Terminology & Concept Recap

00:00 Now, we switch gears and move on to three lectures on single gene disorders. Single gene disorders display Mendelian inheritance patterns. So, there's a book that I recommend. It’s actually a really great reference tool for when you’re in practice. But it’s a classic that lists all the known single gene disorders.

00:24 It’s called Mendelian Inheritance in Man by Victor McKusick, probably not something I said that you need for your exams but you will like to see it in the future. Let’s have a quick terminology recap before we get started on the details of single gene disorders. Probably these are terms that you are already familiar with, at least the majority of them. First, let’s take a look at this one, the locus 1.

00:53 You’re familiar with locus as the place where a gene is on the chromosome. At this locus, we have genotype big A, little a and that is heterozygous. This individual is heterozygous for genes at both loci, and so we have locus A, locus B, locus 1, locus 2 and is heterozygous. The haplotype is what is displayed on one chromosome. Haplo meaning half and you probably are familiar with that also. The one that may be new is the term compound heterozygote. A compound heterozygote is an individual that appears to be homozygous but the two mutant alleles come from a different background. So, they’re mutant in a slightly different way but they come together to form a recessive. In general, we’ll find that recessive alleles are fairly uncommon. So often, when a mutation has happened at a certain locus, it happens in multiple different places. You probably recall that from when we were looking at HapMap in our molecular genetics series. Compound heterozygote is probably the only really new term on this list for you, so two different mutations for the same thing, different origin. An exception to this would be in inbreeding or consanguinity where you have two individuals from the same family that have the same exact mutation in the genes. So, another concept to recap, pleiotropy.

02:39 Although we are dealing with single gene disorders that come on one gene, one gene, we’ve already learned may have multiple effects. We’ve explored that in detail with the sickle cell beta globin gene having effects in multiple places. Another couple of concepts to recap are penetrance versus expressivity. Now, these ones are particularly important because you are going to have a hard time or we, in general have a hard time picking out environmental impacts and such from penetrance and expressivity because both affect the ratio and the degree of expression of these single gene types. Something that has variable penetrance means that even though all of these squares in this image have the genotype for that particular disorder, only some of them express it. We express that as a percent. Something might have a well-known 90% penetrance.

03:45 You could probably find that out in McKusick’s book. Variable expressivity then means that there’s a varying degree of expressivity. It could be incomplete dominance or it could be that the heterozygote, one has a greater impact on the expression versus the homozygous has less impact on the expression or vice-versa. Variable degrees of expression can be seen.

04:17 Sometimes, of course, we see the variable degrees of expression as well as penetrance, right? So, things get even more complicated to pick out. A lot of the time in genetic counseling, we’re making pedigrees and trying to predict outcomes. Because of penetrance and expressivity, you might not always be able to predict the outcome or characterize the disease that is in place in that family. These are two concepts to really keep in mind when considering genetic counseling.