Patterns of Inheritance

When a person has the genotype for a disease but does not express the phenotype associated.

What is incomplete penetrance?

If a female who is heterozygous or the hemophilia gene has asymmetric X-chromosome inactivation in the liver where the mutated X-chromosome is found in higher numbers the patient could present with MILD hemophilia manifestations.

Give an example of manifesting heterozygosity in Hemophilia.

A pedigree

The following is an example of what?

All those with the genotype for the disease express the phenotype for the disorder.

What does it mean if a disorder is fully penetrant?

When a disease causing mutation affects multiple organ systems.

What is pleiotropy?

A compound heterozygote.

What is the term for a person with two different mutant alleles at the same locus that has a phenotype of a disease?

Blood typing

Co-dominance is seen in what common manner?

Yes Yes Generations can be skipped as individuals can be carriers without ever knowing until a child becomes affected with the disease.

Autosomal recessive disease: Are males and females affected with equal frequency? Is male to male transmission seen? Are generations typically skipped?

Huntington disease is a autosomal dominant disorder. Her father is likely Aa or the disorder. There is a 50% chance that she has the disorder but it has not shown yet because it has a delayed age of onset. If she has the Aa genotype and her husband is aa there is a 50% chance that she will transmit it to her child. 0.5 x 0.5 = 0.25 Without undergoing genetic testing there is a 25% or 1/4 chance that she will transmit the mutant gene to her child.

A 23 year old female is pregnant and has come for genetic counseling. Her father (of 50 years) is diagnosed to have Huntington disease. What is her risk of transmitting the mutant gene to her child? Why?

Yes Yes No - every affected child has an affected parent

Autosomal dominant disease: Are males and females affected with equal frequency? Is male to male transmission seen? Are generations typically skipped?

Dominant-negative. Ex. Osteogenesis imperfecta and marfan syndrome.

Autosomal dominant mutations manifest in the heterozygous state. One explanation is that the mutated product interferes with the function of the normal gene. What is this called? Give an example.

Haplo-insufficiency. Ex. Familial hypercholesterolemia

Autosomal dominant mutations manifest in the heterozygous state. One explanation is that the mutation causes a loss of protein function which results in half the normal gene product being made with leads to this disorder. What is this called? Give an example.

Gain-of-function Ex. Huntington disease and achondroplasia

Autosomal dominant mutations manifest in the heterozygous state. One explanation is that the mutation results in increased levels of gene expression or the development of new function of the gene product. What is this called? Give an example.

If a female is an carrier of the mutated gene and asymmetric X-chromosome inactivation occurs where the mutated X-chromosome is in found in higher levels in affected areas then the patient could manifest with mild symptoms even though it is a X-linked recessive disorder.

Describe how a female can have manifesting heterozygosity of an X-linked recessive disorder.

Mother - 100% Father - 0%

If a mother has a mitochondrial disease what is the likelihood that her offspring will also have the disease? If a father has a mitochondrial disease what is the likelihood that his offspring will also have the disease?

II-2: Aa II-3: Aa III-4: aa

Given below is a family with familial hypercholesterolemia. Write the genotype of the individual II-2, II-3, and III-4.

Only from the mother.

How are mitochondrial inherited disease transmitted?

Because males receive only one X chromosome from their mother these pedigrees mostly show males as being affected. Also, male to male transmission is never seen.

How can you identify X-linked recessive disorders on a pedigree?

If we are given the penetrance percentage we simply multiply that percent by the percent chance that the offspring will have the disorder and we get the recurrence percentage.

How do we determine the recurrence of a disorder with incomplete penetrance?

Skipping of generations is not common and no male to male transmission occurs. Affected males always transmit the disease to their daughters but never to their sons. More females affected than males.

How do you identify X-linked dominant disorders in a pedigree?

It is the result of heteroplasmy which is the unequal distribution of mutant and non-mutant mitochondria from the mother. Some mitochondria are mutant, some are not. If the offspring derives a large majority of his/her mitochondria from the mutant strain they will be more severely affected than a child who has few or none of their mitochondria derived from the mutant mitochondria.

How does variable expression occur in mitochondrial diseases?

1. The relationship no longer exists 2. Consanguinity - mating between individuals that are closer than 2nd cousins. 3. Monozygotic twins 4. Dizygotic twins 5. Adoption out of the family - share genetic material with siblings 6. Adoption into the family - do not share genetic material with siblings 7. Stillborn

Identify symbols #1-7

There is no calculation for it but the recurrence is most likely low.

