GENETIC DISORDERS 1

Dr. Gonzalo B. Roman | September 23, 2020

OUTLINE • True or False: All genetic diseases have a family

I. INTRODUCTION V. BIOCHEMICAL history
A. Genetics AND MOLECULAR o Genetic diseases often have the
B. DNA to proteins BASIS OF characteristic of being heritable to
II. MUTATION MENDELIAN generations but it does not mean that every
A. Point mutation within DISORDERS case must have a positive family history.
coding sequence A. Enzyme defects o It’s not uncommon to see sudden
B. Mutation within non- B. Defects in appearance of a genetic disease in a family
coding sequences receptor and without precedent. The first individual that
C. Deletions and transport system has the mutation may be the first in their
insertions C. Alterations of family to manifest that condition.
D. Alterations in protein non-enzyme o One reason is that the new mutation may
coding genes other proteins arise from when the genetic material is
that gene mutations D. Genetically passed on from one generation to the next.
E. Alterations in non- determines o Another reason is an autosomal recessive
coding RNA adverse effects inheritance.
F. Trinucleotide repeat to drugs o So if an individual with the recessive gene
mutations VI. DISORDERS marries another who also has the recessive
III. MAJOR CATEGORIES A. Marfan’s gene then there is a possibility that their
OF GENETIC B. Ehler’s Danlos offspring will manifest the condition.
DISORDERS • More than 80% of babies born with an inherited
A. Dominant genetic disease have no known family history
B. Recessive • True or False: Genetic diseases are necessarily
C. Codominance congenital.
IV. MENDELIAN o Not all genetic diseases are congenital.
DISORDER REFERENCES: Congenital means you are born with it.
A. Autosomal Dominant Robbins and Cotran 10th Ed o For example, being born with a cleft lip, a
B. Autosomal Doc Roman’s PPT ventricular septal defect of the heart, or no
Recessive legs (phocomelia).
C. X-linked NUMBER OF PAGES: 15 o There are some genetic diseases that are
inherited but do not manifest at birth. At birth,
a child looks normal, he grows up normal but
I. INTRODUCTION TO GENETIC DISEASES then later on, he will manifest the disease. He
• Congenital vs. Inherited is not born with the disease but will acquire it
o Congenital – diseases you are born with later because of his genes. He has a
o Inherited – found in the genes; not predisposition because of inherited genes.
necessarily congenital because some • Examples of conditions easily seen at birth:
diseases do not manifest until adulthood like 1) Gastroschisis – open abdomen; intestines
Huntington’s disease and other organs protrude out of an opening
• True or False: Genetic Disease is a disorder that is in the abdominal wall
transmitted through the family line
o Most people think that genetic disease must
be one that is transmitted from one
generation to the next. This is not totally
correct.
o In medicine, genetic disease refers to one
that is caused by abnormalities in the genetic 2) Polydatctyly – many fingers
material usually in the stage of germ cell
development or early embryonal stage.
o It usually occurs in the family but sometimes
it can occur sporadically.
o One mutation can happen in an individual
and that individual will be the first in his family
line to manifest the disease and then he can
pass on the mutation to his offspring and so 3) Congenital heart defect – not visible
on. externally

