BIOL-S402F Medical Genetics

and Immunology
(Part B: Medical Genetics)
Lecture 8
By Dr. Andy YY CHEUNG
cheungyy@hkmu.edu.hk
Course outline:
4. Molecular Basis of Genetic Diseases
a. Gregor Mendel and the Laws of Inheritance Lectures 7
b. DNA as the Basis of Inheritance
c. Common monogenic genetic diseases Lectures 8
d. Complex diseases

5. Genetics in Diseases and Development

a. Cytogenetics Lectures 9
b. Common chromosomal abnormalities
c. Epigenetics Lectures 10
d. Mitochondrial DNA inheritance
e. Development and sex determination Lectures 11
f. Clinical genetics and ethical issues
6. Cancer Genetics
a. Genetic factors and environmental factors in cancers
b. Mutations in cell cycle regulatory genes Lectures 12
c. Mutations in the DNA repair system
d. Epigenetics in cancer
Human genome

• All of the genes found in a single individual

• 2.9 billion nucleotide base pairs in 23 chromosomes
inherited from each parent
• 46 chromosomes
• humans have two copies of every gene (except for some on
the X and Y chromosomes

Buckingham, L. (2019). Molecular diagnostics: fundamentals, methods and clinical applications. FA Davis.
Mutation, variant and polymorphism

• A transmissible (inheritable) change in the DNA sequence is a mutation or

polymorphism
• A DNA sequence change that is present in a relatively small proportion of a
population is a mutation
• The term variant may also be used, particularly to describe inherited
sequence alterations, thus reserving the term mutation for somatic
changes, for example, changes found only in tumor tissue
• A change in the DNA sequence that is present in at least 1% to 2% of a
population is a polymorphism
• Both mutations and polymorphisms may or may not produce phenotypic
differences.
Buckingham, L. (2019). Molecular diagnostics: fundamentals, methods and clinical applications. FA Davis.
DNA mutation (Gene mutation, Chromosome mutation)

• DNA mutations can affect a single nucleotide or millions of

nucleotides, even whole chromosomes, and thus can be classified
into three categories: gene, chromosome, and genome mutations
• Gene mutations affect single genes and are often, but not always,
small changes in the DNA sequence
• Chromosome mutations affect the structures of entire
chromosomes These changes require movement of large
chromosomal regions (hundreds of thousands to millions of base
pairs) either within the same chromosome or to another
chromosome
Buckingham, L. (2019). Molecular diagnostics: fundamentals, methods and clinical applications. FA Davis.
DNA mutation (Genome mutation)

• Genome mutations are changes in the number of

chromosomes
• A cell or cell population with a normal complement of
chromosomes is euploid
• Genome mutations result in cells that are aneuploid
• Aneuploidy is usually (but not always) observed as increased
numbers of chromosomes, because the loss of whole
chromosomes is not compatible with survival

Buckingham, L. (2019). Molecular diagnostics: fundamentals, methods and clinical applications. FA Davis.
DNA mutation (Genome mutation)

• A single copy of each chromosome (23 in humans) is a haploid

complement
• Humans are normally diploid, with two copies of each
chromosome
• Aneuploidy can result when there are more than two copies of a
single chromosome or when there are multiple copies of one or
more chromosomes
• Down syndrome is an example of a disease resulting from
aneuploidy, where there are three copies of chromosome 21 i.e.
Trisomy 21 or T21
Buckingham, L. (2019). Molecular diagnostics: fundamentals, methods and clinical applications. FA Davis.
Monogenic disorder

• Monogenic disorder involves single gene

• and likely follows the “Mendelian” transmission
patterns (recessive or dominant)
• Exception: sex-linked
Single nucleotide polymorphisms (SNPs)
Alternation of nucleotide sequence may change
amino acid(s) of a protein
Single nucleotide polymorphism (SNP)
vs mutation

• Both SNP and mutation refer to variations that result in

the nucleotide sequence differences in organisms
• The key difference between SNP and mutation is
that SNP represents a single nucleotide difference in DNA
while mutation represents any change of DNA including
single to many nucleotide differences
Mutation types and effects on protein product
 Pedigree
A pedigree, as related to genetics, is a chart that diagrams the
inheritance of a trait or health condition through generations of a
family. The pedigree particularly shows the relationships among
family members and, when the information is available, indicates
which individuals have a trait(s) of interest.

https://www.genome.gov/genetics-glossary/Pedigree
Mendelian inheritance (dominant and recessive)

Autosomal dominant inheritance Autosomal recessive inheritance

• Square symbols indicate males and circles indicate females;

• open symbols indicate that the person is phenotypically unaffected,
• and filled symbols indicate that the phenotype is present to some extent.

