Genetics Diseases

(Gene Mutation/Mendellian Inherintance)

dr.Yanuarita Tursinawati ,M.Si,Med

Fakultas Kedokteran
Universitas Muhammadiyah Semarang
2017
 Single gene mutation
inheritance

 Also called Mendelian or monogenic inheritance

 Genetic condition caused by the alteration or mutation
of a spesific/ single gene.
 There are estimated to be over 4000 human diseases.
 Can be passed on to subsequent generations through :
1. Autosomal(Autosomal dominant vs Autosomal
recessive)
2. X-linked ( X-linked dominant vs X-linked recesssive)
 Autosomal Dominant ,
ex: Achondroplasia,
Marfan Syndrome,etc

Single Gene Autosomal

recessive ex :
Disorder thalassemia,
PKU,etc

X-Linked Recessive
ex: Hemofilia,
Fragile X
syndrom,etc
How to arrange
Pedigree?
 Autosomal Dominant
Inheritance
• Characteristic

1. Transmission is vertical (from generation to generation), no skip

generation

2. Number of affected males and females is equal

3. Male-to-male transmission is observed

4. Disorder may arise as a new mutation (de novo mutation)

5. Phenotype can vary from affected person to affected person in

same family

6. Only one copy of a mutant allele is necessary for expression of

the trait (Aa and AA  affected)

7. Ex : Achondroplasia , Marfan Syndrome etc

 Achondroplasia
• Achondroplasia is a form of short-limbed dwarfism.
• Achondroplastic Dwarfism, Chondrodystrophia
Fetalis, Chondrodystrophy Syndrome atau
Osteosclerosis Congenital
• Achondroplasia  "without cartilage formation.“
• The problem is not in forming cartilage but in
converting it to bone (a process called ossification),
particularly in the long bones of the arms and legs.
• The condition occurs in 1 in 15.000 to 40.000
newborns
 Etiology
• Achondroplasia is caused by missense mutations in the
fibroblast growth factor receptor-3 (FGFR3) gene located on
the chromosome 4p16.3  endochondral occification
disorder.
• The FGFR3 protein is involved in the development and
maintenance of bone and brain tissue  regulates bone
growth by limiting / inhibiting the formation of bone from
cartilage in the long bones.
• The nucleotide 1138 in exon 10 on chromosome 4, has the
highest mutation rate known :
a. In 97% of patients, ( G>A)
b. 3% have a cytosine replaces the normal guanine at (G>C)
 Cause of Mutation
• 80 % Caused by a de novo mutation (a new
mutation that occurs in a germ cell and is
then passed on to an offspring.)
• Appears that the vast majority of FGFR3
mutations arise as new mutations during
spermatogenesis before Meiosis I
• Studies show correlation with paternal age 
All mutations studied so far occur on the
paternal chromosome
Recurrence risk ?
• Heterozygote affected vs Heterozygote affected
each child has a 50 % chance of being heterozygotes / Dd (affected); a 25 % chance of
being normal homozygote (dd), a 25 % being severely affected homozygot
Recurrence risk ?
• Heterozygote vs normal:
each child has a 50 % chance of being heterozygotes / Dd (affected); a 50 % chance of being normal
homozygote (dd)
 Physical examination
• Short arms and legs with particularly short upper arms
and thighs (rhizomelic)
• Short stature , not more than 1,2 m
• Long narrow trunk
• An enlarged head (macrocephaly) with a prominent
forehead ( frontal bossing)
• Midface hypoplasia,
• Prominent lumbar lordosis,
• Genu varum (bowed legs),
• a trident-hand configuration.
• Generally of normal intelligence , with delayed motor
milestone
• Female  small pelvic size
 Autosomal recessive
• Characteristic

1. Number of affected males and females is equal

2. Skip generation (+)

3. Phenotype is little vary from affected person to affected person in

same family

4. One copy of mutant allele (heterozygote / Aa)  carrier  does

not develop the condition.

