‫د‪ .

‬حممد اخلطيب‬
‫‪http://dentistry2018.weebly.com/‬‬

‫هناء حممد الشريف‬

‫أفنان عبد اهلادي جنم‬

‫‪Wed, MAR, 23, 2015‬‬

‫مكتبة تالع العلــي – ‪ABC Books‬‬

‫شارع الجامعة األردنية – جسر كلية الزراعة‬

‫عمارة العساف – ‪ 532‬داخــــل المج ّمع‬

‫هاتـــف ‪:‬‬
‫‪0797121818‬‬
‫‪06/5336475‬‬

‫‪Ljneh Asnan‬‬ ‫‪Dental Correctionn‬‬

‫‪Dental.c2013@gmail.com‬‬ ‫‪D.correction2013 @gmail.com‬‬
 MENDELIAN INHERITANCE
•● Single Gene Defects ●•
Genetic Diseases (GD):
 Chromosomal Abnormalities

 Single Gene Defects (our lecture)

 Non-Traditional Inheritance

 Multifactorial Disorders

 Cancer Genetics

Topics of Discussion:
• Basic concepts of formal genetics
• Autosomal dominant inheritance
• Autosomal recessive inheritance
• Factors that may complicate inheritance patterns
• Probability

Pedigree
Pedigree is the family tree and the Representation of the ancestry of an individual’s family.it is a Symbolic
representations of family relationships and inheritance of a trait.
We will do a primary pedigree to determine the type of inheritance, and to tell wither this inheritance is
autosomal dominant or autosomal recessive or sex-linked or whatever type of these things .

Obtaining a pedigree:
A three generation family history should be a standard component of medical practice. Family history of the
patient is usually summarized in the form of a pedigree so and in order to draw the pedigree we have to ask
the family certain questions :

1- Wither they have a similar case in their relatives (sisters, brothers, niece ..etc) .
2- Ask if there were siblings who have died (because of that disease).
3- Inquire about miscarriages, neonatal deaths
4- Be aware of siblings with different parents (if they have 2 wives)
5- Ask about consanguinity between the wife and husband
6- Ask about ethnic origin of family branches (when we talk about the large family)

 P a g e 1 | 17
Pedigree Symbols
There are lines and symbols when we are going to

Draw the pedigree .

1- We have vertical line . This means we are talking about

generations (first generation and second generation 
between them we put a vertical line)
2- Then we have horizontal line where there is a mating
between male and female ( ‫)تزاوج‬
3- Dotted vertical: this means that child is not their
child and he is adopted(in the family or outside the family)
4- Then we have this horizontal line which means
sibling (brothers and sisters in family )
5- Then we have two females and line between
them  they are identical twins ,they are completely
the same .
6- Fraternal twins are not identical twins.

7- When we have two lines(‫ )ــــ‬this means that the parents are
cousins or niece and get married . strong blood relation.
8- If we have two obliquely parallel lines this means there is a former
Relationship(divorced)
9- If we have an arrow this means that this patient is the one where we start diagnosing from him ,
from that patient we start drawing the pedigree
p.s. we call this case ;proband or index case
(look at the figure to see points
10,11,12,13,14,15)

10- When we put number in square or

circle this means the number of that
child in family , this is no. 3 in family
and this is no. 2
11- If square and circle are filled it means
that he\she is a patient and affected
and has the disease.
12- Or if we have dots like these it means
he is obligate carrier , it means
recessive type of disease.
13- Deceased individual means that
patient died by the disease.
14- If we have line like this  Still birth :
died after birth.
15- adopted in\ outside the family.
This is the symbols for drawing a
pedigree…

 P a g e 2 | 17


CASE
*Normal female + normal male = mating (horizontal line)

*And these are their children ,4 in number( siblings )

*Number 4 is affected ,that's why it's filled with different color.

CASE
҂ The index case\proband is in the 4th generation
the arrowed male is the patient we start from ,that get married
(number 2 in IV generation in the figure) and has a son that is
affected with that disease. (look at V generation)

҂ When we draw a pedigree for the patient

we draw his\her brothers and sisters , so in
this case he has two sibling that have died
.and two are twins ,the sister is
affected(filled circle ). (look at IV
generation)
҂ the father and mother of the proband are
relatives (look at III generation , father and
mother in this 3rd generation  number 4
and 5) they have strong blood relation.

҂ We can see the disease in each

generation so it's a .