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PATHO: Genetic Disorders 1
• True or False: Familial diseases are necessarily
genetic.
o Familiar diseases are those that cluster
within a family.
o There are families that may have a high
incidence of diabetes, hypertension or
malignancy. These diseases often affect
more than one member of the family. Maybe
it’s because they share common genetic
material. However, family clustering does
not necessarily indicate that the disease is
genetic.
o For example, hepatitis can cluster within a
family because they eat the same food and
are exposed to the same environmental
influence.
o Another example is hypertension. It’s the
same thing with hepatitis. Maybe that family
loves to eat fatty food so HPN is common in
that family
• Genetic diseases have their origin from an
abnormality in the gene.
• Genetic diseases may be roughly divided into three:
1. Chromosomal Disorders
§ Caused by numerical or structural
abnormalities of the chromosomes
§ Uncommon but associated with high
penetrance
§ Trisomies: Down Syndrome,
Turner Syndrome
2. Single gene disorders
§ Caused by defects of individual
genes; one segment of the DNA has
a problem; gene defects are not
detectable by simple chromosome
analysis (gene sequencing must be
used to find these conditions)
§ Such mutations and their associated
disorders are highly penetrant,
meaning that the presence of the
mutation is associated with the
disease in a large proportion of
individuals.
§ Because the diseases are caused by
single gene mutations, they usually
follow the classic Mendelian pattern
of inheritance and are also referred
to as Mendelian disorders.
§ Thalassemia, hemophilia
3. Multifactorial Disorders
§ Result of the combined effect of
genetic and environmental factors
§ More common than the other two
§ Caused by interactions between
multiple variant forms of genes and
environmental factors.
§ Such variations in genes are
common within the population and
are called polymorphisms.
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§ No single susceptibility gene is
necessary or sufficient to produce
the disease.
§ Diabetes mellitus, hypertension,
psychiatric diseases, cancer (you
may have the genes for diabetes but
if you take care of yourself by not
eating too much carbs and
maintaining your weight, you may be
able to avoid the disease)
CAUSES OF BIRTH DEFECTS IN HUMANS
• Most of the causes of birth defects are unknown.
Despite the advances in modern medicine, we still
do not know why and how some birth defects
happen. 20% of birth defects are hereditary.
• The lifetime frequency of genetic diseases is
estimated to be 670 per 1000.
• We have different cells in our body making up our
tissues and organs. Most of these cells are being
replaced regularly. They are dividing. This division
of cells is regulated by the nucleus of the cell which
contains the blueprint of the entire organism. The
chromosomes will have the genetic blueprint in the
form of DNA and are transcribed into three letters
which are called trinucleotides. It can be a GAC,
GAT, etc. These will be transcribed and translated
into proteins so that the cell will know how to act and
develop as a particular cell.
GENETICS
• Genes are the basic unit of inheritance.
• Genes are composed of sequences of DNA.
• They are the blueprint of proteins and they influence
all aspects of body structure and function.
• Humans have approximately 20 000 protein-
coding genes and an additional 9 000 to 10 000
genes that encode various types of RNA.
• An error in one of these genes can lead to
recognizable genetic disease.
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DNA TO PROTEIN
• DNA directs the synthesis of all body proteins.
• DNA is the one that tells the cell what to produce
e.g. collagen, elastin, protein that will become an
enzyme, part of a cell wall or a receptor.
• Proteins are made up of polypeptides which are in
turn made up of amino acids. Alter the content of an
amino acid and you will alter the protein.
• The body contains 20 different amino acids that are
specified by four nitrogenous bases: cytosine,
thymine, adenine and guanine.
• If your code is UUU, then that codon will produce
phenylalanine.
• UAA, UAG, UGA – stop codons; ribosomes will be
signaled to stop producing amino acids
• AUG – start codon
• Combination of these amino acids will produce
proteins
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• From the DNA in the nucleus, it’s going to be
transcribed into mRNA and the mRNA will go to the
ribosome and be translated into a protein.
• In the picture, you have a trinucleotide of TTC, AGT
and CAG in the DNA template. The mRNA will be
formed with the complementary nucleotides (A=U,
C=G) AAG, UCA and GUC and they produce codons.
These codons will produce lysine, serine and valine.
The combination of these amino acids will produce a
certain protein. For example, this will produce an
enzyme.
• A DNA problem can happen if G (red circle) is
changed to another letter because of mutation. For
example, it changed into T. The complementary base
will then be A. The sequence of the second codon
will change from UCA to UAA. UAA is a stop codon.
As a result, valine will no longer be produced. You will
then have an abnormal protein/enzyme that can
affect an individual.
II. MUTATION
• The basic problem in genetic disease is mutation.
• Alteration of genetic material
• Permanent change in the DNA
o In the germ cell (sperm cell and ovum) –
can lead to inheritable diseases
o In somatic cells – can lead to cancer and
some congenital diseases
• What causes mutation? Mutations can arise
spontaneously at low frequency because of the
chemical instability of the purine and pyrimidine
bases.
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• Most of these errors during DNA replications are not
really significant. They do not cause much problem.
• Natural exposure of an organism to certain
environmental factors (mutagens).
• Radiation can cause mutation. Example, when
Japan was bombed during World War II, a lot of
people there developed cancer (leukemia).
• Chemicals can also induce mutations. Most popular
is cigarette smoke which contains tons of mutagens TYPES OF MUTATIONS
hence, no wonder that it can cause a lot of human In the diagram, BEAST stands for a beast. If we
malignancy like in lungs and some other organs too. substitute B with F, it will now have a different
Food items like hotdogs, ham are very rich in nitrates meaning, FEAST. Now, if we insert another letter, R,
and nitrites and they can also cause mutation. Some it again has a different meaning, BREAST. If we delete
a letter, we remove A, again the meaning is altered, it
acne products contain benzoyl peroxide which is
also a carcinogen or mutagen. becomes BEST. If we interchange or inverse ST in
BEAST, the meaning is changed, it becomes BEATS.
• Infection can also be a cause of mutations like
oncoviruses.
o Human Papillomavirus (HPV) - sexually
transmitted virus which can cause cervical
cancer among females. It can also cause
warts, but by different strains. The wart is
caused by HPV type 1 and cervical cancer is
usually caused by HPV type 16, type 18, type
33, and type 36.
o H. Pylori - bacteria that spreads through
contaminated food usually found in the
gastric mucosa and can produce pathologies
and gastric ulcers in the stomach. They can
also cause mutation and produce gastric It is the same thing with genetic material. The normal
carcinoma. sequence in the diagram is CAG CCC ACT which
codes for Gln-Pro-Thr.

If we insert T after the 3rd base, then the sequence of

amino acids changes. This is called a Frameshift
Mutation. The codon for Proline changed and now it is
Serine and from Threonine it became Histidine. Hence,
now we have an altered sequence and the protein that
is supposed to be made of Glu-Pro-Thr is now changed
to another protein with a different amino acid sequence,
Gln-Ser-His. If the new protein produced has similar
characteristics like the normal protein, not much
problem will happen. But if the properties of new protein
are very much different with the properties of the normal
one, then we have a big problem. This is Frameshift
Mutation.

So basically we have inherited genes, exposure to
environmental mutagens and the chance of
combination of genes and exposure to environmental
mutagens happening. If all three come together then
there is a high chance of developing a condition. Most
cancers develop when the three of them are present in
an individual.
Insert Mutation is when we insert 3 letters. When we
insert 3 letters, the sequence does not change but a
new amino acid is being added in between. So,
instead of having Gtn-Pro-Thr, we now have Gln-Phe-
Pro-thr. Hence we have a protein with an extra amino
acid.
So, basically this is what mutation does, it will alter the
code of the body.