Tierney L, et al. Current Medical Diagnosis & Treatment, 42nd ed; 2003.
Sex-linked inheritance
Non-Mendelian Genetics
-Sex-linkage
Autosomal dominant-
Huntington’s Disease (HD) (OMIM: #143100)

Nature 557, S44-S45 (2018)

Genetics of Huntington’s Disease
• HD occurs worldwide, but is more common in populations of European descent
• HD (or HTT) gene on chromosome 4p16 codes for a novel protein termed Huntingtin
• Mutation in HD consists of an expanded and unstable trinucleotide (CAG)n repeat
• In normal individuals, the range of repeat numbers is 9 to 36
• In those with HD, the repeat number is above 37 (Duyao et al., 1993)
• Most autosomal dominant diseases, heterozygotes tend to be less severely affected than
homozygotes
• Most cases are inherited, but some new cases occur as spontaneous mutations.

HD appears to be the first human disease of genetically documented homozygosity

that displays complete phenotypic dominance.

I Nonaffected persons
1 2 have genotype hd hd
because hd is recessive.
II
1 2 3 4 5 6 7
Affected persons have
genotype HD hd
III
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
because the HD allele
is very rare.

Tierney L, et al. Current Medical Diagnosis & Treatment, 42nd ed; 2003.
Description of Huntington’s Disease
• an autosomal dominant progressive neurodegenerative disorder with a
distinct phenotype characterized by chorea, dystonia, incoordination,
cognitive decline, and behavioral difficulties
• caused by an abnormal expansion in the polyglutamine (polyQ) track of
the Huntingtin (HTT) protein
• Chorea is a movement disorder that causes sudden, unintended, and
uncontrollable jerky movements of the arms, legs, and facial muscles
• Dystonia is a movement disorder that causes the muscles to contract
involuntarily
• What are signs of cognitive decline?
• You forget things more often
• You miss appointments or social events
• You lose your train of thought
• You have trouble following a conversation
• You find it hard to make decisions, finish a task or follow instructions
• You start to have trouble finding your way around places you know well
• There is progressive, selective neural cell loss
Brain damage in Huntington’s Disease
(neurodegenerative disorder)

Malcolm S. Kirk/Peter Arnold, Inc.

FIGURE 18.3 Section of a normal brain (left) and an HD A neuron with an inclusion body (orange color)
brain (right). The HD brain shows extensive damage to
the striatum.

Cummings, M.R. (2010) Human Heredity: Principles and issues.

Autosomal dominant
 Huntington’s Disease
HD gene -Chr4p16
Thalassaemia
What is anaemia? What is Thalassaemia?
• Anaemia means that there is a reduced number of • Thalassaemia is one of the most common inherited
red blood cells, or a low level of haemoglobin, in the genetic blood disorders in the world, which is mostly
body prevalent in Mediterranean countries, the Middle East,
• Out of all the different kinds of anaemia, Iron and in Asia
Deficiency Anaemia—which is due to insufficient iron • Clinically, there are two main categories of
in the diet—is the most common Thalassaemia- the alpha (α) and beta (β)
• Thalassaemia major is another type of anaemia that
is caused by a lack of haemoglobin but it does not
relate to the absorption of iron, since it is an
inherited disorder

http://www.thalassaemia.org.hk/en/thala01.php
- and -globin gene clusters
HbE Gower-1 HbE Gower-2

Hemoglobin Portland I

• The α-globin gene cluster on chromosome 16 and the

Weatherall, D.J. (2001) Nature Reviews Genetics
2, 245–255.
β-globin gene cluster on chromosome 11
• Vertical arrows indicate the location of DNaseI
hypersensitive sites that are thought to be involved in
globin gene regulation
• The products of the Gγ- and Aγ genes are γ-chains with
either glycine (Gγ) or alanine (Aγ) at position 136
• The insert shows the sequential activation of the
embryonic, fetal and adult globins
• A megaloblast is a large red-cell precursor, a
macrocyte is a large red cell and a normocyte is a
normal-sized red cell
Key: LCR, locus control region
Autosomal recessive-
-thalassemia transmission pattern

Additive effects of recessive alleles

Genetics of Alpha-thalassemia (OMIM: # 604131)
*commonly due to deletion

Goh, L. P. W., Chong, E. T. J., & Lee, P. C. (2020). Prevalence of alpha (α)-thalassemia in
Southeast Asia (2010–2020): A meta-analysis involving 83,674 subjects. International journal of
environmental research and public health, 17(20), 7354.

