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HUMAN GENETIC DISEASES

Human Genetic Diseases

—  Long generation time

—  Low number of progeny

—  ‘Uncontrolled’ mating

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Frequency of Genetic Diseases

—  6-8% of hospitalized children due to genetic
diseases; 0.4-2% to chromosomal abnormalities;
22-31% gene influenced
—  1% overall frequency of monogenic disorders
—  5.3% of individuals below 25 will have a disease
with an important genetic component (single
gene, chromosomal, or complex trait)
—  60% of individuals will have a genetically
influenced disease at some time in life

Male
Proband

Female

Deceased individual
Sex unspecified

Prenatal death
Number of children
of sex indiicated

Miscarriage

Affected

Adopted into a family

Heterozygotes for
Autosomal trait

Adopted out of a family

Carrier of X-linked
Recessive trait

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Marriage

Twins of unknown
zygosity
Extramarital mating

Divorce
Numbering individuals
in pedigrees

Consanguineous
mating
Proband

Monozygotic twins
No offspring

Dizygotic twins

AUTOSOMAL
Dominant
Recessive

MONOGENIC
X-LINKED
Dominant
Recessive
GENES

MULTIFACTORIAL
GENETIC
DISEASES

STRUCTURE
CHROMOSOMES

NUMBER

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AUTOSOMAL RECESSIVE DISEASES

The phenotype of the heterozygotes is

indistinguishable from that of the healthy
homozygotes

(A: wild-type allele, a: mutated allele)

AA, Aa = healthy

aa = affected

Each individual is healthy carrier of at least 8 recessive genetic

diseases, of which 3 lethal

AUTOSOMAL RECESSIVE DISEASES

Aa Aa AA Aa1 AA Aa2

A a
AA Aa1 Aa2 Aa2
AA Aa
A Homozygous Heterozygous
Unaffected Unaffected

Aa aa AA Aa1 Aa2 a 1a 2
a Heterozygous Homozygous
Unaffected Affected 1/4 1/2 1/4

Compound heterozygotes: individuals carrying two differently mutated alleles (a1a2)

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AUTOSOMAL RECESSIVE DISEASES

Consanguinity

Aa AA

AA Aa Aa AA

AA Aa Aa AA

aa Aa Aa aa
AA AA

AUTOSOMAL RECESSIVE DISEASES

⇒ Males and females are both affected

⇒ The affected individual usually has both

parents healthy (with no symptoms)

⇒ Both parents are carriers (heterozygotes) and

transmit the disease to 25% of the progeny

⇒ Stronger incidence in consanguineous

families

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Cystic Fibrosis
Clinical features: chronic pulmonary disease,
exocrine pancreatic insufficiency, slow growth,
azoospermia, increased chloride concentration in
sweat

Frequency: 1 : 2,500

Genetics: autosomal recessive (more

frequent in the caucasic population)

Molecular defect: Mutations in the CFTR gene . The delF508 (Phe-

coding triplet) is the most frequent with 70% in the North Europe
population.

Pathogenesis: Loss of function of the CFTR protein, a Chloride

channel. The mutant form of CFTR prevents chloride transport,
causing mucus build-up. Mucus clogs the airways
and disrupts the function of the pancreas & intestines

Phenylketonuria (PKU)
(OMIM: 261600)
—  Autosomal recessive
—  Caused by accumulation of the amino acid phenylalanine.
—  Patients do not have a functional enzyme to metabolize
phenylalanine

The enzyme phenylalanine

hydroxylase (PAH) converts the
amino acid phenylalanine to
tyrosine

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Phenylketonuria (OMIM: 261600)

•  Neurological impairments
•  Behavioral psychiatric defects
•  Low pigmentation
Phenylketonuria
•  Metabolic defects

