So, the way in which the statistics are done in these kinds of families
is there's logarithm of the odds ratio score, the lod score.
And a lod score greater than three, And there's a way of defining that statistic.
Suggest that you have landed in the right region for
this particular genetic variant.
Now it doesn't tell you what the genetic variant is,
the region might be huge, it might encompass dozens and dozens of genes, and
the challenge to the investigator is to either get the region smaller by acquiring
More recombination events, in other words, more generations.
Or by tediously tracking through the particular region
of linkage to find the gene that actually causes the disease.
A Lod score less than two suggests that the region that you've been looking
does not have the disease locus contained.
And in between, you just need to do more.
So I'm going to show you one example Of how this technology was used to crack
a common, a relatively common disease that's inherited in an autosomal fashion,
what's so called Mendelian disease.
This is a very, very large kindred.
You can see With affected individuals shown in dark,
many of the individuals are dead because it's a large family.
And the disease might kill them early, but in fact, age will kill many of them.
So you have to have phenotypes.
You have to have DNA on large, large numbers of patients, and do mapping.
This particular phenotype happens to be a family,
a French Canadian family in fact with a disease called hypertrophic
cardiomyopathy that results in a thickened ventricle.
This exercise in mapping initially would cover perhaps
several hundred dinucleotide repeat regions across the genome.
Mapping those would identify a region of the genome
in which the disease gene would occur.
So you can imagine with mapping 400 markers,
you would arrive at a very very large chunk of the genome.
In which the disease gene occur.
So that was what was done.
First this a small region of chromosome 14 in that particular family.
And you can see there's a Lod score that is very,
very high in this particular region of linkage.
So, with that particular marker, it's likely that the disease
chain the actual mutation that causes the disease is located in that region.
But that region spans hundreds of thousands of base pairs.
So with advancing technologies and the ability to define those regions in more
detail, and to define the genes in those regions.
Came the ability to actually isolate the specific gene and the specific mutation
that causes the disease in that family and the way to do
that is to have a large family with a high Lod score and some physiologic rationale.
This is a map of the disease genes called the beta-myosin heavy chain gene.
It's a gene that's expressed in the heart as an important
part of the contractile apparatus.
This gene was identified as a disease gene in the disease hypertrophic cardiomyopathy
in 19 89.
To this day it's not very clear how a mutation is beta
myacin heavy chain results in the phenotype of hypertrophic cardiomyopathy.
Nevertheless, the discovery has been a huge boon to clinicians because we can now
use genetic testing to identify mutation carriers and non-mutation carriers.
This is a cartoon from the very first publication that identified the mutation
in this particularly family, but we now know that there are literally hundreds
of mutations in this particular gene that cause the disease in other families.
And there are literally dozens of genes in which mutations can
cause the disease not just in betamyosin heavy chain, but in other genes.
And the interesting thing about those genes is that they all
encode proteins that interact in some way with the beta myosin heavy chain gene
to effect the way the heart contracts.
So it's a great story of going from a family,
doing traditional linkage, finding the region, finding the gene and then using
that information to uncover the cause of the disease in many many other families.
And start to understand the underlying path of physiology,
start to develop genetic testing, which we talk about more in the case studies.
And I emphasize again, the reason that that was successful is that it starts
with this very very large Family.
Very small families, individuals with hypertrophic
cardiomyopathy are just simply not informative using this linkage approach.
But what the good news is is that with newer sequencing technologies which I'll
talk about in a couple of modules.
We can actually crack cases of patients who have unusual phenotypes and
don't have much of a family history and we'll talk about that later.