5. Both copy of mutant allel (homozygote/aa)  affected

6. Risk of AR disorder increased b consanguinity and specific racial

7. Example : Thalasemia, cystic fibrosis, Inborn Error Metabolism,

albino,Congenital Adrenal Hyperplasia
• Carier (heterozygot) vs carier (heterozygote)
each child has a 25% chance of being homozygous wild-type (unaffected); a 25% chance of being
homozygous mutant (affected); or a 50% chance of being heterozygous (unaffected carrier).
 DISEASE OF HAEMOGLOBIN
SYNTHESIS
Common genetic autosomal recessive blood disease :

A. Thalassaemias ( and ) Reduce or absence of globin

chain synthesis in hemoglobin.

B. Haemoglobinopathies/Hb variants (Hb E,Hb Malay,Hb

Lepore)  Structural changes of globin chains synthesis in
hemoglobin

C. Combination

Decreased oxygen carrying capacity of hemoglobin 

Anemia
 Stucture of Hemoglobin
Composition of
Adult Hb

 



HbA (22) 98%
HbA2 (22) ~ 2.5%
HbF (22) <1%
 Beta Thalassemia
 Thalassemia from Greek word  thalassa
(Mediterranean Sea) + haima (blood) .
 Discovered by Thomas B. Cooley in 1925

 Beta thalassemia has deficient /absent β globin chain

due to point mutations in beta globin gene  increase
α globin chain.
 .

Commonly found in Mediterranean, Middle East, Southeast Asian

(including Vietnamese, Laotian, Thai, Singaporean, Filipino,

Cambodian, Malaysian, Burmese, and Indonesian) .

 The distribution and the frequency (%) of
beta thalassemia carriers in Indonesia
-thalassemia
HbE
P’baru

4 2
Dayak
Batak

Banjar
1 5 3

M’hasa
0

Kaili
5 2

M’kasar
Minang

8 1
P’bang

4
3 9
Bangka

6
Java

Alor
8 Sumba
Bali

Sasak

1 6
Bima

4 3 3
6 5
4 33
7

A.S. Sofro & F. Lanni, University of Gajah Mada

 Patophysiology
• Mutation of beta globin chain gene on Chr 11
• The most frequent mutation is HbE (29%), followed by IVS1-
nt5 (19%), and Cd 35 (8%)
 In Indonesia: 28 types of mutations
HbE : Mutation in codon 26 , GAG AAG
Thalassemia
1. NonSense Mutation
Codon 15 (TGGTrp to TAGStop) o thalassemia
normal Cd 15
12 13 14 15
ACTGCCCTGTGGGGCAAG……………….146 amino acid
Cd 15 mutation
ACTGCCCTGTAG stop translation…… 14 amino acid

Other nonsense mutations in Indonesian population

• Cd 17 (AAGLys to TGAStop)  16 amino acid
• Cd 26 (GAGGlu to TAGStop)  25 amino acid
 FRAMESHIFT MUTATIONS

 Cd 35 (deletion C)
 Cd 8-9 (insertion G)  21 amino acid
 Cd 41-42 (deletion TCTT)  58 amino
acid
 Cd 123-124-125 (deletion 8 bp)  135
amino acid
 SPLICING MUTATIONS
C
IVS1-nt5 (G to C)
CAGGTTGGT

Exon1 intron1 Exon2 intron2 Exon3

1
2

3
Normal splicing RNA Translation Normal -globin chain
146 amino acids

Abnormal splicing RNA (?%) Abnormal -globin chain

1 29 amino acid

2 54 amino acid

3 150 amino acid

 Pathophysiology -thalassemia
Excess of -globin chains

4 (very unstable) 


precipitates 

Bone marrow Peripheral circulation

Mature eritrocyte
RBC precursor

• physical damage
• metabolic changes

• ineffective erythropoiesis Hemolysis in microsirculation

(spleen)
 Types of beta thalassemia
• On the basis of synthetic ability β-genes are
designated as :

a. β gene –normal amount of β-chain

b. β+ gene –reduced amount of β-chain

c. β0 gene –no β-chain synthesize

• So, there are three types:

