Genetic Risk Assessment by Bruce Korf for OPENPediatrics

In this video, Dr. Korf talks about calculating genetic risks based on Mendelian Inheritance and Bayes’ Theorem.

Please visit: openpediatrics.org

OPENPediatrics™ is an interactive digital learning platform for healthcare clinicians sponsored by Boston Children's Hospital and in collaboration with the World Federation of Pediatric Intensive and Critical Care Societies. It is designed to promote the exchange of knowledge between healthcare providers around the world caring for critically ill children in all resource settings. The content includes internationally recognized experts teaching the full range of topics on the care of critically ill children. All content is peer-reviewed and open access-and thus at no expense to the user.

For further information on how to enroll, please email: openpediatrics@childrens.harvard.edu

Please note: OPENPediatrics does not support nor control any related videos in the sidebar, these are placed by Youtube. We apologize for any inconvenience this may cause.

Genetic Risk Assessment, by Dr. Bruce Korf. In collaboration with the University of Alabama at Birmingham.

My name is Bruce Korf. I'm a medical geneticist at University of Alabama at Birmingham. In this lecture, we'll consider principles of genetic risk assessment. We will calculate genetic risks based on Mendelian inheritance, and utilize Bayes' theorem in genetic risk calculations.

We'll begin with autosomal recessive inheritance. Remember that both parents are carriers, and they have a one in four chance of having an affected homozygous child. So if a couple are both carriers, which you know because they've had an affected child, their risk of having another affected child is simply one in four. Consider a couple where one partner has a sibling with an autosomal recessive trait, and her partner has no known history of the condition.

We can estimate that her risk of being a carrier is 2/3, and we know this because there were four possibilities for her-- that she would be homozygous affected, that she would be a carrier having inherited the mutation from her father, a carrier having inherited the mutation from her mother, or homozygous unaffected. We know that she is not affected, and so there are only three possibilities left, of which two would make her a carrier, hence the 2/3.

To calculate the risk for her partner, we need to use data on the population frequency of carrier risk. If this were a pedigree with cystic fibrosis, and he were of northern European descent, the risk of his being a carrier would be about 1 in 25. So this couple's risk, then, of having an affected child would be 2/3, her risk of being a carrier times 1 in 25, his times 1 in 4. That is that they're both carriers, and then have an affected child. And so the total risk is one in 150.

Now let's consider autosomal dominant inheritance. Remember here that individuals who are heterozygous would be affected, and they have a 50% chance of transmitting the trait to any offspring. And so this individual, who is known to be affected, would face a 50% chance of having another affected child. For an x-linked recessive, remember that carrier females transmit the trait to half their males and carrier status to half their daughters.

So if this individual is known to be a carrier, her risk of having another affected child would be 50% if the child is male and essentially zero if the child is female, although she could end up being a carrier. Well, now let's consider the instance of incomplete penetrance. For example, here where this individual has transmitted the trait telling you she must have inherited it, and yet is phenotypically unaffected.

Well, let's assume, first of all, that there is 80% penetrance and 80% probability that a person who inherits a mutation will show the phenotype. And consider this couple and this couple. Now in this case, she is known to be affected, and hence, their risk of having an affected child is one half that they transmit the mutation times 0.8, which is the probability that a child who inherits the mutation will show the phenotype, which comes to 0.4.

Now in this case, this individual is not phenotypically affected. That means either he didn't inherit the mutation, or he did, and he's non-penetrant. The chance that he inherited the mutation is one half. The chance that he's non-penetrant is one minus 0.8, which is 0.2. Then the chance, then, that he transmits the mutation is another one half, and the chance that the child would be phenotypically affected is 0.8, and this comes to 0.04.

Pedigree Analysis by Bruce Korf for OPENPediatrics

In this video, Dr. Korf talks about analyzing pedigrees to infer mode of inheritance.

Please visit: openpediatrics.org

OPENPediatrics™ is an interactive digital learning platform for healthcare clinicians sponsored by Boston Children's Hospital and in collaboration with the World Federation of Pediatric Intensive and Critical Care Societies. It is designed to promote the exchange of knowledge between healthcare providers around the world caring for critically ill children in all resource settings. The content includes internationally recognized experts teaching the full range of topics on the care of critically ill children. All content is peer-reviewed and open access-and thus at no expense to the user.

For further information on how to enroll, please email: openpediatrics@childrens.harvard.edu

Please note: OPENPediatrics does not support nor control any related videos in the sidebar, these are placed by Youtube. We apologize for any inconvenience this may cause.

Multifactorial Inheritance by Bruce Korf for OPENPediatrics

In this video, Dr. Korf talks about evidence supporting a multifactorial mode of inheritance, models explaining multifactorial inheritance, and the genetics of common disorders.