• Some common changes in α-thalassemia in Southeast Asia

• The most common deletions of α-thalassemia mutations are indicated by grey bars
indicating the length of deletion (adapted from Farashi & Harteveld, 2018 [6])
• The genes are shown in boxes with a scale in kilobases (kb)
Clinical descriptions of Alpha-thalassemia
• Alpha-thalassemia is one of the most common hemoglobin genetic
abnormalities and is caused by the reduced or absent production of the
alpha-globin chains
• Four clinical conditions of increased severity are recognized:
1. the silent carrier state (clinically and hematologically normal);
2. thalassemia trait (microcytosis, hypochromia, and mild anemia);
3. hemoglobin H (HbH) disease (moderate to severe microcytic,
hypochromic, hemolytic anemia, mild jaundice, moderate
hepatosplenomegaly); and
4. Hb Bart hydrops fetalis syndrome (severe anemia, generalized edema,
ascites, marked hepatosplenomegaly, skeletal and cardiac
malformations, usually death in utero)
- thalassemia (OMIM: # 604131)

Piel, F.B. (2014) N Engl J Med 371, 1908–1916.

Autosomal recessive-
-Thalassemia transmission pattern
Monohybrid cross

http://media.centerfornurses.com/content/uploads/2019/08/disease-transference_02-mobile-1.png
Genetics of Beta-thalassemia (OMIM: # 613985)

Taher, A. T., Musallam, K. M., & Cappellini, M. D. (2021). β-Thalassemias. New England Journal of Medicine, 384(8), 727-743.
 Common genotypes and basic classification of beta thalassemia

Abbreviations:
β0 : β-thalassemia mutation that eliminates globin transcription or translation
β+ : β-thalassemia mutation that decreases globin transcription or translation
βE : the β-globin mutation that results in Hb E

Taher, A. T., Musallam, K. M., & Cappellini, M. D. (2021). β-Thalassemias. New England Journal of Medicine, 384(8), 727-743.
 Clinical descriptions of Beta-thalassemia

Taher, A. T., Musallam, K. M., & Cappellini, M. D. (2021). β-Thalassemias. New England Journal of Medicine, 384(8), 727-743.
Gobal distribution of β-Thalassemia mutations
* commonly due to point mutation
IVS1 110 G IVS1 110 GA
A CD 39 CD 39 CT
CT IVS1 6 IVS2 1 GA
TC IVS1 5 GC
IVS1 1 GA CD 8 –
IVS2 745 CG AA CD
CD 6 –A 44 –C

CD 41/42 –TTCT
CD 17 AT
IVS2 654 CT
–28 AG
CD 26
GA(HbE)
IVS1 5 GC
CD 19
AG

–29 AG
–88 CT IVS1 5 GC
CD 8/9 +G
IVS1 1 GC
619 bp DEL
CD 26
GA(HbE)
CD 41/42 –
TCTT

Figure 3 | The global distribution of the -thalassaemia mutations. The common mild mutations are shown in bold.
-thalassaemia also occurs in the regions shaded in grey, but little is known about its molecular pathology in these areas.

Weatherall, D.J. (2001) Nat Rev Genetics 2, 245–255.

Autosomal recessive-
Inheritance pattern of hemoglobin S (Sickle cell disease)
Monohybrid cross
Father A S Mother A S
Chromosome 11
Has sickle Has sickle Key
cell trait cell trait
A Normal gene
One copy of One copy of
sickle cell gene sickle cell gene Normal
hemoglobin
(A)
S Sickle cell
gene
Abnormal
hemoglobin
(S)

Child A A Child A
S Child S A Child S S
Does not have Has sickle Has sickle
Homozygous recessive
Has sickle
sickle cell cell trait cell trait cell anemia
anemia One copy of One copy of Two copies of
Two copies of sickle cell gene sickle cell gene sickle cell gene
normal gene

Figure 9-1 Inheritance pattern of hemoglobin S.

Source: From National Heart, Lung, and Blood Institute, Disease and Conditions Index. Available at
http://www.nhlbi.nih.gov/health/dci/Diseases/Sca/SCA_Causes.html. Accessed January 20, 2010.