1. Minor / Trait , genotype β β0 or β β+

2. Intermedia, genotype β+ β+ or β0 β+

3. Major (Cooley anemia), genotype β0β0

 Clinical manifestation of
Beta thalassemia
• Beta Thalassemia minor (trait)
• Asymptomatic
• Minor anemia
• Beta Thalassemia major (Cooley Anemia)
• Anemia microcyte & hipocromic due to inadequate
production + ineffective erythropoiesis + haemolysis
• ↑Erythropoiesis marrow expansion & thinning of cortex of
skull bone Thalassaemia facies
• Dark skin  accumulation of Fe
• Lack of O2 Congestive heart failure and death
• Beta Thalassemia intermedia
• symptoms similar to Cooley Anemia but less severe
 CLINICAL MANIFESTATION OF -THALASSEMIA
HETEROZYGOTE + o &
HOMOZYGOTE o HOMOZYGOTE ++

 


 
 

Severe anemia Mild to severe anemia

Liver & spleen enlargement Liver & spleen may/not >>
only consists of HbA2 and HbF Still has HbA
HbF > 90% or less HbF range from 10 to > 90%
NORMAL FETUS: HbF < 1 %
 ↑Haemolysis ↑demands of phagocytic function 
hyperplasia of phagocytes Hepatosplenomegaly

To compensate anaemia extramedullary haemopoiesis in liver,

spleen Organomegaly
 Alpha thalassemia
• An absence or deficiency of α-chain synthesis due to
deletion mutation of α-genes.

• Types of α thalassemia:

1. -a/aa: silent carriers with little signs

2. Thalassemia minor : mild anemia

a. (--/aa) : cis double deletion more common in SEA

b. (-a/-a) : trans double deletion

4. --/-a: Hb H disease (intermedia)

5. --/--: Hb Bart’s hydrops fetalis

 Clinical manifestation of
Alpha thalassemia
 Silent carriers genotipe -a/aa : asymptomatic / “normal”

 Alpha Thalassemia minor (trait) dg genotipa –a/-a atau --/aa

• no anemia / “normal” , microcytosis
 Alpha Thalassemia intermedia (“Hemoglobin H”) , genotip (--/-a)
• 75% reduction of α-chain

• Variable ranging from mild to severe anemia with microcytosis & hemolysis

• Severe RBC abnormalites

• bone deformities, splenomegaly
 Alpha Thalassemia major / Hb Bart’s , genotipe --/--
• fatal hydrops fetalis
- fluid build-up in fetal compartments, leads to death
• occurs in utero
o-Thalassemia deletions homozygote (--/--)/
Hydrops Fetalis
Pathophysiology -thalassemia

 Excess of:
-globin chains (fetus) 
 -globin chains (adult)
  

4 (HbH)
4 (Hb Bart)

Precipitates mostly in mature red cells

hemolysis in spleen and peripheral circulation

 The prevention strategy of
thalassemia
A. Problems ????
Undetected Thalassemia Intermedia or carriers
thalassemia?

B. Prevention strategy on thalassemia :

1.Retrospective family screening among thalassemia

patients

2.Prosperctive strategy  in certain population to identify

thalassemia carrier, such as in school / office.

C.Using premarital, preconception, prenatal or neonatal

screening strategy to measure Hb,MCV and MCH.
Government, medical practitioners and Obstetricians
must have enough knowledge and play role in screening
strategy :

1.Compulsory thalassemia carrier screening test before

marriage (premarital screening)  Cyprus

2.Compulsory thalassemia carrier screening test during

pregnancy Singapore

3.Prenatal Diagnosis for thalassemia  Singapore

 X-Linked recessive
• Chracteristic

1. Mutation in a gene on the X chromosome

2. Incidence is much higher in males than females.

3. Only one defective copy necessary for disease in males

because males are hemizygous for X chromosom

4. No male-to-male transmission Affected males will have all

normal sons and all heterozygote (carrier) daughters

5. Female are carriers  normal phenotype

6. Skip generation (+)

7. Ex : Color blindnes, Hemophilia Duchenne muscular

dystrophY, Fragile X Syndrom, Androgen Insuficiency
Syndrome (PAIS/CAIS)
 FRAGILE X SYNDROME
• Fragile X syndrome is trinucleotide repeat disorders

which is the first etiology of heritable mental

retardation and etiology number two of genetic

mental retardation after Down Syndrom (Sultana

M.H Faradz, 2003).