Please visit: openpediatrics.org

OPENPediatrics™ is an interactive digital learning platform for healthcare clinicians sponsored by Boston Children's Hospital and in collaboration with the World Federation of Pediatric Intensive and Critical Care Societies. It is designed to promote the exchange of knowledge between healthcare providers around the world caring for critically ill children in all resource settings. The content includes internationally recognized experts teaching the full range of topics on the care of critically ill children. All content is peer-reviewed and open access-and thus at no expense to the user.

For further information on how to enroll, please email: openpediatrics@childrens.harvard.edu

Please note: OPENPediatrics does not support nor control any related videos in the sidebar, these are placed by Youtube. We apologize for any inconvenience this may cause.

Multifactorial Inheritance, by Dr. Bruce Korf. In collaboration with the University of Alabama at Birmingham.

My name is Bruce Korf. I'm a medical geneticist at University of Alabama at Birmingham. This talk will focus on the principles of multifactorial inheritance. We'll look at the evidence that supports a multifactorial mode of inheritance, some of the models that explain multifactorial inheritance, and then talk about what is known about the genetics of common disorders.

The paradigm that underlies the integration of genetics in medical practice is that we're all born with a genetic liability, sometimes overwhelmingly so, causing a genetic disorder like sickle cell anemia. But most of the time, much more subtle. And it requires the passage of time and exposure to environmental factors in order to transition from what might be described as a pre-symptomatic state ultimately to a disease state. The hope is that if we could identify the genes that contribute to this liability, we might be able to help avoid the exposure to environmental factors and reduce the likelihood of transition to disease. Or if that transition should occur, understand better how and why disease has occurred, and perhaps have better approaches to treatment.

The evidence that multifactorial inheritance is occurring is that a trait has a tendency to recur within families more frequently than might be expected due to chance, but on the other hand, does not follow the principles of Mendelian genetics. For example, a 50% recurrence risk for a dominant, or a 25% risk of having affected children if both parents are carriers for a recessive. Multifactorial, as the name implies, involves a combination of the action of multiple genes interacting with one another and/or with environmental factors.

In most cases, the specific genes that underlie multifactorial traits are not known, and genetic counseling for multifactorial traits is based on empirical data. These are fairly typical data for congenital anomalies that are attributed to multifactorial inheritance where you see a recurrence risk in a first degree relative, that is to say where a parent or sibling is affected, is in the range of 3%. And you'll note that the risk dilutes very quickly as one goes to more distant relatives.

What kind of evidence would support multifactorial inheritance? One would consist of identification of familial clustering. Geneticists use the variable lambda to indicate the risk of relatives affected with a trait compared with the population risk. Lambda sub R is the generic case where relatives of type R are compared with the population risk. Lambda sub S is a commonly used variable, in which we're looking at the ratio of the risk in sibs compared with the population risk.

In the case of cystic fibrosis, which is, of course, an autosomal recessive trait, the risk in sibs if both parents are carriers-- that is, if a child has already been born with CF-- would be 0.25, or one in four. The risk in the population, at least of northern European descent, is 0.0004 and hence, lambda sub S is 500, a very high number. For Huntington disease, an autosomal dominant, the risk in sibs, of course, is 0.5. The risk in the population is about 0.0001, so lambda sub S is about 5,000.

The table shows several examples of congenital anomalies or other multifactorial traits, when you see that the lambda sub S is in the tens, as low as 16, as high as 49. Nowhere near as high as the autosomal recessive or autosomal dominant examples that we've shown. But of course, the risk would be one if the risk is the same in sibs as in the general population, which it isn't for these disorders.

Non-Mendelian Inheritance Patterns by Bruce Korf for OPENPediatrics

In this video, Dr. Korf talks about sex-limited inheritance, epistasis, digenic inheritance, anticipation in the role of triplet repeat expansion mutations, genomic imprinting, and mitochondrial inheritance.

Please visit: openpediatrics.org

OPENPediatrics™ is an interactive digital learning platform for healthcare clinicians sponsored by Boston Children's Hospital and in collaboration with the World Federation of Pediatric Intensive and Critical Care Societies. It is designed to promote the exchange of knowledge between healthcare providers around the world caring for critically ill children in all resource settings. The content includes internationally recognized experts teaching the full range of topics on the care of critically ill children. All content is peer-reviewed and open access-and thus at no expense to the user.

For further information on how to enroll, please email: openpediatrics@childrens.harvard.edu

Please note: OPENPediatrics does not support nor control any related videos in the sidebar, these are placed by Youtube. We apologize for any inconvenience this may cause.

My name is Bruce Korf. I'm a Medical Geneticist at University of Alabama at Birmingham. This lecture will focus on non-Mendelian inheritance patterns. This lecture will explain the following ideas: sex-limited inheritance, epistasis, digenic inheritance, anticipation in the role of triplet repeat expansion mutations, genomic imprinting, and mitochondrial inheritance.

