Identify the standard symbols used in pedigrees and explain how pedigree analysis is used in determining mode of inheritance.
Pedigree analysis allows you to study an inherited trait in a group of related individuals to determine the pattern and characteristics of the trait, including its mode of inheritance, age of onset, and phenotypic variability
Describe the common features of Autosomal Recessive Inheritance
Only homozygotes are affected
Similar amount of both males and females affected
Consanguinity is often present
If both parents are affected, all children should be affected
If one parent is affected, all children are carriers
If one parent is affected and one is a carrier, ½ are affected and ½ are carriers
Describe the common features of Autosomal Dominant Inheritance:
More males affected than females
Affected individuals have affected parent, will have 50% of affected children
Unaffected family members will have no affected children
Describe the common features of X-linked recessive Inheritance
More males affected than females
No father to son transmission
Daughters of affected men are all carriers
Carrier females will have 50% affected sons
Affected females will have affected fathers AND affected or carrier mothers
Describe the common features of X-linked dominant inheritance
Females affected twice as often as males
Affected males transmit trait to all daughters but no sons
Affected females transmit trait to 50% of daughters and 50% of sons
Explain why some mutations are dominant and list examples.
1) Haploinsufficiency: half of the normal amount of protein is not enough.
Ex: familial hypercholesterolemia. The receptor needed to get cholesterol from blood to cells is mutated causing elevated levels of serum cholesterol.
2) Dominant negative effect: a mutant protein interferes with the function of a normal protein
Ex: Osteogenesis imperfecta
3) Gain of function: New or enhanced property of the protein
Ex: Achondroplasia, Huntington disease
What is Allelic Heterogeneity?
Many genes have more than one mutant allele. Allelic heterogeneity is caused by different mutations in the SAME gene
Different alleles may lead to clinically indistinguishable phenotypes, different severity and/or extent of symptoms, and different clinical presentations.
What is Locus Heterogeneity?
The same condition can be caused by mutations in different genes. Locus heterogeneity is caused by mutations in DIFFERENT genes.
What is Penetrance?
The likelihood that the disease allele will result in the disease
Describe Delayed Onset
An individual may pass the allele on to offspring but due of unrelated causes prior to showing the disease (ie a disease that presents later in life such as Huntington’s disease).
What is Germline Mosaicism?
Mutation in the germ stem cell that results in mutated gametes
Ex: A family with two children affected with a dominant disease without prior family history= likely mosaicism of the gonads (highly unlikely that two mutations will occur spontaneously in two siblings).
Diverse effects of a single gene on several organs
Ex: Marfan syndrome- mutations in fibrillin gene leads to connective tissue weakness. Can affect cardiac, skeleton, and eyes differently in different affected individuals.
Describe Variable Expressivity
The degree of clinical manifestation of the SAME mutant allele in different individuals.