Just to remind you about certain identifications and definitions :

when we have 2 alleles both of them are
capital this means this is s dominant and they
are homozygous which means both alleles are
the same .

when we have small alleles (2 small alleles )

these 2 also are homozygous but they are
recessive type of alleles.

when we have 2 alleles different from each

other but also they are expressed , which
means both alleles although they are not
homozygous but both are expressed together ,
we call it co-dominant (like blood groups).

 P a g e 3 | 17
Patients with AB blood group they express the A and B genes , so we call it co-dominant . Or it might be
heterozygous one capital and one small. So we should keep this in mind.

Autosomal dominant (AD) :

Autosomal dominant means one Allele is enough to give a clinical picture or phenotype characteristics even
the other allele is normal. So here this father has 1 allele affected and the mother is normal, so 50% of their
children might have the disease.

• D abnormal gene
• d normal gene
• Each child of an affected person has a 50% chance
of being affected
• Affected persons are usually heterozygous

this is a theory but in population In the same family all could be normal or
all could be affected . So there is 50% chance to have the disease and there
is no differences if we have male or female, So both are equally affected
with this disease.
characteristics of AD :
 The dominant gene is expressed when it's heterozygous ,which means one allele is there.
 An affected individual has a 50% chance of having an affected child.
 An affected child will have one affected parent ( father \mother).
 Autosomal dominant traits have low frequencies in the population
 Autosomal dominant traits are usually lethal when
homozygous ..if both alleles are affected then he cannot
survive !!
 No skipping of generation, which means the pedigree which
we saw it before( case 2) is autosomal dominant disease
because all generations have that disease.

AD doesn’t mean always it's disease , we have certain

characteristics which they are normal physiological
characteristics but they are dominant. For example:
 freckles ‫النمش‬, people who have it they are AD
 widow's peak is AD and Straight hair line is AR
 earlobe :free is dominant the attached is recessive .
 The tongue if u can bend or not it's AD
 The finger  bending finger is AD

Anyone can draw a pedigree of his family

 P a g e 4 | 17
Autosomal Dominant Inheritance

 Polydactyly : extra fingers .You can see all the generations have the characteristics ..

The mother(in I ) here give to her daughters(in II) ,the mother (number 1 in II) here gives to her sons (number
1 and 3 in III) and he(number 1 in III) gives to his sons and daughters(number 2 and 3 in IV) .. so here there is

Autosomal Disorders:

Now will take about some diseases of those a little bit in more details ;)

 P a g e 5 | 17
When we say syndrome it means more than one
organ is affected in these persons.

They have white hair just one part will be white

hair ,There is a fairy skin and there is visual
problems and in general they are diff " they cannot
hear".

And here also u can see in each generation-

there is some people they are affected because of
this disease, and having Hearing loss and changes in
coloring (pigmentation) of the) hair, fair skin, and
visual problems.)

An autosomal dominant genetic disease caused by a

mutation of the HTT gene on Chromosome 4, The
function of the normal huntingtin protein is still being
studied, but the dominant allele causes progressive
neurodegeneration beginning between ages 30 and
50. This affects many parts of the body like central
nervous system.
The Life expectancy is ~20 years after the onset of
symptoms, and Due to the late-onset nature, most
parents have already had children before they become
symptomatic…

affects either the eyes , skeletal and cardiovascular system. The physical characteristics they are
very tall with a very tall extremities and the fingers (hand and foot)are like balloon at the end .
This can present by the problem of fibrillin .
Famous people that have this disease : Abraham Lincoln, Almotanabbi, some people
said barack obama !!

 P a g e 6 | 17
 progeria means the children become very old , and you
can see how they are look like .

They are children less than 15 years of age and they look
like someone that is 50 or 70 years age and this is also an
AD type of disease.

achondroplasia in general it's a new mutation, almost 7 cases of each 8

cases are new mutations ,You can see the family pedigree. The family has no
body that has achondroplasia before the current patient.

Patients with will have short limbs relative to trunk length, a prominent
forehead, low nasal root, and redundant skinfolds in the arms and legs.

it's a tumor affecting the eye and again also it's an AD disease, it's not
the type of disease which can give you a clinical picture, the person is
genetically affected but clinically he looks like normal .

This is obligate carrier, put a dot inside the shape to denote

those persons in pedigree

Pedigree illustrating the inheritance pattern of retinoblastoma, a

disorder with reduced penetrance of light to the eye . The
unaffected obligate carrier, denoted by a dot, has the same
genotype as the affected pedigree members.