In sex-limited expression, a phenotype is only seen either in males or females but not in both. The example here is that of male pattern baldness, which is typically expressed only in males. It is an autosomal dominant trait, but females have a low likelihood of manifestation. In this case then, a female has transmitted the trait and could be said to be non-penetrant having an affected father and an affected son. Other examples of sex-limited expression would be hereditary breast and ovarian cancer, where obviously ovarian cancer does not occur in men, and breast cancer only rarely does.

Epistasis involves the influence of one gene on the expression of another. The classic example involves the ABO blood group system. This system is a two-allele system in which individuals with the A allele produce an antigen on red blood cells called A, and those with the B allele, an antigen called B. Heterozygotes, who have an A and a B allele will produce both antigens. If you look at the pedigree above, you see a male with type A blood and a partner with type O blood had a child with type AB. This would seem to be impossible, because the mother does not have a B allele to transmit in this pedigree.

What actually is going on though is an example of an epistatic interaction. The enzymes that are the product of the A or the B allele act on a substrate, the H substance, which is a precursor either to A or B. H itself is the product of another enzymatic reaction from a previous precursor. Individuals who have what is called the Bombay phenotype fail to produce H because of a deficiency of the enzyme required to go from the precursor to the H substance.

These individuals then fail to make either the A or the B antigen, but not because they lack the A or the B enzyme, but rather because they lack the H substance. So one can presume that the mother in this case has this phenotype due to mutation in an enzyme upstream of the A or the B enzymes. In this case, therefore, the enzyme that would act to produce H substance acts in an epistatic manner to produce a phenotype similar to deficiency of the A or B enzyme.

Digenic inheritance is a relatively recently discovered phenomenon in which heterozygosity for two distinct genes can produce a phenotype that otherwise would require homozygosity for one or the other gene. Consider this pedigree where there are two gene loci, and this individual is heterozygous for a mutation in locus 1, and this individual heterozygous for a mutation in locus 2. Notice that this child inherits the locus 1 and locus 2 mutations and is affected, even though he is not homozygous for either one.

There are a number of disorders where this digenic inheritance pattern has been identified, most notably retinitis pigmentosum. Neither allele, if heterozygous by itself, would be sufficient to produce the phenotype. This tends to occur when the gene products interact with one another and when a partial deficiency of one compounded with a partial deficiency of another leads to inadequate function and, hence, a phenotype.

Using Standard Pedigree Symbols by Bruce Korf for OPENPediatrics

In this video, Dr. Korf reviews the use of standardized pedigree symbols in assembling a family history.

Please visit: openpediatrics.org

OPENPediatrics™ is an interactive digital learning platform for healthcare clinicians sponsored by Boston Children's Hospital and in collaboration with the World Federation of Pediatric Intensive and Critical Care Societies. It is designed to promote the exchange of knowledge between healthcare providers around the world caring for critically ill children in all resource settings. The content includes internationally recognized experts teaching the full range of topics on the care of critically ill children. All content is peer-reviewed and open access-and thus at no expense to the user.

For further information on how to enroll, please email: openpediatrics@childrens.harvard.edu

Please note: OPENPediatrics does not support nor control any related videos in the sidebar, these are placed by Youtube. We apologize for any inconvenience this may cause.

Using Standard Pedigree Symbols, by Dr. Bruce Korf. In collaboration with the University of Alabama at Birmingham.

My name is Bruce Korf. I'm a Medical Geneticist at University of Alabama at Birmingham. In this lecture, I will review the use of standardized pedigree symbols in assembling a family history.

Females are depicted by circles and males by squares. A partnership is shown by connecting the two figures. If the parents are blood relatives of one another, a double symbol is used to indicate consanguinity.

Here we show children of this couple. The triangle indicates a miscarriage, and they have a daughter and a son. Now you see siblings of the mother. The filled symbols indicate individuals who are affected by a particular phenotype. One can use any kind of manner of depicting a phenotype. If multiple phenotypes are being tracked, for example, one can divide the symbols into sectors, indicating a specific phenotype in each sector.

A slash through a figure indicates that an individual is deceased. Here you see a relationship that is no longer active. In some cases, it's convenient to show multiple sibs by indicating a number of sibs within a symbol. And the proband, or the individual who brought the family to attention, is depicted by an arrow.

In taking a family history, remember to ask about deceased relatives, miscarriages, ancestry, sibs with different parents, or children who are adopted, either into or out from the family.

Please help us improve the content by providing us with some feedback.

Dr. Bruce Korf - Neurofibromatosis

Dr. Bruce Korf - NF Conference Part 2

Dr. Korf discusses the current standing of the NF 'landscape' and what we should expect to see in the future with regards to research and available treatments

Genomic Medicine - Bruce Korf (2014)

May 21, 2014 - Current Topics in Genome Analysis 2014
A lecture series covering contemporary areas in genomics and bioinformatics. More: