Classification of Genetic Diseases

Single gene mendelian medical disorders

Chromosomal disorders
Multifactorial inheritance
Mitochondria inheritance
Somatic mutation

Single gene mendelian medical disorders

OMIM http://www.ncbi.nlm.nih.gov/omim

Autosomal dominant 3,802 reports

Autosomal recessive 3,771 reports
X-linked 1,848 reports
Y-linked 266 reports

Over-all about 0.5-1% of live birth

Genetic terminology
Genotype vs Phenotype
Allele vs Locus (Loci)
A a

B B

A and B are loci.

A or a is an allele of locus A.
Locus A is heterozygous but
locus B is homozygous.

Achondroplasia

The achondroplasia patient 15 years from now

What is the risk of his child?

How to know the risk

P

What is the risk of his child?

Your role
Understand mode of
inheritance
Risk calculation
Counseling

Mode of Inheritances
- Classification of genetic diseases
-Understand how genotypes are inherited.
-Understand how genotypes lead to phenotypes.

Risk calculation

How to know classification of

genetic diseases of the patient?

(How to know inheritance

of this patient?)

The achondroplasia patient 15 years from now

What is the risk of his child?

Punnetts Square

The achondroplasia patient 15 years from now

What is the risk of his child?

50%

Please self describe characteristic of classical autosomal dominant pedigree

The achondroplasia patient pedigree

Why is his parent normal?

What is the
risk of this
child?

The achondroplasia patient pedigree

New Mutation

Why is his parent normal?

Fitness vs Denovo Mutation

Familial
Hypercholesterolemia

Severe Osteogenesis Imperfecta

Who was most likely new mutation?

Mosaicism

Gonadal Mosaicism

Recurrence risk of AD new mutation family is not zero.

Genetic concept:
Advanced parental age
MATERNAL

PATERNAL

Chromosomal
disorders
(nondisjunction)

Single gene defects:

Autosomal dominant
(point mutation)

The achondroplasia patient 15 years from now

What is the risk of his child?

Why is his parent normal?

Retinoblastoma

Example of Retinoblastoma pedigree

I
1
How II2 is ill?

II

How III1 is not ill?

Risk of III4, IV2, IV3?

III

P
1

IV

2
P

3
P

Example of Retinoblastoma pedigree

I
1
How II2 is ill?
AD inheritance

II
1

III

P
1

IV

2
P

3
P

Example of Retinoblastoma pedigree

I
1
How II2 is ill?
AD inheritance
How III1 is not ill?
Non-penetrance
20%

II
1

III

P
1

IV

2
P

3
P

Example of Retinoblastoma pedigree

I
1
How II2 is ill?
AD inheritance
How III1 is not ill?
Non-penetrance
20%
Risk of III4 = 40%

II
1

III

P
1

IV

2
P

3
P

Example of Retinoblastoma pedigree

I
1
How II2 is ill?
AD inheritance
How III1 is not ill?
Non-penetrance
20%
Risk of III4 = 40%
IV2 = 40%

II
1

III

P
1

IV

2
P

3
P

Example of Retinoblastoma pedigree

I
1
How II2 is ill?
AD inheritance
How III1 is not ill?
Non-penetrance
20%
Risk of III4 = 40%
IV2 = 40%
IV3 = 1/15

II
1

III

P
1

IV

2
P

3
P

II
1

II1 is 3 yr old.
II2 is 1 yr old. Diagnosis?

II
1

Two year later.

II2 is 3 yr old. Diagnosis?

II
1

Three year later

II2 is retinoblastoma.
Why?

II

II
1

II1 was ill at 3 yrs but

II2 is ill at 4 yrs.
Why?
Variation in expression
(age of onset)

II

Neurofibromatosis I
Example of
Variation in
Expression:
Severity of
Phenotype

AD Inheritance- Exceptions

New mutation
Reduced penetrance
Variable expressivity
Germline mosaicism

Examples of AD Disorders

Skeletal dysplasia
Achondroplasia
Osteogenesis imperfecta

Connective tissue disorders

Marfan syndrome
Ehlers Danlos syndrome

Craniosynostosis
Crouzon syndrome
Apert syndrome

Neurocutaneous syndrome
Neurofibromatosis
Tuberous sclerosis

Adult-onset genetic disorders

Familial hypercholesterolemia
Huntington disease
AD polycystic kidney disease

Please do self
study to
understand these
diseases
phenotypes. No
need to remember
all detail at this
point.