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• Mutations can interfere with gene expression at
various levels
• Six general principles relating to the effects of gene
mutations
o Point mutations within coding sequences
o Mutations within non coding sequences
o Deletions and insertions
o Alterations in protein-coding genes other that
mutations
o Alterations in noncoding RNAs
o Trinucleotide-repeat mutations
A. POINT MUTATIONS WITHIN CODING SEQUENCES
• Point mutation is a change in which a single base is
substituted with a different base.
• Base pair substitution
o One base pair is replaced by another.
o Many of these mutations do not change the
amino acid sequence (silent mutations).
o A protein is made up of a whole long
sequence of amino acids so changing one
amino acid will not alter the protein much
hence they usually are silent. But sometimes,
they can be problematic for us.
o Consists of missense mutation and
nonsense mutation
Let’s look at this example, in the DNA level, TTC was
changed to TTT because of mutation, so instead of
producing an AAG, we have AAA. Fortunately, both AAG
and AAA codes for Lysine and hence no problem (silent
mutation) because even though we changed the genetic
material, there is still the same amino acid. Now, if we
change the 1st letter of TTC to ATC which will be UAG in
the mRNA. UAG is a stop codon which means the
ribosome when it reaches this codon, it will stop producing
the protein (nonsense mutation).
Now, if we change TTC to TCC, it will be AGG on mRNA
hence, instead of producing lysine, it will now produce
Arginine. It doesn’t cause much problem because lysine
and arginine have similar characteristics as they are both
basic (conservative missense mutation). If we change
TTC to TGC, Lysine changes to threonine and threonine
is very much different from lysine because Thr is polar
(hydrophobic) and Lys is hydrophilic (non-conservattive
missense mutation) and now the protein becomes
abnormal protein.
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MISSENSE MUTATION
• Base pair substitution that causes a change in a
single amino acid.
• Termed as missense mutations because they alter
the meaning of the sequence of the encoded protein.
• Two types of missense mutations are conservative
and non-conservative
• Conservative Missense Mutation - substituted
amino acid is biochemically similar to the original and
typically causes little change in the function of the
protein.
• Non-conservative Missense Mutation - replaces
the normal amino acid with a biochemically different
one.
• Examples would be sickle cell anemia and BRAF
point mutation
SICKLE CELL ANEMIA
It is caused by a single point mutation in the B-
hemoglobin gene that converts CTC into CAC.
Hence, instead of coding for glutamic acid, it codes
for valine. Sickle cell anemia affects about 1 in 500
individuals affecting the codon in B-globin.
BRAF POINT MUTATION
Here what happens is, instead of producing valine,
we have glutamic acid and here we have gain of
function meaning, the change from valine to
glutamic acid leads to the activation of the RAF
protein which causes unlimited proliferative
signalling in cancer cells. This is an example of Non-
conservative Missense Mutation (gain of
function favouring the development of cancer).
This mutation accounts for the following
malignancies: Melanoma, Papillary Thyroid cancer,
Ovarian cancer, Colorectal cancer and non-smoke
cancer of the lungs
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B. MUTATIONS WITHIN NON-CODING SEQUENCES
BRAF Point • Transcription of DNA is initiated and regulated by
Mutation promoter and enhancer sequences. So problems
can occur not only in the coding areas of the DNA
The left image but also within non-coding sequences.
shows a normal cell. ● Deleterious effects may also result from mutations
But because of that do not involve the exons. Point mutations within
mutation, it introns may lead to defective splicing of intervening
becomes out of sequences.
control and the ● Point mutations or deletions involving regulatory
nucleus divides sequences may interfere with binding of transcription
continuously and factors which leads to lack of transcription.
produces many
cancer cells C. DELETIONS AND INSERTIONS
because of a single ● Small deletions or insertions involving the coding
mutation. sequence can have two possible effects on the
encoded protein.
NONSENSE MUTATION
• Base pair substitution which produces one of the NO FRAMESHIFT/INTACT READING FRAME
three stop codons (UAA, UAG or UGA) in the ● If the number of base pairs involved is three or a
messenger RNA. multiple of three, the reading frame will remain
• May change an amino acid codon to a chain intact, and an abnormal protein lacking or gaining
terminator or stop codon. one or more amino acids will be synthesized
• Stop codons terminate the translation of polypeptide.

● For example, in this condition we have AUG AAG

• For example, the top one is normal DNA and if we
replace 1 letter (here 10th base is being replaced),
CAG becomes TAG and TAG will become UAG in the
mRNA which is a stop codon and hence terminates
translation. we now have a shorter version and is
known as nonsense mutation. And usually the protein
that is produced here because of shortening is a non-
functional protein.
• Example would be β-thalassemia
UUU GGC UAA. If we remove AAG (Lys), then Lys
is not produced in the resultant protein but it still
produces the other amino acids until it reaches the
stop codon. Same thing, if you insert 3 letters then,
the rest of the amino acids will still be produced.
FRAMESHIFT MUTATION
• If the number of base pairs involved is not a multiple
three, an alteration of the reading frame of the DNA
strand producing a frameshift mutation.