Both are Aa but one affected and the other obligate carrier

you can see these build up of cholesterol ,It's an AD

 P a g e 7 | 17
 Neurofibromatosis type 1 (NF1)

A Multiple neurofibromas in an adult with type 1

neurofibromatosis.

BLisch nodules (benign hamartomas of the iris) visible on a

slit-lamp examination of an individual with type 1
neurofibromatosis.

this could be “café-au-lait spots" could be very small or could

be very large or could be in the eyes  again it's AD type of
disease.

It's also an autosomal dominant disease that affecting the teeth, teeth become blue like , the bone is brittle
and the teeth will be broken very easily in those persons and it affects 1 in 8,000 individuals.

Defective dentin,Pulp canals are sclerosed and greatly narrowed,Teeth appear

grayish anf opalescent, May also be seen in osteogenesis imperfecta

"Inheritable disease with blue sclera and brittle bones"

Important terms :

 Hemizygous: Having half the number of alleles

 Expressivity: The severity or intensity of the phenotype of an allele.
 Penetrance: The degree to which a gene expresses any observable phenotype

♥PEDIGREE 1 "new mutation"

New Mutation: An affected person may be the first person in the

family with the condition, due to a mutation arising for the first time in
sperm, egg, or embryo. Like in: achondroplasia .

we see the autosomal dominant diseases in each generations but in some

cases we draw the pedigree and we cannot see that picture in each
generation. If we look here for example: 1st generation nothing all normal ,
2nd generation all are normal, 3rd generation we have the disease.

 P a g e 8 | 17
♥PEDIGREE 2 " skipped inheritance "

If we look here the grandmother has the disease BUT nobody in the 2nd
generation has . There is one In the 3rd generation who has the disease.
This means here that the penetrance Of that disease is not very effective.

If we examine those for example we will find one of them he had the
disease(in the 2nd generation) .It's not expressed in the clinical picture
.He has the gene ,but the gene is not expressed in that one . That's why
we see sometimes there are skipped inherited.

♥PEDIGREE 3 "Germline Mosaicism"

Germ line Mosaicism: A new mutation may arise in testis or

ovary, resulting in an unaffected parent transmitting the condition to
two or more childrenndition it can complicate the pedigree.

" Gonadal mosaicism" that's in the gonads ,it's a mosaicism and that's why
we have 2 …? In that family that we can see. So in this co

So THE Apparent sporadic cases have Possible explanations like :

 Variable expressivity
 New mutation
 Non-penetrance
 Gonadal mosaicism


 Incomplete Penetrance. Some people who have the gene mutation do not show the
clinical effects.

 Penetrance Limited to one gender. For example, when prostate cancer risk is
inherited in an autosomal dominant manner, women who inherit the mutation are
not affected; they can, however, pass the mutation on to their sons .

 Variable Expressivity. The gene mutation has variable clinical manifestations: the disorder
may range from mild to severe; or a range of different complications may occur among people with
the mutation.

 P a g e 9 | 17
Autosomal Recessive(AR):
When we talk about the autosomal recessive , the mother and
the father they should carry the recessive allele So if the mother
carries one gene and the father carrying the other allele so 25%
are normal , 25% are affected and 50% are carriers for the
disease. 1:2:1" the ratio between them.

Theoretically 75% of them are normal 25% they have the

disease .

Father and mother both of them are equally affected with the
disease.

 Carrier parents are Heterozygotes carry the recessive

allele but exhibit the wild type phenotype.

 Normal parental phenotype

 “Inborn errors of metabolism”

 AR diseases are Associated with specific ethnic groups

- Always IN AR you can see that there is a skip of generation ,may be

some of those are carrier (we don't know), here the father is carrier and the
mother is carrier .

-Heterozygosity in AR sometimes adds advantages , If the

patient is carrier for thalassemia or carrier for sickle cell

anemia or carrier for G6PD deficiency he will be protected

of certain infections like malaria .we call it heterogenity

advantage for that type of mechanism.

We have many autosomal recessive diseases like :

Cystic Fibrosis, PKU, Homocystinuria,
Galactosemia, Friedreich Ataxia ,
Alkaptonuria, Hemoglobin S, Thalassemia .

