Lecture given by Leon MUTESA, MD,PhD , a genetician teaching at UR( UNIVERSITY OF RWANDA, HUYE CAMPUS,SCHOOL OF MEDICINE AND PHARMACY, DEPARTMENT OF GENERAL MEDICINE AND SURGERY).

1. Part II. Medical Genetics
2012, Doc I

2. Chap 1 Modes of Inheritance

3. Modes of Inheritance
Inheritance patterns describe
how a disease is transmitted in
families.
 These patterns help to
predict the recurrence risk for
relatives.
 In general, inheritance
patterns for single gene
disorders are classified based
on whether they are
autosomal or X-linked and
whether they have a dominant
or recessive pattern of
inheritance. These disorders
are called Mendelian
disorders, after the geneticist
Gregor Mendel.

4. Symbols commonly used in Pedigree

5. Autosomal dominant
• only one copy of a disease allele is
necessary for an individual to be
susceptible to expressing the
phenotype.
• With each pregnancy, there is a one in
two (50%) chance the offspring will
inherit the disease allele.
• Unless a new mutation has occurred,
all affected individuals will have at
least one parent who carries the
disease allele.
• Autosomal dominant inheritance is
often called vertical inheritance
because of the transmission from
parent to offspring.
• Across a population, the proportion of
affected males should be equal to the
proportion of affected females.

6. Autosomal dominant
• Variable expressivity: variations of
phenotype in individuals carrying a
same genotype !!
• Complete penetrance: all individuals
who have the disease-causing mutation
have clinical symptoms of disease
• Incomplete penetrance or reduced
penetrance:
Some individuals fail to express the trait,
even though they carry the disease
allele
Incomplete penetrance

7. Autosomal dominant
Example: Myotonic Muscular
Dystrophy can include myotonia,
cataracts, arrythmia, MR, etc.
⇒However, individuals who carry the
myotonic dystrophy gene, even within
the same family, will express the
condition in a variety of ways.
Variable expression

8. Autosomal dominant
Evidence for autosomal dominant inheritance:
The disease is passed from the father (II-3) to the
son (III-5), this never happens with X-linked traits.
 The disease occurs in three consecutive
generations, this never happens with recessive
traits.
 Males and females are affected, with roughly the
same probability.
 However, II-1 does not express the disease. He
must have inherited the mutant allele because he
passed it on to two children, III-1 and III-3. II-1 is a
classical example of incomplete penetrance, he has
the allele for the disease but he does not express it.

9. Autosomal dominant

10. Autosomal dominant

11. Examples of diseases
1. NEUROFIBROMATOSIS
Diagnostic criteria for NF1
• Two or more of the following: *
• Six or more café-au-lait spots 1.5
cm or larger in post-pubertal
individuals, 0.5 cm or larger in pre-
pubertal individuals
• Two or more neurofibromas of any
type or one or more
plexiform neurofibroma
• Freckling in the axilla or groin
• Optic glioma (tumor of the optic
pathway)
• Two or more Lisch nodules (benign
iris hamartomas)
• A distinctive bone lesion: dysplasia

12. Examples of diseases
1. NEUROFIBROMATOSIS

13. Examples of diseases
1. ACHONDROPLASIA
• Short stature
• Rhizomelic (proximal) shortening of
the arms and legs
• Limitation of elbow extension
• Trident configuration of the hands
• Genu varum (bow legs)
• Thoracolumbar gibbus in infancy
1. Exaggerated lumbar lordosis, which
develops when walking begins
• Large head with frontal bossing
• Midface hypoplasia

14. Examples of diseases
2. ACHONDROPLASIA

15. Examples of diseases
3. OSTEOGENESIS IMPERFECTA

16. Autosomal recessive
• For rare traits, the pedigree usually
involves mating between two unaffected
heterozygotes and the production of one or
more homozygous offspring.
• Typically, the parents of an affected
individual are not affected but are gene
carriers.
• With each pregnancy of carrier parents:
– 25% of the offspring will inherit two
copies of the disease allele and will
therefore have the phenotype.
– 50% of the offspring will inherit one
copy of the disease allele and will be a
carrier.
– 25% of the offspring will inherit no
copies of the disease allele
• As with autosomal dominant inheritance,
the proportion of affected males should be
equal to the proportion of affected females
in a given population.

17. Autosomal recessive
Risk 1

18. Autosomal recessive
Risk 2

19. Autosomal recessive: pedigree

20. Autosomal recessive
The consanguinity
increases the risk
Consanguinity: if parents are related (consanguinity)
there is an increased risk that both parents carry the same
recessive allele

21. Autosomal recessive
The consanguinity
increases the risk

22. Examples of diseases
1.Sickle cell disease
2.Cystic fibrosis
3.Metabolic diseases
(albinism, etc)

23. Examples of diseases

24. Albinism

25. Haplo-sufficiency in heterozygous
Haplosufficiency: The single functional allele provides enough active protein for the
cell’s need

26. Complementation
Children have normal phenotype when ever the parents carry
mutations in different genes ⇒e.g. Hearing loss

27. X-Linked dominant inheritance
• Only one copy of a disease allele
on the X chromosome is required
for an individual to be susceptible
to an X-linked dominant disease.
• Both males and females can be
affected, although males may be
more severely affected because
they only carry one copy of genes
found on the X chromosome.
• When a female is affected, each
pregnancy will have a one in two
(50%) chance for the offspring to
inherit the disease allele. When a
male is affected, all his daughters
will be affected, but none of his
sons will be affected.