Β-THALASSEMIA
A point mutation in haemoglobin affecting the codon for
glutamine, from CAG it becomes UAG and since there
is a mutation, the production of hemoglobin stops at
UAG (stop codon) and the other codons ahead of the
mutation are not translated anymore and hence we have
a defective haemoglobin.
• In this example, normally it is coding for histidine
because all are CAT. Now, if we delete an ‘A’, it
becomes CTC instead of CAT and the ribosome
instead of producing histidine, it produces leucine and
hence results in formation of incorrect amino acid
sequence which causes malfunctioning of protein.

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D. ALTERATIONS IN PROTEIN CODING GENES • A sequence of 3 nucleotides is repeated. Like for
OTHER THAN GENE MUTATIONS example here (previous picture), the CAG is
• Structural variations (copy number changes, repeated here so we have double amplification.
amplifications or deletions and translocations) Sometimes it is not just two, sometimes it can be
o Translocations result aberrant gain or loss of three, it can be four and sometimes it can be
protein function hundreds of trinucleotide amplification and these will
o Translocation (e.g. Philadelphia produce an abnormal protein.
chromosome – t(9;22) between the BCR • Important triple repeat mutation: Fragile X Syndrome,
and ABL genes in chronic myeloid leukemia Huntington Chorea, Friedrich Ataxia
(Translocation of 2 chromosomes,
translocation of chromosome 9 and 22)
• As with mutations, structural changes may occur in
the germline or be acquired in somatic tissues. In
many instances, pathogenic germline alterations
involve a contiguous portion of a chromosome rather
than a single gene, such as in the 22q
microdeletion syndrome
• With the widespread availability of next-generation
sequencing (NGS) technology for assessing FRAGILE X SYNDROME
genome-wide DNA copy number variation at very • Here in fragile X syndrome, there is actually 250
high resolution, potentially pathogenic structural of the CAG (here we only have double) up to 4,000
alterations have now been discovered in common tandem repeats of the sequence of CGG within
disorders such as autism. Cancers often contain the regulatory region of a gene called familial
somatically acquired structural alterations, including mental retardation or FMR1 gene.
amplifications, deletions, and translocations.

E. ALTERATIONS IN NON CODING RNAs

• It is worth noting that in the past, the major focus of
gene hunting was discovery of genes that encode
proteins. We now know that a very large number of
genes do not encode proteins but produce
transcripts—so-called noncoding RNAs
(ncRNAs)—that serve important regulatory
functions.
• Examples—small RNA molecules or microRNAs
(miRNAs) and long noncoding RNAs (lncRNAs).
• In these FMR1 gene located in the long arm of X
F. TRINUCLEOTIDE REPEAT MUTATIONS chromosome. q stands for the long arm, p stands
• Belong to a special category of genetic anomaly. for the short arm. This is bound to region 7 and if
the repeat is less than this, more or less the patient
• Amplification of a sequence of three
can be normal. But if the repeat becomes increase,
nucleotides.
the patient can have an intermediate manifestation
• Although the specific nucleotide sequence that
so the repeat becomes more, when it reaches more
undergoes amplification differs in various disorders,
than 200, it becomes more pathologic.
almost all affected sequences share the nucleotides
• In most normal individuals, the number of repeats is
guanine (most of the time) and cytosine (usually
small averaging 29 so it’s not much a problem. Such
CAG).
expansion of trinucleotide sequence, it prevents
normal expression of FMR1 gene thus giving rise to
familial condition. This usually presents with
intellectual disability. The thing is trinucleotide
repeat mutations are dynamic meaning the degree
of amplification increases during gametogenesis.
With each gametogenesis, amplification becomes
more and more until it reaches a huge level.

