Overview of Mendelian Genetics

Question 1

What is the distribution of causes of congenital malformations?

Answer 1

60% unknown
20% multifactorial
7.5% single gene defect
6% chromosomal abnormalities
The rest is external maternal factors

Question 2

What are single gene defect?

Answer 2

Often termed mendelian because they follow inheritance patterns predicted by his classic experiments

Question 3

What are the four categories of single-gene disorders?

Answer 3

>50% Autosomal dominant
~36% Autosomal recessive
<10% X-linked
Mitochondrial
Y-linked

Question 4

Define locus.

Answer 4

The position of a gene on a chromosome

Question 5

Define allele.

Answer 5

The alternative versions of a gene that may occupy a given locus

Question 6

Define polymorphism.

Answer 6

The occurrence in a population of two or more alternative genotypes (may or may not be deleterious)

Question 7

Define genotype.

Answer 7

The genetic constitution of an individual

Question 8

Define phenotype.

Answer 8

The observable expression of a genotype as a morphological, biochemical or molecular trait

Question 9

Define homozygote.

Answer 9

Individual with a pair of identical alleles at a given locus

Question 10

Define heterozygote.

Answer 10

Individual with different alleles at a given locus

Question 11

Define compound heterozygote.

Answer 11

Individual with 2 different mutant alleles at a given locus

Question 12

Define double heterozygote.

Answer 12

Individual with 1 mutant allele at each of 2 different loci

Question 13

Define autosomal dominant dominance.

Answer 13

Heterozygotes are phenotypically affected

Question 14

What are the criteria of autosomal dominance?

Answer 14

1) phenotype appears in every generation
2) offspring have 50% chance of inheritance
3) phenotypically normal individuals do not transmit the phenotype
4) no difference in male/female transmission

Question 15

Examples of autosomal dominant diseases.

Answer 15

Marfan's disease
Huntington's disease
Familial hypercholesterolemia
Achondroplasia
Neurofibromatosis
Non-insulin dependent diabetes

Question 16

3 exceptions to autosomal dominance.

Answer 16

1) New mutation in gamete of phenotypically normal parent
2) Variable pentrance
3) Variable expressivity

These phenomena may mask other things

Question 17

Define penetrance.

Answer 17

The probability that a gene will have any detectable phenotypic expression at all

Question 18

Conditions of penetrance.

Answer 18

An all or none concept
Failure accounts for skipping of generations
Reported as %age of individuals to carry mutant genotype which express the mutant phenotype

Question 19

Example of reduced penetrance.

Answer 19

Split-Hand Deformity

70%penetrance * 50% dominant risk = 35% overall risk

Question 20

Define Expressivity.

Answer 20

The degree of expression of the phenotype

Question 21

Conditions of expressivity.

Answer 21

Severity of disease manifestation can very considerably
Environmental factors play a role
Unrelated genes may affect function of the mutant gene product

Question 22

Define autosomal recessive dominance.

Answer 22

Only homozygotes are phenotypically affected

Question 23

4 criteria of autosomal recessive dominance.

Answer 23

1) Affected phenotype is apparent only in sibs
2) Recurrent risk for each sib is 25%
3) Consanguineous parents increases likelihood of inheritance
4) Males and females equally likely to be affected

Question 24

Examples of autosomal recessive diseases.

Answer 24

Cystic Fibrosis
Sickle cell anemia
Tay-Sachs disease
Phenylketonuria (PKU)

Question 25

Conditions of autosomal recessive dominance.

Answer 25

Complete absence of phenotype except in sibs

Both parents are carriers of 1 copy of the defective gene

Question 26

Define X-linked recessive dominance.

Answer 26

“mother to son” transmission

Question 27

3 criteria of X-linked recessive dominance.

Answer 27

1) Incidence of phenotype is much higher in males than females
2) Mutant gene is transmitted from father to all daughters/no sons
3) Heterozygous females are usually unaffected but may show some variable expression of the trait (manifesting heterozygote)

Question 28

What are some X-linked dominant diseases?

Answer 28

Females are affected but males affected more severly, often lethal

Examples include Ornithine Transcarbomoylase Deficiency and Hypophosphatemic Rickets

Question 29

Since males have only one X chromosome they are _____ for X genes.

Answer 29

Hemizygous

Question 30

Why do female carriers of X-linked recessive traits sometimes exhibit phenotypes?

Answer 30

Due to unfavorable lyonization

Question 31

What are some examples of X-linked recessive diseases?

Answer 31

Hemophilia A
Duchenne Muscular Dystrophy
Glucose-6-Phosphate Dehydrogenase Deficiency
Red/Green Color Blindness

Question 32

Why do women not experience twice the gene products in X-linked disorders?

Answer 32

They undergo “dosage compensation” at the morula stage of development.

This was described by Mary Lyons in 1961.

Question 33

What is the Lyon Hypothesis?

Answer 33

All females are mosaics with respect to their X chromosomes. Inactivated X chromosomes are referred to as Barr Bodies.

Question 34

What is Somatic Cell Mosaicism?

Answer 34

Mutation occurs in somatic cell and results in clone of mutant cells derived from original mutant.

Question 35

What is the classic example of Somatic Cell Mosaicism?

Answer 35

Cancer

Question 36

Is there such thing as Y-linked genes?

Answer 36

Yes, several X-linked genes have Y-linked counterparts.

Other Y-linked genes are required for production of testes and sperm.

Question 37

What are the 3 criteria for Mitochondrial Disorders?

Answer 37

1) Purely maternal inheritance
2) Sons and daughters are equally affected
3) Wide variability of expression

Question 38

Diseases linked to mitochondrial disorders.

Answer 38

Leber’s hereditary optic atrophy (LHON)
Mitochondrial encephalomyopathy lactic acidosis, and stroke like episodes (MELAS)
Myoclonus epilepsy with ragged red fibers (MERRF)

Question 39

Define mitochondrial disorders.

Answer 39

Mother to everybody transmission