In this podcast, we're going to talk about some examples of non-mendelian
inheritance. We talk about recurrence risk is the likelihood of getting a
genetic condition. We've been talking about single gene conditions whether they
may be autosomal dominant or autosomal recessive conditions or sex linked
conditions. But, what about multifactorial inheritance, how do you deal with
recurrence risk? Well, you have to deal with what's called
empiric risk. And so, for example, these are just some empiric risks of
conditions we know. The prevalence of cleft lip or palate in the general
population is 0.001. The same for clubfoot. Congenital hip dysplasia may be
0.002. We just know from empiric risk that first-degree relatives
have 0.04% chance, for example, of having cleft lip or palate. Second-degree
relatives 0.007 chance. Third degree relatives 0.003. So, when you're dealing
with multifactorial inheritance, you can't really calculate recurrence risk,
you have to look at what the data show and just give that information to
patients. Some non-mendelian genetics oppose that I think is important for you
to know about. The first one relates to mitochondrial genes and you know this
already from your study of biochemistry. Mitochondrial genes are maternally
inherited, so you can see, the mutation in this individual, this woman and she's
passing the mitochondrial defects through women to subsequent generations.
The human mitochondrial DNA. You probably remember this from your
study of biochemistry, is relatively small. The mutation rate from
mitochondrial DNA is perhaps 10 times higher than that of the mutation rate
for nuclear DNA. There are many known mitochondrial
diseases. They affect all organ systems. Expression of mitochondrial diseases is
variable and it's variable primarily due to heteroplasmy. This just shows an
example of what we mean by that. The disease phenotype is variable as more
and more mitochondria mutations accumulate in an egg. Offspring
can show effects from no effects to relatively mild effects to relatively
severely affected. Now, I want to talk about gene silencing because for some
human genes one allele may be transcriptionally inactive, that is
there's no messenger RNA that's encoded by that gene and that's dependent upon
the parent from which the allele was received and this is something that
we've discovered only relatively recently. Gene silencing, we would say an
allele is transmitted by the mother would be inactive, may be the same allele
transmitted by the father would be active. So, in gene silencing a normal
child would have only one transcriptionally active copy of a gene.
Under most circumstances, you have to transcriptionally active copies of the
gene. So, the process where one gene is silenced is known as imprinting. The
transcriptionally silenced gene is said to be imprinted and we know now that
there are several dozen human genes that are imprinted. Imprinted genes tend to be
heavily methylated and the histones associated with these imprinted genes
tend to be hypoacetylated. So, imprinting of genes on the autosomes is
in a sense similar to x chromosome inactivation. We know that imprinting
appears to be a normal process, but imprinting can cause problems because
what would happen if there's a chromosomal aberration, say a chromosomal
deletion in a region that involved imprinted genes. There's a four mega base
pair region on chromosome 15 on the long arm that if it's deleted can cause
problems. If the deletion is inherited from the father, the child is going to
have a disease known as Prader-Willi syndrome. The child will have short
stature, poor muscle tone, relatively small hands and feet, will be obese
have some mild intellectual impairment, and will show hypogonadism. That's
Prader-Willi syndrome. If the same deletion, instead of occurring on the
paternal chromosome 15 occurs on the maternal chromosome 15, the child has
Angleman syndrome. In this case, the child has severe intellectual retardation or
intellectual impairment, seizures, and ataxic gait. The diagram on the bottom
explains how this occurs. So, we know that on chromosome 15 those regions that have
active Prader-Willi genes and inactive Angleman genes. It turns out that on
chromosome 15, the paternal chromosome 15 has the Angleman genes silenced and on
the maternal chromosome 15 the Prader-Willi genes are silenced. So,
here's what happens: you have a deletion on the paternal chromosome 15, you lose
the active Prader-Willi genes, and the individual child has Prader-Willi
syndrome. If the deletion occurs on the maternal chromosome 15, you are deleting
the act of Angleman gene, the child still has the act of Prader-Willi genes, so the
child has Angleman syndrome. If the single act of copy of these genes is
lost through a chromosome deletion there's no active gene product, so the
disease results. Another situation we've come to understand is the anticipation,
that is whether a nucleotide repeats. Myotonic dystrophy, it's an autosomal
dominant disorder. It can appear earlier and earlier in each subsequent
generation. The disease is caused by a trinucleotide repeat expansion.
It's a CGT repeat in a protein kinase gene and this repeat expands in
subsequent generations. So, the disease is manifest earlier and earlier in each
subsequent generation. The southern blot, on the right, shows a homozygous
individual normal 4-5 repeats, a
heterozygous individual may show 175 repeats of the
disease gene with his trinucleotide repeat. Here's a heterozygous individual,
several generations later that shows 900 repeats of the trinucleotide repeat. So,
in this instance, the disease would manifest at a younger age than in this
instance, for example. There are a variety of diseases that are associated with
nucleotide repeat expansions. Huntington disease is a trinucleotide repeat
expansion of NA CAG repeat. Normal individuals show 6-34 or
so repeats. If you show above say 35 repeats, that suggests that
you have the disease phenotype. The more repeats you have, the more severe the
disease, and the early the onset of disease. Huntington disease, as you know,
is an autosomal dominant condition. Loss of motor control, you'll have dementia
eventually coming into play and a very much an affective disorder. Friedreich
ataxia, another nucleotide repeat syndrome. This one's an autosomal
recessive 6 to 32 repeats in a GAA repeat, that's normal. 200 to 1,700
repeats suggests you have the mutation and the disease manifests. As limb ataxia
disordered speech, motor functions, they may be cardiomyopathy that can be
weaknesses in the lower extremities. Fragile X, another trinucleotide repeat
and a CGG repeat. This is an x-linked recessive disorder 4 to 39 repeats as
normal. You get above 200 repeats and you begin to show the disease phenotype.
Mental disability, large ears and jaws, maybe microorganism in males. And we
know there are several dozen diseases now that relate to nucleotide expansions.
So, there are conditions and genetic disease that you may encounter that did
not necessarily follow simple Mendelian patterns of inheritance. We've talked
about osteogenesis imperfecta in relation to germline mosaicism. We've
talked about retinoblastoma whether is incomplete penetrance. We
talked about Huntington disease, trinucleotide repeat, but an age
dependent penetrance, variable expression. We mentioned neurofibromatosis, locus
heterogeneity like adult polycystic kidney disease, some diseases of show
pleiotrophy where there's more than one effect. We mentioned for example Marfan
syndrome, cystic fibrosis. We've mentioned sex linked diseases like hemophilia or
Duchenne's muscular dystrophy. We haven't mentioned mitochondrial diseases but a
classic one would be leapers optic neuropathy and there many, many
mitochondrial diseases. We talked about Prader-Willi, Anglemen syndrome for
genomic imprinting. Beckwith Wiedemann is another example of a disease showing
imprinting. And, of course, the nucleotide repeat expansions like Huntington
disease, fragile-x, maybe 20 or so more diseases related to nucleotide repeat
expansions.