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HUNTINGTON’S DISEASE
• So these is what basically happens, from a healthy
gene this protein is produced. This is the amino
acid for CAG (points to dark orange circles in the
picture on the next page). But when there is a
trinucleotide or CAG repeats it lengthens and now
you have an abnormal protein and this protein
happens to be toxic to the neurons so it produces
what is known to be Huntington’s disease.
• Autosomal dominant means that if you marry
someone with this, then there is a very good chance
that your offspring will also manifest the disease.
FRIEDRICH ATAXIA
• Recessive means if you are normal, then none of
your offspring will manifest these but if you are a
carrier and your spouse is also a carrier, maybe
your child have a 25% manifesting these so it can
be inherited.
• GAA repeats
III. MAJOR CATEGORIES OF GENETIC DISORDERS
• Virtually all Mendelian disorders are the result of
mutations in single genes that have large defects.
• Disorders related to mutant genes of large effect.
• Disorders with multifactorial inheritance.
• Chromosomal disorders.
• Single gene disorder with non-classic (does not
follow the usual Mendelian laws) pattern of
inheritance.
- Triple-repeat mutations
- Mutations in mitochondrial DNA
- Those whose transmission is influenced by
genomic imprinting or gonadal mosaicism.
• It is estimated that every individual is a carrier of
several deleterious genes, (fortunately most are
recessive – meaning to say we have an allele that
carries it and an allele that is normal that’s why we
do not manifest the condition and therefore do not
have serious phenotypic effects).
• Autosomal recessive traits make up the largest
category of Mendelian disorders. They occur when
both alleles at a given gene locus are mutated.
• About 80% - 85% of these are familial. The
remainder represent mutations acquired de novo by
an affected individual.
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• (If most are recessive, it means that you have an
allele that is abnormal and that abnormal allele does
not manifest because you have a normal allele from
your other parent which is dominant. This is one of
the reasons why we discourage interfamilial union
because if it runs in the family and you are carrier
and you married one of your relatives who is also a
carrier, then there’s a big (25%) chance that your
offspring would manifest the condition. This is the
medical reason why marriage between families are
discouraged.
• Some autosomal mutations produce partial
expression in the heterozygote and full expression
in the homozygote. (Example: sickle cell disease –
if you have homozygous for sickle cell, then you
would manifest the sickle cell disease. But if you’re
only heterozygous, then you have only partial
expression and your sickling of red cell will only
happen if proper conditions are met.)
• A single mutant gene may lead to many end effects,
termed pleiotropism; conversely, mutations at
several genetic loci may produce the same trait
(genetic heterogeneity). Sickle cell anemia is an
example of pleiotropism.
• Recognition of genetic heterogeneity not only is
important in genetic counseling but also is
relevant in the understanding of the pathogenesis
of some common disorders, such as diabetes
mellitus.
Laws of Mendel
A person can be homozygous for
the y color or heterozygous for
the y color.
This is Punnet Square. If you try
to cross them, Y and Y will
produce yellow color (YY).
A. DOMINANT
• Autosomal dominant disorders manifested in the
heterozygous state, so at least one parent of an
index case is usually affected; both males and
females are affected, and both can transmit the
condition. When an affected person marries an
unaffected one, every child has one chance in two
of having the disease.
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• This is what happens in Huntington’s chorea
which is an autosomal dominant disorder.
• The affected individual usually produces a
Huntington protein which can be toxic to the
neurons.
• Since it is autosomal dominant, both the mother
and the father are affected because they have the
big H. If we mix together, 75% of the offspring will
be affected and only the small h and a small h here,
it would be normal. Only 25% will be normal. It
follows the laws of Mendel.
• Question: Will the man and the woman will develop
the disease?
• Yes, both parents will show the disease because
both of them are heterozygous for the mutated allele.
• And since this is an autosomal disorder, just one
copy of the mutated allele is sufficient to cause the
disease.
B. RECESSIVE
• Sickle cell disease
o Each child’s chances are:
o 25% of not having the disease (SS)
o 25% of having the disease (ss)
o 50% of carrying the disease (Ss)
• Sickle cell anemia is caused by substitution of
normal hemoglobin (HbA) by hemoglobin S (HbS).
• When an individual is homozygous for the mutant
gene, all the hemoglobin is of the abnormal, HbS,
type, and even with normal saturation of oxygen the
disorder is fully expressed (i.e., sickling deformity of
all red cells and hemolytic anemia).
• In this hereditary disorder, not only does the point
mutation in the gene give rise to HbS, which
predisposes the red cells to hemolysis, but also the
abnormal red cells tend to cause a logjam in small
vessels, inducing, for example, splenic fibrosis,
organ infarcts, and bone changes. The numerous
differing end organ derangements all are related to
the primary defect in hemoglobin synthesis.
• In the heterozygote, only a proportion of the
hemoglobin is HbS (the remainder being HbA), and
therefore red cell sickling occurs only under unusual
circumstances, such as exposure to lowered
oxygen tension.
• This is referred to as the sickle cell trait to
differentiate it from full-blown sickle cell anemia.
Although Mendelian traits are usually described as
dominant or recessive, in some cases both of the
alleles of a gene pair contribute to the phenotype—
a condition called are good examples of
codominant inheritance.
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• On the other hand, profound childhood deafness,
an apparently homogeneous clinical entity, results
from many different types of autosomal recessive
mutations
C. CODOMINANCE
• When both alleles contribute to the phenotype.In
these example of flower where we cross white
Camilla to the red Camilla and both colors are
dominant and so we call that as dominance. If we