If two parents have an child who is afflicted with a new mutation condition what are their chances of recurrence?

Deceased = a line through their symbol Proband = arrow

In a pedigree, what symbol indicates the individual is deceased? What symbol indicates the individual is the proband?

A square for males and a circle for females. Affected individuals are shaded.

In a pedigree, what symbol is used for males and what symbol is used for females? Affected individuals are indicated by what?

1. I-2: Unaffected, non-carrier female 2. II-3: Unaffected, non-carrier male 3. II-7: Unaffected, carrier male 4. III-9: Affected female

In the following photo, how would you point out the individuals circled in red listed #1-4? How would you describe each?

50%

In the pedigree seen here, what is the chance that the next child of the circled couple will be affected?

When the father is of an increased age.

New mutations are most common in what scenario?

1. High carrier frequency in the population 2. birth of an affected child to an affected individual 3. Consanguineous mating

Psuedo-autosomal dominant disorders are commonly explained by what three explanations?

1. BCFG and ADEH 2. ACEG and ACEG or BDFH and BDFH

The following are examples of the two homologous chromosome 15 in two parents. 1. If uniparental disomy non-disjunction, from the mother, occurred in meiosis 1 what chromosome 15 pair would you expect the child to have? 2. If uniparental disomy non-disjuction, from the father, occurred in meiosis 2 what chromosome 15 pair would you expect the child to have?

Spermatogenesis, therefore the disease is rarely spread to another generation.

Y-linked inheritance commonly affects what?

True

The following are factors that can increase or decrease the incidence of an autosomal recessive trait in the population? True or false 1. Consanguinity 2. Heterozygote advantage 3. Genetic isolation 4. Assortative mating

II-3 Huntington's disease is a triplet repeat disorder. The mutant allele in II-3 has the most triplet repeats and therefore is likely to have an earlier age of onset and increased severity.

The following is a family with Huntington's disease. Below the pedigree is a Southern blot analysis of the chromosome affected. Which of the individuals likely has the earliest age of onset and why?

2/3. The parents are both unaffected but they have two children who are affected meaning they are both carriers. As a result the punnett square would show 1/4 AA, 1/2 Aa, and 1/4 aa. Because III-4 does not have the disease they could only be AA, Aa, or aA meaning there is a 2/3 chance they are a carrier.

The following pedigree shows an autosomal recessive disease. What is the likelihood that individual III-4 is a carrier of the mutant allele?

Autosomal dominant

Tim is affected with disease. Looking at the following pedigree, what mode of inheritance does the disease follow?

1. The gene that is only on in one parent could have its sequence deleted and, because it is turned off in the other parent there are zero copies of the gene available. 2. Uniparental disomy can occur. This causes the child have two copies of the turned off gene.

What are two mechanisms that lead to disorders related to imprinting?

Some diseases, like Huntington's disease, only show symptoms later in life so initially there is incomplete penetrance because the symptoms have not yet developed and won't develop until an older age.

What is a common reason for incomplete penetrance early in life?

An unaffected individual in a family with a history of a disease who has approached the physician for consultation.

What is a consultant?

It is a disorder that requires a mutation in two genes in order to produce a disorder. NOTE: A mutation in only one of the genes will not result in disease manifestation. The mutation must be in at least one allele of both genes.

What is a digenic disorder?

The location of a gene on a chromosome

What is a locus?

An affected individual in the family who has approached the physician for consultation.

What is a proband?

It is a disorder where repeats of three nucleotides are inserted into part of a gene which affects the translation and/or function of the gene product

What is a triplet repeat disorder?

When different mutations at the same locus cause the same disease.

What is allelic heterogeneity?

When multiple mutations to a gene occur in the population that presents with the same disease. Ex. Cystic fibrosis

What is allelic heterogeneity?

The different form/version of a gene.

What is an allele?

As generations continue triplet repeat disorders tend to increase in size/amount of triplet repeats. As the amount of triplets increases the disease tends to have an earlier age of onset and increased severity.

What is anticipation in relation to triplet repeat disorders?

When one germline has a mutation that continues to proliferate throughout the progeny while other germline cells that also continue to proliferate do not have the mutation. It is difficult to predict the recurrence of germlilne mosaic disorders and likely not possible.