AUTOSOMAL DOMINANT DISEASES

The affected individual is heterozygous

a: normal allele, A: mutated allele

aa: normal - healthy

AA, Aa: affected

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AUTOSOMAL DOMINANT DISEASES

AUTOSOMAL DOMINANT DISEASES

Aa aa
Aa aa

Aa Aa aa aa aa Aa
A Heterozygous
Affected

aa Aa Aa aa aa aa
a Homozygous
Healthy
1/2 1/2

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AUTOSOMAL DOMINANT DISEASES

⇒ Both males and females are affected

⇒ “ Vertical Transmission” all generations are involved

⇒ The affected parent passes the disease

to 50% of the progeny

⇒  An affected individual often has one of the

parents affected by the same disease

Achondroplasia

Clinical features: nanism with short limbs and

arms and characteristic faces

Frequency: 1:15,000-1:40,000.

Genetics: autosomal dominant, the phenotype

is more severe in homozygotes, nearly 80% of
patients have de novo mutations

Molecular defect: Mutations in the FGFR3

gene.

Pathogenesis: “Gain of function” with “ligand-

independent activation” of the tyrosine kinase
activity of FGF3.

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Neurofibromatosis, type I
Clinical features: caffelatte
spots, skin tumours, high risk of
malignant tumours.

Frequency: 1:3,000-1:5,000.

Genetics: autosomal dominant,

variabile espressivity, nearly 50% of
patients have de novo mutations.

Molecular defect: Mutations in the NF1 gene. (350 kb, approx

60 exons).

Pathogenesis: Loss of function of the NF1 gene (gene “tumor

suppressor”).

Complications to the
autosomal dominant inheritance
§  Incomplete Penetrance
Not all the individuals with a mutated allele are affected

§  Variable Expressivity

Severity of the phenotype is varying among affected individuals

§  de novo Mutations

The disease likely originate from a novel (de novo) mutation when
the parents and grand-parents are not affected

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Complications to the
autosomal dominant inheritance

Waardenburg Syndrome:
autosomal dominant with variable expressivity
I quadrant: deafness
II quadrant: divergent colour of the eyes
III quadrant: white patch of the hair
IV quadrant: precocious hair whitening

Complications to the
autosomal dominant inheritance
de novo Mutations

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Complications to the
autosomal dominant inheritance
de novo Mutations

recessive genetic diseases ?

Pre-mutations and Anticipation

22 29
32
30 50

22 43
22 40
200

100
150

Huntington’s Disease

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Complications to the
autosomal dominant inheritance
Mosaicism
Zygote

De novo mutation in the first

developmental phases

Embryo
Mosaicism

Generalized
Embryo Mosaicism
Placenta
Mosaicism Placenta

No mosaicism

Complications to the
autosomal dominant inheritance
Mosaicism

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Complications to the
autosomal dominant inheritance
Mosaicism

aa aa

aa aa aa aa aa

Aa Aa aa aa aa

Germinal Mosaicism

Complications to the
autosomal dominant inheritance

A common recessive trait (blood group O) can resemble a

dominant trait.

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Complications to the
autosomal dominant inheritance

A common recessive trait (blood group O) can resemble a

dominant trait.

X-LINKED DISEASES
• Males have a single X chromosome (emizygotes)
• Females have 2 X chromosomes

Recessive Dominant
A: normal allele a: normal allele
a: mutated allele A: mutated allele

A: normal AA: normal a: normal aa: normal

a: affected Aa: normal A: affected Aa: affected
aa: affected AA: affected

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X-LINKED RECESSIVE DISEASES

X-LINKED RECESSIVE DISEASES

XAY XAXa XaY XAXA

XA Xa XA

XAXA XAXa XAXa

Heterozygous
XA Homozygous Heterozygous Xa Unaffected
Unaffected Unaffected
Female Female Female