mix them, both will manifest.
• The same thing with humans, in blood typing of
people A is dominant but B is also dominant. For
example, if this person is heterozygous for A
meaning to say A, O then A is dominant, he will
have a blood type of A. If you pair him with a woman
whose blood is heterozygous for B, B and O then B
is dominant so she will manifest as blood type B.
• Now if you pair them together, then A and B will
manifest. If you mix:
o A with B then you will have AB;
o A with O = AO, blood type A;
o B with O = blood type B;
• with O = blood type O.
• With these pairing, children will have different blood
types. So don’t be surprised if a person is A and the
mother is B and then they have an O child. It is
because of these. With the A allele, B allele, and O
allele, A and B are dominant.
• Question: If both parents are O, can they have a
child whose A and B, will that be possible?
• With the simple laws of Mendel, it is not possible but
actually it is possible and we will learn that later on
when you go to clinical pathology on the topic blood
typing I will explain that more.
IV. MENDELIAN DISORDERS (SINGLE GENE)
• Pleiotropism - a single mutant gene may leading to
many end effects
o An example of pleiotropism is sickle cell
disease – when an individual is exposed to
low oxygen, the red cell will sickle and thus
are prone to hemolysis. Not only this but
when the RBC’s are sickle in shape they
can clog the vessels producing “logjam”
which disturbs the blood flow and can
cause infarct, bone changes, splenic
fibrosis and other problems to the areas
being supplied. This is pleiotropism, the
numerous differing end organ
derangements all are related to the primary
defect.
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PATHO: Genetic Disorders 1
• Genetic Heterogeneity - mutations at several loci
may producing the same trait
o An example of genetic heterogeneity is
congenital deafness which may result
from many different types of autosomal
recessive mutations
• Transmission patterns of single gene disorders:
o Autosomal dominant disorders (AA)
o Autosomal recessive disorder (Aa)
o X- linked disorder
A. AUTOSOMAL DOMINANT DISORDERS
• Manifested in the heterozygous state.
• At least one parent is affected.
o Both males and females are affected.
o Both can transmit condition to offspring
o If the affected person marries an unaffected
person, their child will have 50% chance of
having the disease.
• Some persons derived their disorders not from their
parents, but from new mutations – either the egg
or sperm cell of their parents.
o Due to abnormal gametogenesis usually
occur to those with older parents
particularly the father but older mothers are
also prone.
o With every autosomal dominant disorder,
some proportion of patients do not have
affected parents. Such patients owe their
disorder to new mutations involving either
the egg or the sperm from which they were
derived. Their siblings are neither
affected nor at increased risk for disease
development.
o Proportion of patients who develop the
disease as a result of a new mutation is
related to the effect of the disease on
reproductive capability.
• Clinical features can be modified by variations in
penetrance and expressivity.
o Penetrance is the probability of the gene to
be expressed thus complete penetrance
means that the gene will be expressed to all
population who has that gene.
o Incomplete penetrance:
§ Some individuals inherit the mutant
gene but are phenotypically normal
§ Genetic trait is only expressed in a
part of the population
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o Variable expressivity
§ Trait is seen in all individuals carrying
the mutant gene but is expressed
differently among individuals
§ Variation in expression of that gene.
Example you may have the gene that
express polydactyl(extra finger) that
finger could be full size, or not fully
developed as other fingers or there
could be bone but it is just attached
to a piece of skin
§ Thus, phenotypic expression is NOT
fully expressed
• The molecular mechanisms of autosomal dominant
disorders depend upon the nature of mutations
and the type of protein affected.
o Reduced production of a protein
o Production of dysfunctional or inactive
protein
o Whether such a mutation gives rise to
dominant or recessive disease depends on
whether the remaining copy of the gene is
capable of compensating for the loss.
• Many autosomal dominant disorders arising from
deleterious mutations fall into one of a few familiar
patterns:
o Diseases involved in regulation of complex
metabolic pathways that are subject to
feedback inhibition (e.g. Familial
hypercholesterolemia)
§ In familial hypercholesterolemia, the
gene encoding for LDL receptor is
defective. Thus, without the LDL
receptor the cholesterol won’t be
internalized by the cell leading to
Hypercholesterolemia.
§ Leads to atherosclerosis in affected
heterozygotes that may cause heart
attack
o Key structural proteins such as collagen
and cytoskeletal elements of the red cell
membrane are affected. (e.g., spectrin)
o When the gene encodes one subunit of a
multimeric protein, the product of the
mutant allele can interfere with the
assembly of a functionally normal
multimer.
o Dominant negative - mutant allele that
impairs the function of a normal allele
§ For example, the collagen molecule
is a trimer in which the three collagen
chains are arranged in a helical
configuration. Each of the three
collagen chains in the helix must be
normal for the assembly and stability
of the collagen molecule. Even with a
single mutant collagen chain,
normal collagen trimers cannot be
formed, and hence there is a marked
deficiency of collagen.
| Page 10 of 15
PATHO: Genetic Disorders 1
• Gain of function mutations is less common than
loss of function and can take two forms:
a) Increase in normal function of a protein
b) Impart a wholly new activity completely
unrelated to the affected protein’s normal
function
§ Transmission is almost always
autosomal dominant (eg.Huntington
Disease)
• Since the individual with a new mutation is an
asymptomatic heterozygote, several generations
may pass before the descendants of such a person
mate with other heterozygotes and produce affected
offspring.
• Many of the mutated genes encode enzymes. In
heterozygotes, equal amounts of normal and
defective enzyme are synthesized due to the natural
“margin of safety”
• Includes almost all inborn errors of metabolism