28. Examples of diseases
1. FRAGILE X SYNDROME
• Characterized by moderate mental
retardation in affected males and mild
mental retardation in affected
females.
• Fragile X is the most common form of
inherited mental retardation.
1. Fragile X syndrome is associated with
increased CGG repeats in the FMR1
gene, which is on the X chromosome.
• Males with fragile X syndrome often
have abnormal facies, including a
long face, large ears, prominent jaw
and macroorchidism (abnormally
large testes).
• Affected females tend to have milder
features than the males.

29. Examples of diseases
1. FRAGILE X SYNDROME

30. Examples of diseases
1. FRAGILE X SYNDROME
Fragile X syndrome is
associated with increased
CGG repeats in the FMR1
gene, which is on the X
chromosome.

31. Examples of diseases
2. INCONTINENTIA PIGMENTI
• Disorder of skin pigmentation with
neurologic, ophthalmologic, and
dental involvement.
• Lethal alleles in males
• Skin, hair, nails, dental
abnormalities, seizures,
developmental delay, mental
retardation, ataxia, spastic
abnormalities, microcephaly,
cerebral atrophy, hypoplasia of the
corpus callosum
• Ocular defects, atrophic patchy
alopecia, dwarfism, clubfoot, spina
bifida, hemiatrophy, and congenital
hip dislocation

32. X-Linked recessive inheritance
• Two copies of a disease allele on the X chromosome are required
for an individual with two X chromosomes (a female) to be affected
with an X-linked recessive disease.
• Since males are hemizygous (they have only one X chromosome),
one copy of an X-linked recessive disease allele is affected.
• Females are usually carriers because they only have one copy of
the disease allele.
• For a carrier female, with each pregnancy there is a one in two
(50%) chance her sons will inherit the disease allele and a one in
two (50%) chance her daughters will be carriers.
• Affected males transmit the disease allele to all of their daughters,
who are then carriers, but to none of their sons.
• Women are affected when they have two copies of the disease
allele. All of their sons will be affected, and all of their daughters will
be unaffected carriers

33. X-Linked recessive inheritance

34. Examples of diseases
1.Duchenne Muscular Dystrophy
2.Hemophilia A
3.Daltonism
4. Anhydrotic Ectodermal Dysplasia

35. Examples of diseases
1.Duchenne Muscular
Dystrophy
• progressive muscle disease, with
diagnosis made usually around 4
years. Boys typically require the use
of a wheelchair by the age of 12.
• Respiratory infections and
cardiomyopathy are the most
common causes of death, typically in
the third decade.
1. Approximately 70% of males with
DMD have deletions or duplications in
the DMD gene on chromosome X.

36. Examples of diseases
2. Hemophilia A

37. Examples of diseases
3. Hypohydrotic Ectodermal Dysplasia
X-linked recessive disease
characterized by failure to form
ectodermal derivatives. Sweat
glands and teeth may be missing
(anhidrosis and anodontia,
respectively), and there may be
scant hair, and malformation of
the iris.

38. X-chromosome inactivation
(Lyonization)
• Process by which one of the 2 X chromosomes in
female mammals is inactivated
• The inactive X is condensed into transcriptionally
inactive heterochromatin
• This inactivated X chromosome is called « Barr
body »
• Lyon hypothesis (1961) states that in cells with
multiple X chromosomes, all but one are inactivated
during mammalian embryogenesis. This happens
early in embryonic development at random in
mammals

39. X-chromosome inactivation (Lyonization)
• In men and women with more than one X chromosome, the number
of Barr bodies visible at interphase is always one less than the total
number (n) of X chromosomes ( Barr body = n-1)
In some cases, females who carry
X-linked genetic diseases can be
affected by those diseases, if X-
inactivation is not random.

40. Co-dominance
AB are codominant
A and B have antigenes
O no antigene
e.g.: ABO blood group
Means that both alleles are
expressed in the phenotype
of individuals that have
heterozygous alleles

41. Co-dominance
However, there are other
markers that affect blood
groups. One of these is known
as the Rhesus factor and is
either positive or negative.
Positive is dominant and
negative is recessive.
⇒This means that we have
two types of gene for the
same thing. It is possible to
work out the possible
outcomes of offspring

42. Co-dominance (exercise)
In CHUB hospital, four newborns were accidentally mixed up. The
doctors know that the blood groups of the babies are O, A, B and
AB, respectively. The blood groups of the four putative parents pairs
were determined. Indicate the baby corresponding probably to
each parent couple:
(a) ABxO,
(b) AxO,
(c) AxAB,
(d) OxO

43. Co-dominance (exercise)
In CHUB hospital, four newborns were accidentally mixed up. The
doctors know that the blood groups of the babies are O, A, B and
AB, respectively. The blood groups of the four putative parents pairs
were determined. Indicate the baby corresponding probably to
each parent couple:
• (a) ABxO, baby with blood group B
• (b) AxO, baby with blood group A
• (c) AxAB, baby with blood group AB
• (d) OxO baby with blood group O