XAY XaY XAY

Y Unaffected Y Unaffected
Affected Male
Male Male

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X-LINKED RECESSIVE DISEASES

1 2
I

XAXa

1 2 3 4 5
II

XAXa XAXa

1 2 3 4 5
III

XAXa XAXA

XAXa

1 2 3 4
IV

XAXA XAXA

XAXa XAXa

X-LINKED RECESSIVE DISEASES

⇒ Never transmitted male to male

⇒ Only males affected (healthy parents, carrier

mother)
⇒ All males sons of the affected males are healthy
and all females daughters are carriers

⇒ A carrier female has 50% risk of having sons

affected and 50% to have daughters carriers

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Emophilia

Clinical features: coagulation problems,

hemorraegias

Frequency: 1:10,000 males.

Genetics: two forms, A and B both X-linked recessive.

Carrier females rarely show symptoms

Molecular defects: Mutations in factor VIII (A) and IX (B) of the

coagulation.

Pathogenesis: Loss of function of factor VIII and IX. Defects in

the formation of fibrin and clots

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Duchenne Muscular Dystrophy

Clinical features: progressive muscular
weakness, age of onset 3-4 years. Respiratory
and cardiac difficulties. Lethal between 10 and
20 years.

Frequency: 1:3,000 males.

Genetics: X-linked recessive, approx 1/3 of

patients with de novo mutations

Molecular defects: Several types of

mutations (60% deletions) of the DMD gene.
Becker Dystrophy: milder allelic variant

Pathogenesis: : Loss of function of the DMD

gene encoding distrophin, a structural
muscular proteins.

Male to male
transmission?

Affected female

Family with a recessive trait X-linked in which

consanguinity produce a female affected and an
apparent male to male transmission.

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X-LINKED DOMINANT DISEASES

X-LINKED DOMINANT DISEASES

⇒ Never transmitted male to male

⇒  100% of the daughters of an affected father

are affected

⇒ Both males and females can be affected.

Often females are affected in a milder and
more variable form compared to males
⇒  An affected mother has 50% risk to have
affected children

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X chromosome inactivation

XX XY
Gene dosage compensation
The inactive X chromosome
is heterochromatic, late-replicating
BARR BODY

Ipotesi di Lyon

Mosaicism caused by X-chromosome inactivation

Zygote









Early

Stage







Random

X-chromosome

Inactivation















Adult

Female

mosaic

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XY NORMAL

XY DMD

XX DMD
CARRIER

RANDOM X
INACTIVATION

VARIABILITY OF MOSAICISM

INCREASING CLINICAL EXPRESSION OR SEVERITY IN HETEROZYGOTES

X with mutant allele active X with normal allele active

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Mitochondrial DNA
13/87 subunits of Oxidative
phosphorylation

Defects in
•  ATP production
•  Reactive oxygen species
•  Apoptosis

Diverse clinical range of diseases

Neuromuscolar diseases
predominate

Interaction between the

mitochondrial
and the nuclear genome

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Heteroplasmia

Homoplasmia

MITOCHONDRIAL inheritance

• Mutations in the mitochondrial DNA (mtDNA)

• Males and females are affected
• Only females transmit the disease

Variability in the expression due to the different amount of mutated mtDNA

HOMOPLASMIA (wild type or mutated mtDNA molecules)

HETEROPLASMIA (mixed population of wild type or mutated mtDNA
molecules)

Threshold effect: clinical outcome of the disease is determined by the ration

wild type / mutated

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Characteristics of Autosomal Dominant Inheritance

Characteristics of Autosomal Recessive Inheritance

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Eredità autosomica dominante con penetranza incompleta

Characteristics of Y-linked Inheritance

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Characteristics of X-linked Recessive Inheritance

Characteristics of X-linked Dominant Inheritance

 

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Autosomal recessive disease

Ereditarietà mitocondriale

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Autosomal dominant disease: Huntington disease (HD).

Autosomal recessive disease

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X-linked disease: Daltonismo

Ereditarietà mitocondriale

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X-linked dominant

Autosomal dominant disease

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