5 metabolic disorders tested in newborn screening

Disorder Effects Screened Treatment
and
TREATED
Congenital Severe Normal Hormone
Hypothyroidism Mental
Retardation
Congenital Death Alive& Hormones
Adrenal normal
Hyperplasia
Galactosemia Death or Alive & Diet
Cataracts Normal Restriction
Phenylketonuria Severe Normal Diet
Mental restriction
Retardation
G6PD deficiency Severe Normal Avoid
anemia, triggering
kernicterus factors
B. AUTOSOMAL RECESSIVE DISORDERS
There is now an expanded newborn screening test that
detects 28 disorders

• Make up the largest category of Mendelian disorders.

• Occurs when both alleles at a given locus mutated
• Three features:
1) Trait does not usually affect the parents
of the affected individual (because the
state will not manifest), but the siblings
may show the diseases
2) Siblings have one chance in four of
having the trait
3) If mutant gene occurs with low frequency in
the population, there is strong likelihood of
consanguineous marriage
• Expression of the defect tends to be more uniform
than in autosomal dominant
• Complete penetrance is common
• Onset is frequently early in life
• New mutations are rarely detected clinically.

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PATHO: Genetic Disorders 1
C. X LINKED DISORDERS
• All sex-linked disorders are X-linked and almost all
are recessive. They account for only a small number
of clinical conditions
o Several genes are located in the male-
specific region of Y; all of these are related
to spermatogenesis.
o Males with mutations affecting the Y linked
genes are usually infertile and hence, there
is no Y linked inheritance
o The Y chromosome, for the most part, is not
homologous to the X chromosome and so
mutant genes on the X do not have
corresponding alleles on the Y. Thus, male
is said to be hemizygous. These are
expressed in males
Hemizygous has only one allele since males only
have one X chromosome and has no counterpart
in the Y chromosome
Females can be either homozygous or heterozygous
since they have two X chromosome
• An affected male does not transmit the disorder
to his sons, but all the daughters are carriers
• Sons of heterozygous woman have 50% chance of
receiving the mutant gene.
• Heterozygous female usually does not express the
full phenotypic change because of the paired
normal allele
• When we have affected father with unaffected
mother sons will be unaffected since the X
chromosome from the mother is unaffected and
also the Y chromosome from the father is
unaffected. The daughters will be a carrier since
one of their X chromosomes is from the affected
father. They are only carriers since it is only a
recessive trait.
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• When the mother is a carrier and the father is
unaffected for every birth they may either have an
unaffected daughter, carrier daughter, affected son
or unaffected son. When the son(XY) gets the
affected X chromosome from the carrier mother he
will become affected since he is hemizygous thus
there will be no other x chromosome that will
counteract the affected allele.
• There are only a few X-linked dominant
conditions. They are caused by dominant
disease-associated alleles on the X chromosome.
These disorders are transmitted by an affected
heterozygous female to half her sons and half
her daughters and by an affected male parent to
all his daughters but none of his sons, if the
female parent is unaffected. Vitamin D– resistant
rickets and Alport syndrome are examples of this
type of inheritance.
V. BIOCHEMICAL AND MOLECULAR BASIS OF
MENDELIAN (SINGLE GENE) DISORDERS
• We have the genetic code in the nucleus and
transcribed to produce mRNA which goes out of
the nucleus through the nucleopore and give the
information to the ribosomes which translates the
information to produce a protein.
• If there is an alteration in the nucleotide sequence,
this will still be transcribed and translated but the
protein produced will be deficient or defective.
• Mendelian disorders result from alterations
involving single genes.
• Genetic defect may lead to the formation of an
abnormal protein or a reduction in the output of a
gene product
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PATHO: Genetic Disorders 1
• The mechanisms involved in single-gene disorders
can be classified into four categories:
o Enzyme defects and their consequences
o Defects in membrane receptors and
transport system (eg. receptors for
cholesterol)
o Alteration in structure, function, or quantity
of non-enzyme protein
o Mutation resulting in unusual reaction to
drugs
A. ENZYME DEFECTS AND THEIR CONSEQUENCES
DECREASED AMOUNT OF END PRODUCT
• Mutations may result in the synthesis of an enzyme
with reduced activity or reduced amount of normal
enzyme -> “metabolic block”
• We have a substrate, and these substrates can be
acted upon by an enzyme. Sometimes it’s a
complicated metabolic process and you can have
intermediate product which can be acted upon by
another enzyme to produce another intermediate
product or the final product.
FAILURE TO INACTIVATE A TISSUE-DAMAGING
• If for example the genes we are coding for are in
SUBSTRATE
enzyme A and you have a problem in that same
enzyme (defective or not adequate), it means that
the substrate cannot process cannot produce the
intermediate and the process will not proceed.
• If the defective genes code for enzyme 2, that
means that enzyme 2 will be deficient and again,
same thing will happen as mentioned above.
• The biochemical consequences of enzyme
defect in such a reaction may lead to three major
consequences:
o Accumulation of substrate
o Metabolic block and a decreased amount of
end product
o Failure to inactivate a tissue-damaging
substrate
ACCUMULATION OF THE SUBSTRATE
• Depending on the site of block, may be
accompanied by accumulation of one or both
intermediates.
• An increased concentration of intermediate may
stimulate the minor pathway thus lead to an excess
of M1. Under these conditions, tissue injury may
result if the precursor, the intermediates, or the
products of alternative minor pathways are toxic
in high concentrations
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• Galactosemia is deficiency of galactose-1-
phosphate uridyl transferase
o Accumulates galactose which consequent
tissue damage
• Lysosomal storage disease
o Within the lysosome we have enzymes that
degrade complex substrates into small
diffusible products.
o If you have defect in those enzymes, the
complex substrates will not be degraded
and so they will be trapped and will
accumulate (toxic).