Achondroplasia

Osteogenesis imperfecta

Marfan syndrome

tall stature
Ectopia lentis
Dilated arotic root

Ehlers-Danlos syndrome

Crouzon syndrome

Apert syndrome

Neurofibromatosis type I

Tuberous sclerosis

Angiofibroma
Ashleaf
Shagreen

Summarized AD pedigree

Example of Autosomal
Recessive in Thailand

Alpha Thalassemia Hydropfetalis

Beta Thalassemia

Autosomal recessive medical disorders in general are rare.

1:20,000 to 1:100,000
Nevertheless,
some are more common in particular populations.
Cystic fibrosis

1:2,000 to 1:4,000 in Caucasian.

Phenylketonuria

1:10,000 in Caucasian.

Sickle cell anemia

1:500 in African.

Thalassemia (alpha & beta)

Why?

1:100 in South-East Asia &

Mediterranean

Autosomal recessive medical disorders in general are rare.

1:20,000 to 1:100,000
Nevertheless,
some are more common in particular populations.
Why?
-Selective advantage (of carrier)
-Common ancestor
-Mating within small population because of racial,
geographic and ethnic differences.
-Genetic drift

Founder Effect
A high frequency of a specific gene mutation in
a population founded by a small ancestral
group

Original
population

Marked population
decrease,
migration, or
isolation

Generations
later

Autosomal Recessive Inheritance

Absolute risk of birth defect between couple

First degree relative
Unrelated person
First cousins

30-50%
2-3%
4-5%

Risk of birth defect from AR

x pC x pC (pC = probability of being carrier)
In this case II1 = ?

Risk of birth defect from AR

x pC x pC (pC = probability of being carrier)
In this case II2 = ?

The probability of being carrier in AR pedigree

Consider
II1 & II2
I1 & I2 & II3
III2
III3
(General Population)

Risk of birth defect from AR

x pC x pC (pC = probability of being carrier)
In this case = x 2/3 x = 1/24

Carrier frequency is approximately equal to

Disease frequency1/2 x 2
For example if incidence of alpha thal is 1/100,
the carrier frequency in this population is
1/1001/2 x 2 = 1/5
General frequency 1 = N2 + 2ND + D2
N is close to 1 and we know D2 = disease frequency.
2ND = Disease frequency1/2 x 2

Summary of AR pedigree

Autosomal Recessive Inheritance

Hemoglobinopathies, thalassemias
Cystic fibrosis
Most of inborn errors of metabolism
Spinal muscular atrophy

X-linked Recessive Inheritance

Summarized X-linked pedigree

Who are oligate carriers in this pedigree?

2/3

Carrier?

Does X-linked
Female show
Phenotype?
How?
Carrier detection?

X-linked Recessive Inheritance

Hemophilia A
Hemophilia B
Duchenne muscular dystrophy
Wiskott-Aldrich syndrome (X-linked
immunodeficiency)
X-linked agammaglobulinemia
X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy

X-linked Dominant Inheritance

X-linked Dominant Inheritance

Affected heterozygous females are seen.
Affected males with normal mates have
no affected sons and no normal
daughters.
Both male and female offspring of female
carriers have a 50% risk of inheriting the
phenotype.
The phenotype is about twice as common
in females as in males.

X-linked Dominant Inheritance

Affected heterozygous females are seen.
Affected males with normal mates have
no affected sons and no normal
daughters.
Both male and female offspring of female
carriers have a 50% risk of inheriting the
phenotype.
The phenotype is about twice as common
in females as in males.

Clues

Pedigree similar to AD,

but no male-to-male
transmission,
with F:M = 2:1

X-linked dominant,
lethal in male
Only female
survives

X-linked Dominant Inheritance

X-linked hypophosphatemic
rickets
Incontinentia pigmenti
Rett syndrome

Y-linked Inheritance
Only males affected
Male to male transmission
Examples:
SHOXY (Leri-weil, Langer mesomelic
dysplasia)
Testes specific protein
Sex determining region Y
Zinc finger protein Y
Azoospermia factor 2
Azoospermia factor 1

Summary
Mendelian medical disorders
The family is suffering from a single
gene disorder?
Mode of inheritance
New mutation & germline mosaicism
Penetrance
Variation in expression
Risk calculation
Carrier identification