• Primarily affects male, but 1/3 of the carier female

are also found to be affected, though the severity of

MR <<

• Prevalence ; 1 in 2.000 in male, 1 in 4.000 in female

• The underlying cause of Fragile X is a single gene mutation, Fragile X Mental

Retardation 1 gene (FMR1) mutation at X chromosome which encode FMRP

Protein (in brain and testis).

• The promoter region (5’ UTR) of FMR1 gen at Xq27.3 contains a CGG repeats.

Normally : 6-50 repeats which are stably transmitted from generation to generation.

• 45-54 CGG repeats have what is called an “intermediate” or “grey zone allele”

• If mutated, FMR1 can produce repeats sequence that can expand in future

generations :

1. Premutation : 55-200 repeats

2. Full mutation: >200 repeats

 Fragile X Syndrome
Typical Premutation
Fullmutation
(CGG) < 45 (CGG) 55 - 200 (CGG) > 200

mRNA

FMRP
Fragile X syndrome
Clinical
normal - Primary ovarian insufficiency (POI)
Early menopasue female
- Fragile X-associated
FMR1 gene “Shut
down” / methylated
Tremor ataxia syndrome (FXTAS) male >>
- Depression and anxiety Mental Retardation 
Fragile X syndrom
 Inheritance
• X-linked ressesive disorder : the chances that the son or daughter will be
inherited is 50%.
• A man never passes the fragile X gene to his sons, since he passes only
his Y chromosome to them, which does not contain a fragile X gene.
• The child will be affected or unaffected will depend on whether the
FMR-1 gene harbors full mutation or premutation:

1. If the mother is the carrier of full mutation, her 50% sons and 50%
daughters will inherit the mutation. Those sons will be clinically affected

2. If the mother is a carrier of premutation, the chance that the premutation

will be converted to full mutation varies accordingly as the number of
CGG repeats generally increase in the mother.

CGG repeat of mother chances of

permutation 
full mutation
60 - 80 14% - 55%
80 - 100 80% - 90%
100- 200 100%
 Sign and symptomps

1. Intelligence and learning

2. Social and emotional

3. Speech and language

4. Sensory

5. Physical
1. Intelligence and learning
 Impaired intellectual  low IQ level
 Attention disorder
 Hyperactivity
 anxiety
2. Social and emotional
 Not comfortable meeting new people
 Lack of eye contact
 Tend to being anxious Tantrum
 repetitive actions / stereotypic behaviour
(hand-flaping, buting,persevative speech)
3. Speech and language
 Language difficulties  varies range from mild to
severe problem with basic language skill.
 Basic language skill problen inability to
Pronounce word clearly, to speak and
communicate well.
 This difficulties may be due to the sensory
overload or social anxiety , rather than a problem
with the part of the brain that control speech and
language.
4. Sensory
 Sensitive to loud or even by slight sound in room
5. Physical
 Have certain feature that typical with Fragile X,
such as :
1. Longer face
2. Noticable ear
3. Macroorchidism (enlarged testicle)
4. Loose, flexible joints  can extend joint further
than normal.
5. Valve of the heart problems (mitral valve prolaps)
6. epilepsy
Recurrence Risk ?
• Normal vs carier
25 % normal daughter
25 % carier daughter
S5 % normal son
25 5 affected son
• Affected father vs normal mother
50 % carier daughter
50 % normal son
QUIZ

???
QUIZ