• An enzyme defect can lead to a metabolic block
and a decreased amount of end product that may
be necessary for normal function.
• Albinism is a genetic defect in tyrosinase resulting
in deficiency of melanin
o Tyrosinase is necessary for the
biosynthesis of melanin from its precursor,
tyrosine
• α1-antitrypsin deficiency is the inability to
inactivate neutrophil elastase in the lungs leading
to destruction of elastin the walls of lung alveoli,
leading eventually to pulmonary emphysema
• Elastase destroys elastin
B. DEFECTS IN RECEPTORS AND TRANSPORT
SYSTEM
• Biologically active substances have to be actively
transported across the cell membrane.
• Familial Hypercholesterolemia – genetic defect in
a receptor mediated transport system
o Reduced synthesis or function of LDL
receptors leads to defective transport of
LDL into the cells
o Secondarily to excessive cholesterol
synthesis (hypercholesterolemia) by
complex intermediary mechanisms
• Cystic Fibrosis – transport system for chloride and
bicarbonate ions in exocrine glands, sweat ducts,
lungs, and pancreas is defective
o Cystic fibrosis gene located din
chromosome 7
o Complex mechanisms not fully understood
o Impaired anion transport leads to serious
injury to the lungs and pancreas
| Page 13 of 15
PATHO: Genetic Disorders 1
C. ALTERATIONS IN STRUCTURE, FUNCTION OR
QUANTITY OF NON-ENZYME PROTEINS
• Genetic defects resulting in alteration of non-
enzyme proteins often have widespread secondary
effects
• Results in defects in structure of molecules
o Defect in the structure of globin molecule
(hemoglobinopathies, sickle cell disease)
• Other proteins can be affected:
o Collagen (osteogenesis imperfect)
o Spectrin (spherocytosis)
o Dystrophin (muscular dystrophies)
D. GENETICALLY DETERMINED ADVERSE
REACTIONS TO DRUGS
• Certain genetically determined enzyme
deficiencies are unmasked only after exposure
of the affected individual to certain drugs
• G6PD deficiency
o Under normal conditions, does not result in
disease (a good anti-malarial medication).
o On individuals with the deficiency, a severe
haemolytic anemia results upon
administration of an anti-malarial drug
(primaquine)
• Pharmacogenetics is of considerable clinical
importance
o It is hoped that advances in
pharmacogenetics will lead to patient-
tailored therapy, an example of
personalized medicine
o Trying to personalize medicine for
individuals
VI. DISORDERS ASSOCIATED WITH DEFECTS IN
STRUCTURAL PROTEINS
A. MARFAN SYNDROME
• Disorder of connective tissue, manifested
principally by changes in skeleton, eyes and
cardiovascular system.
• Its prevalence is estimated to be 1 in 5000.
• Approximately 70% to 85% of cases are familial and
transmitted by autosomal dominant inheritance.
• Pathogenesis: from an inherited defect in an
extracellular glycoprotein called fibrillin-1
• Main problem: Mutation of FBN1 gene underlie
the syndrome
FIBRILLIN
• Major component of microfibrils in the extracellular
matrix
o Problem with microfibrils = problem with
extracellular matrix
• Fibrils provide a scaffolding on which tropoelastin
is deposited to form elastic fibers
o For strength and organization
• Abundant in the aorta, ligaments, and the ciliary
zonules that support the lens
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o In essence if you have a defect in fibrilin,
these are the areas which will most likely
affected
o Lens displacement. Instead of being strong
lens, it tends to become weak.
o Problematic aorta which can produce aortic
dissection or aneurysm of aorta
o Ligaments will not be strong so there will be
easy dislocation of bones
• Two homologous forms: Fibrillin-1 and Fibrillin-2
o Encoded by two genes: FBN1 and FBN2
o Mapped on chromosome 15q21.1 and
5q23.31
o Mutation of FBN1 gene underlie the
syndrome
CLINICAL FEATURES
• Mechanism for clinical manifestation:
o Loss of structural support in microfibril
rich connective tissue and excessive
activation of TGF-β signalling
o Reduced or altered forms of fibrillin give
rise to abnormal and excessive activation
of TGF-B, since normal microfibrils
sequester TGF-B. Excessive TGF-β
signaling has deleterious effects on
vascular smooth muscle development
o It also increases the activity of
metalloproteases, causing loss of
extracellular matrix
• Skeletal Abnormalities
o Most striking feature
o Typically, the patient is unusually tall with
exceptionally long extremities and long,
tapering fingers and toes.
o The joint ligaments in the hands and feet
are lax, suggesting that the patient is
double-jointed.
o Typically, the thumb can be
hyperextended back to the wrist.
o The head is commonly dolichocephalic
(longheaded) with bossing of the frontal
eminences and prominent supraorbital
ridges.
o A variety of spinal deformities may appear,
including kyphosis, scoliosis, or rotation
or slipping of the dorsal or lumbar
vertebrae.
o Chest is classically deformed = pectus
excavatum (deeply depressed sternum) or
pigeon breast deformity
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PATHO: Genetic Disorders 1
• Ocular changes CLINICAL FEATURES
o Bilateral subluxation • Skin is hyperextensible
o Ectopia lentis - dislocation (usually outward o Skin is vulnerable to trauma
and upward) of the lens • Joints are hypermobile (similar to Marfan expect
with the different abnormal protein)
o Predisposed to joint dislocation
o May lead serious internal
complications
§ Rupture of colon, large arteries,
cornea and renal detachment

• Cardiovascular lesions
o Most life threatening features of this
disorder
o Mitral valve prolapse (40-50% of cases)
o Dilation of the ascending aorta due to
cystic medionecrosis
o Aortic dissection - blood can flow in
between the walls of aorta and can cause
death (majority) caused by rupture of aortic
dissection

B. EHLER’S DANLOS SYNDROMES

• EDSs comprise a clinically and genetically
heterogeneous group of disorders that result from
some mutations of genes that code collagen,
enzymes that modify collagen an less commonly
other protein present in the extracellular matrix.
• Defect in synthesis or structure of fibrillar collagen
• That’s the problem with EDS, it will usually manifest
many symptoms
• Mode of inheritance encompasses all three
Mendelian patterns (it can be autosomal dominant,
autosomal recessive or x linked)
• Six variants have been recognized:

• Tissues rich in collagen are frequently involve: skin,

ligaments and joints
• Abnormal Collagen formed lack tensile strength

GROUP 27.: Pangan, Patel, Rongcal, Sese, Soriano | Page 15 of 15

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