2. Loss of maternally inherited gene results in
      
      1. Mental retardation
      2. Happy demeanor
      3. Non-verbal
4. Prader-Willi (paternal gene is on)
   
   1. Maternal gene is imprinted
   2. Loss of paternally inherited gene results in
      
      1. Weight gain
      2. Language and motor delays