What is germline mosaicism? How can we predict recurrence in a disorder transmitted through germline mosaic lineage?

It is the result of the fact that some genes are turned off in the mother and some genes are turned off the father (usually by methylation). Only one copy of the gene is required so this is a normal process.

What is imprinting?

When there are mutations on different chromosomes or loci (different genes) that cause the same disease phenotype.

What is locus heterogeneity?

Multiple forms/alleles of a gene in a population.

What is polymorphism?

The probability that the offspring of a couple will express a genetic disease.

What is recurrence risk?

Are those that are affected mostly males?

When attempting to identify the inheritance mechanism from a pedigree, and you have determine that it is a recessive disorder, what question should you ask next?

Homozygous individuals usually have a worse prognosis than those that are heterozygous. As a result, unless a question clearly indicates, always assume an individual with an autosomal dominant disorder is heterozygous.

What is the difference between heterozygous and homozygous individuals affected by an autosomal dominant disease?

Incomplete penetrance is when the person has the genotype for a disease but does not express the phenotype. Variable expression is when the person has the genotype but only expresses some of the manifestations of the disease while others express different signs.

What is the difference between incomplete penetrance and variable expression?

Autosomal dominant

When attempting to identify the inheritance mechanism from a pedigree, if you have a dominant disorder with male to male transmission, what type of disease should you be thinking of?

Variable expression is when a disease is expressed differently from one individual to the next. Some patients may have only mild signs while other may have the most severe and none of the mild signs while others may develop all the manifestations of the disease.

What is variable expression?

In trisomy rescue a non-disjunction occurs and the zygote has three homologous chromosomes instead of the normal 2. Many trisomies are not compatible with life and as a result the zygote tries to fix the problem by forcing out one of the homologous chromosome which can result in the fetus having 2 chromosomes of the same number from one parent and no chromosomes of that number from the other parent.

What occurs in the phenomenon of trisomy rescue?

Do all the affected individuals have affected parents?

When attempting to identify the inheritance mechanism from a pedigree, after you identify that problem is not a mitochondrial disease, what question should you ask?

X-linked recessive

When attempting to identify the inheritance mechanism from a pedigree, and you determine it is a recessive disease with a preponderance of males affected, what type of disease should you be thinking of?

Autosomal recessive

When attempting to identify the inheritance mechanism from a pedigree, and you determine it is a recessive disease with males and females affected equally, what type of disease should you be thinking of?

X-linked dominant. A follow up question would be, do all the daugters of affected males have the disorder. If yes than it is X-linked dominant but if no then it is likely autosomal dominant.

When attempting to identify the inheritance mechanism from a pedigree, if you have an dominant disorder with no male to male transmission, what type of disorder should you be thinking of? What other question can you ask to confirm?

Is there male to male transmission?

When attempting to identify the inheritance mechanism from a pedigree, once you have determined it is a dominant disorder, what question should you ask?

Is it a mitochondrial disease?

When attempting to identify the inheritance mechanism from a pedigree, what is the first question you should ask?

Dominant disorders

When attempting to identify the inheritance mechanism from a pedigree, when all infected individuals have infected parents, what type of disease should you be thinking of?

Recessive

When attempting to identify the inheritance mechanism from a pedigree, when there are infected individuals with parents that are unaffected, what type of disease should you be thinking of?

Recessive disorders

When attempting to identify the inheritance mechanism from a pedigree, when there are infected individuals without infected parents, what type of disease should you be thinking of?

When a carrier and affected individual mate. This give a 50% chance that the offspring will be affected, appearing like an autosomal dominant disorder, but in reality it is an autosomal recessive disorder.

When do pseudo-autosomal dominant disorders occur?

Females are rarely affected and usually are only carriers. Because men are more likely affected an affected father would never transmit to a son but always transmit one mutated X gene to the daughter who could subsequently transmit the disease to her son.

Why do X-linked recessive disorders appear to skip a generation?

Because the person has 50% of normal enzyme activity and that amount of activity is enough to maintain normal functioning.

Why do people who are heterozygous for autosomal recessive disorders not have manifestations of the disease?

Because individuals from the same family line share some genetic material and if there is a mutation (even a recessive one) it is more likely that another member of that family will be a carrier of the same mutation.

Why does consanguinity increase the likelihood of disease?