 P a g e 10 | 17

generally it affects more than one organ . it affects the lungs ,the pancreas and also it affects the
testes in male -The main problem here that there will be no excretion of the mucus. It will be
accumulated..the reason the fluoride channels are closed , because of the closure of these channels
there will be no excretion of that sputum and the gene here that is responsible is CFTR gene which is
bound to chromosome 7 responsible for this problem.


it is an AR type of disease and it is very severe if we don't
treat it at the beginning . He will have seizures and
disabilities and many other diseases. But if we started
very early he will live normal and there is no problem.

have a mutation changing one nucleotide. Amino acid

valine instead of glutamic acid and we will have sickle cell
anemia in that patient.

 P a g e 11 | 17


-These diseases that are mentioned they are not as straight forward inheritance . There are many things which
can complicate the type of inheritance when u are studying these families:
1. Co-dominance
2. Epistasis
3. New mutation
4. Germ line Mosaicism
5. Delayed age of onset
6. Reduced penetrance
7. Variable expression
8. Pleiotropy and Heterogeneity
9. Genomic Imprinting
10. Anticipation
We will talk about all of those points bellow ,


proving paternity is One of the problems that can face us ;if you have a perinatal diagnosis
and you discover that the child is not the son/daughter of that man .What will u do if u have something like
this? Will u Tell the mother or the father? .. " you can think about the Q later , now let's continue :P"

Misassigned paternity:

If the biologic father of an affected individual is someone other than the person assumed to be the father,
misleading carrier test results might occur (the apparent father would usually not be a carrier) and risk of
additional affected children could be misstated.

Uniparental disomy:

If a couple in which only one partner is a carrier has an affected child, it may rarely be due to uniparental
disomy: in this case both gene mutations are inherited from the parent who is a carrier, due to an error in the
formation of sperm or ovum.

 P a g e 12 | 17
 De novo mutations:

Although also rare, de novo mutations can account for ~1% of gene mutations in some disorders and thus
provide another explanation for the birth of an affected child when only one parent is a carrier.

Inheritance of ABO blood groups :

1.Co dominance

In humans, ABO blood group is determined by a single gene on Chromosome 9. ABO blood type is an example
of ‘Multiple Alleles’ and Co-dominance.Co dominance : is the expression of two genes at the same time.

A is expressed on A blood group .B expressed on B blood group. Both A and B are expressed in AB blood
group ,in O we don't have any of them expressed.

The gene that's responsible for A is IA. B is IB .Nothing is small i. So O group is TWO small ii.

AB group : A capital and B capital they are expressed .

B group is : IB IBor IBi. A group is : IAIA or IAi .

Very important :

 P a g e 13 | 17
Absence of expected phenotype as a result of masking
expression of one gene pair by the expression of another
gene pair, The homozygous recessive condition masks the
effect of a dominant allele at another locus, The
expression of one gene depends and affects on the other
gene.
So here you can see one of those genes masks the function of
other genes .Blood group coming from A substance produce an
A substance and that A substance binds to the red blood cell
membrane, and B substance binds to RBC membrane .These
substances to be found in RBC membrane there should be H
molecule on RBC's surface ,then substance A and B will bind to
this molecule. Although both of them are controlled by
different genes. A substance has it's own gene and B substance
has it' own gene .If we don't have H antigen this means
although we have A or B substances, they will not bind to
membrane.

on the surface of the RBCs  the first substance should be there is H substance. After that the substance A or
B will be produced and it will bind to the H sabstance and we will have a Red blood cell with A and B or with A
only Or with B only .A or B will bind to H substance. If there is no H protein all ABO genotypes appear as type
O and that what we call this epistasis.Because of the presence of H we can find the others . If it is

absence we cannot see them .So we call it Epistasis type of characteristics.

• It means the appearance of several apparently unrelated phenotypic effects caused by a single gene .
• Refers to a Mendelian disorder with several symptoms
• Different subset of symptoms in different individuals.
• Usually means that a genes is involved in multiple processes

Examples on pleiotropy
1. Cystic fibrosis: an Autosomal Recessive disease that affects mainly sweat glands, lungs and pancrease.
and it affects the lungs , intestines and ovaries

 P a g e 14 | 17
 2. Marfan syndrome: Autosomal dominant and affects EYE, Skeleton and Cardiovascular system.
The same gene can give different types of characteristics. in the cardiovascular system we have
different clinical picture , the sclera has different clinical picture. But The same gene ! So the
expression of that gene in different organs will give u different types of characteristics

3. Osteogenesis imperfecta: , Bones, Teeth, and Sclera

4. Albinism, Pigmentation and Optic Fiber development.

4. :
This is the exact opposite of pleiotropy and it means: different genes can produce identical phenotypes.

