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)

B B

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

Achondroplasia

P

What is the risk of his child?

The achondroplasia patient 15 years from now

P

What is the risk of his child?

How to know the risk

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?)

P

What is the risk of his child?

The achondroplasia patient 15 years from now

Punnett’s Square

P

What is the risk of his child?

The achondroplasia patient 15 years from now

50%

Please self describe characteristic of classical autosomal dominant pedigree

Why is his parent normal?

The achondroplasia patient pedigree

PWhat is the risk of this child?

Why is his parent normal?

The achondroplasia patient pedigree

New Mutation

P

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

Chromosomal disorders

(nondisjunction)

PATERNAL

Single gene defects:Autosomal dominant

(point mutation)

P

What is the risk of his child?

Why is his parent normal?

The achondroplasia patient 15 years from now

Retinoblastoma

P

P

P

1 2

1 2

1 2 3 4

1 2 3

I

II

III

IV

How II2 is ill?

How III1 is not ill?

Risk of III4, IV2, IV3?

Example of Retinoblastoma pedigree

P

P

P

1 2

1 2

1 2 3 4

1 2 3

I

II

III

IV

How II2 is ill?AD inheritance

Example of Retinoblastoma pedigree

P

P

P

1 2

1 2

1 2 3 4

1 2 3

I

II

III

IV

How II2 is ill?AD inheritanceHow III1 is not ill?Non-penetrance20%

Example of Retinoblastoma pedigree

P

P

P

1 2

1 2

1 2 3 4

1 2 3

I

II

III

IV

How II2 is ill?AD inheritanceHow III1 is not ill?Non-penetrance20%Risk of III4 = 40%

Example of Retinoblastoma pedigree

P

P

P

1 2

1 2

1 2 3 4

1 2 3

I

II

III

IV

How II2 is ill?AD inheritanceHow III1 is not ill?Non-penetrance20%Risk of III4 = 40%IV2 = 40%

Example of Retinoblastoma pedigree

P

P

P

1 2

1 2

1 2 3 4

1 2 3

I

II

III

IV

How II2 is ill?AD inheritanceHow III1 is not ill?Non-penetrance20%Risk of III4 = 40%IV2 = 40%IV3 = 1/15

Example of Retinoblastoma pedigree

?

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

I

II

1 2

?

Two year later.II2 is 3 yr old. Diagnosis?

I

II

1 2

?

II2 is retinoblastoma.Why?

I

II

1 2

I

II

1 2

Three year later

?

Why?Variation in expression (age of onset)

I

II

1 2

I

II

1 2

II1 was ill at 3 yrs butII2 is ill at 4 yrs.

Neurofibromatosis IExample 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 AutosomalRecessive 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) 1:100 in South-East Asia &Mediterranean

Why?

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

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

group

Generations later

Founder Effect

Original population

Marked population decrease,

migration, or isolation

Autosomal Recessive Inheritance

Absolute risk of birth defect between couple

First degree relative 30-50%Unrelated person 2-3%First cousins 4-5%

P

Risk of birth defect from AR¼ x pC x pC (pC = probability of being carrier)

In this case II1 = ?

P

Risk of birth defect from AR¼ x pC x pC (pC = probability of being carrier)

In this case II2 = ?

P

The probability of being carrier in AR pedigree

ConsiderII1 & II2

I1 & I2 & II3

III2

III3(General Population)

Risk of birth defect from AR¼ x pC x pC (pC = probability of being carrier)

In this case = ¼ x 2/3 x ¼ = 1/24

P

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 is1/1001/2 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?

Carrier?2/3

Does X-linkedFemale showPhenotype?

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 hypophosphatemicrickets

• Incontinentia pigmenti• Rett syndrome

Y-linked Inheritance• Only males affected• Male to male transmission• Examples:

– SHOXY (Leri-weil, Langer mesomelicdysplasia)

– 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