Individuals with identical phenotypes may reflect different genetic causes.

Examples of genetic heterogenicity:-

 Deafness: we have many diseases and conditions that end up with deafness.
 Albinism.
 Cleft palate.
 Poor blood clotting.

In this condition, we have the same pentrance but different severity, it is usually showed in
dogs and cats in the same pregnancy where they have the same genes but their colors are expressed at
different degrees. Penetrance is complete, but severity of the disease is variable,

- Environmental factors have an effect on this different expression. HOW is that ??!

 we have a Himalaya rabbit, it has black ears and nose, because these areas are usually cold, so to
prove this is true, we bring a cold bag, and put it on a white area, then we observe after a while that
the new hair turns into black in the plae we put the cold, this means the environment affects the
expression.

 P a g e 15 | 17
Pentrance: The probability of a genotype being expressed as an observable phenotype. If the
penetrance is less than 100%, this is referred to as incomplete penetrance. Penetrance may be age
dependent, with some phenotypes not developing until later life.
we talked about RB before, so if we have a pentrance of 90% or 95% for example, then it is a very big
chance to end up being blind, but if we have very reduced pentrance like 10%, we usually don’t have
expression SO NO blindness.
Incomplete pentrance is usually affected by (1) gene to gene interaction, and (2) gene to interaction.

 Diseases genes in which an individual may have the disease genotype without
expressing of the disease.
 Retinoplastoma. Autosomal Dominant
 10% of gene carriers do not show the disease = OBLIGATE CARRIERS: Penetrance =
90%

Observed in many genetic diseases. It complicate the interpretation of inheritance patterns in the families. Some
diseases like Familial Alzheimer Disease won’t be seen in children, we usually see it after 60 or 70 years old.
Other examples:-

 Huntington Disease – AD
 Hemochromatosis – AR FATAL
 Familial Alzheimer Disease
 Familial Breast Cancer

Here we are not talking about genes, we talk about DNA sequence in NON coding regions (outside the
gene) , as we said before around 98% of our DNA is NON-coding. We are mainly considering the tri-
nucleotide repeats, they should be in a certain number only, large increased number would have bad
effects. So for example:-
The expression of myotonic dystrophy is a little, normal is between 10 and 15 , but with generation as
we go on and on, the number might increase, like if it was 100, we will have mild clinical picture.
BUT if it reached thousands and more, then it will be sever, look at the photo of women, the grandma
is not severely affected (looks like normal) , with more generation, here daughter of affected more, but
granddaughter or grandson is even affected more and more. So this is anticipation which describes the
tendency of some traits to become more severe after several generations.

 P a g e 16 | 17
Anticipation A three-generation family affected with myotonic dystrophy. The degree of severity increases
in each generation. The grandmother (right) is only slightly affected, but the mother (left) has a characteristic
narrow face and somewhat limited facial expression. The baby is more severely affected and has the facial
features of children with neonatal-onset myotonic dystrophy, including an open, triangle-shaped mouth.
The infant has more than 1000 copies of TCG trinucleotide repeat, whereas the mother and grandmother each
have approximately 100 repeats

Occurs when all or part of a Parent’s germ line is affected by a disease mutation but the somatic cells are not.
It elevates the recurrence risk for future offspring of the mosaic parent.

One popular example is the protein COLLAGEN, we have three polypeptides in this protein and the 3 of them
should be intact to have the proper function, we might have a mutation in one unit of the three while the
others are normal so some cells and organ would be affected while others are not, it’s called mosiacism
because only a part of the protein is abnormal.

Example: Osteogenesis imperfecta.

10. ” which are frequent cause of the appearance of a genetic disease in an

individual with no previous family history of the disorder. The recurrence risk for the individual’s sibling is very
low, but it may be substantially elevated for the individual’s offspring.

Achnondroplasia = 7/8 are new mutations,

1/8 inherited

however the record per se was a disaster ;( but This sheet contains all the slides and
doctors talk in a simple organized way that is enough to make you enjoy genetics :p,
hope you to enjoy it ;) the corrector

Sorry for any mistake ,Best of luck dear…

 P a g e 17 | 17