Gunder L.M. & Martin, S.A. (2011),Essentials of Medical Genetics for Health Professionals.
 Sickle cell disease (OMIM #603903)

Chromosome 11 –HBB sequence

Sickle cell disease is the result of mutant
Normal HbA 1 2 3 4 5 6 7 8
DNA CAC GTG GAC TGA
beta globin in which the mutation causes
mRNA GGA CTC CTC TTC GUG sickling of hemoglobin
Amin CAC CUG
o acid ACU CCU
GAG GAG AAG
Sickle HbS val
1 his
2 leu
3 thr
4 pro
5 glu
6 glu
7 lys
8
DNA CAC GTG GAC TGA
mRNA GGA CAC CTC TTC GUG
Amin CAC CUG
o acid ACU CCU
GUG GAG AAG
val his leu thr pro val glu lys

https://i0.wp.com/omedicine.org/wp- content/uploads/2018/05/sickle-cell.gif?fit=440%2C372
Cummings, M.R. (2010) Human Heredity: Principles and issues.
Clinical descriptions of Sickle cell disease
• Sickle cell disease is a multisystem disease associated with episodes of
acute illness and progressive organ damage
• Hemoglobin polymerization, leading to erythrocyte rigidity and
vasoocclusion, is central to the pathophysiology of the disease, but the
importance of chronic anemia, hemolysis, and vasculopathy has been
established
• The most common cause of sickle cell anemia is the HbS variant, with
hemoglobin SS disease being most prevalent in Africans (Rees et al., 2010)
How Sickle Cell Anemia Affects the Body
• https://www.youtube.com/watch?v=wsykWqyXSKM
Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease
• https://www.youtube.com/watch?v=CWTW5pDPPDQ
 Maps of the distribution of the inherited disorders of hemoglobin.
( A ) Structural hemoglobin variants. ( B ) Thalassemias.

https://oncohemakey.com/the-present-and-future-global-burden-of-the-inherited-disorders-of-hemoglobin/
Hemoglobin C & Hemoglobin E
Hemoglobin C
HbC is another structural variant of HbA caused by an amino acid substitution (HBB c.19G > A;
p.Glu6Lys) occurring at the same position as HbS
• Although carriers (HbAC) are asymptomatic, the inheritance of HbC from both parents (HbCC)
causes clinically mild hemolytic anemia.
• In HbCC, red blood cells have a reduced solubility, which can lead to crystal formation
• HbC is mainly of clinical significance when inherited in combination with HbS or with β-
thalassemia
• HbSC disease causes chronic hemolytic anemia and intermittent sickle cell crises, although
slightly less severe or frequent than in HbSS. HbC-β thalassemia leads to moderate hemolytic
anemia with splenomegaly
• HbC was prevalent only in Western Africa but carriers are now found much more widely
Hemoglobin E
HbE is a structural variant of normal hemoglobin (HBB c.79G > A; p.Glu26Lys) affecting the
production rate of HbA
• Heterozygotes with HbAE are asymptomatic, whereas homozygotes can present some mild
clinical features similar to individuals with β-thalassemia trait
• Globally, compound individuals with HbE and β-thalassemia represent the highest burden
with a wide range of clinical severity
• The most severely affected individuals are transfusion-dependent
• HbE reaches frequencies up to 60% in parts of Thailand, Laos, and Cambodia, and is highly
prevalent in India, Sri Lanka, and Malaysia
Autosomal recessive-
Cystic fibrosis (OMIM: #219700)
mutations in CF transmembrane conductance regulator i.e. CFTR gene
Chromosome 7q31.2

R117 R334 Membrane-spanning

segments Outside
of cell

CFTR gene
Exon: 1 2 3 4 5 6a 6b 7 8 9 10 11 12 13 14a 14b 1617a 17b 18 19 20 21 22 23 24 Plasma
15 membrane

R347 Inside
of cell

KEY Δ508
Missense mutations
Nonsense mutations
Frameshifts
Deletions
Splicing mutations

FIGURE 11.16 Distribution of mutations in the cystic fibrosis gene, CFTR. More than 1,600 different mutations have
been discovered. The mutations shown here include nucleotide substitutions, deletions, and frameshift mutations. Any
of these mutations in the homozygous condition or in combination with each other (i.e., a compound heterozygote)
results in the phenotype of cystic fibrosis.

Cummings, M.R. (2010) Human Heredity: Principles and issues.

No known cure for cystic fibrosis Homozygous recessive

https://en.wikipedia.org/wiki/Cystic_fibrosis
Mayo Clinic Explains Cystic Fibrosis
https://www.youtube.com/watch?v=FnMKK6gOmxA
CF symptoms depend on the amount of normal proteins
Table 11-1 Relationship Between the Amount of Functional Cystic Fibrosis
Transmembrane Conductance Regulator (CFTR) Gene Produced and
Phenotypic Expression from CFTR Mutations

Percentage of Normal CFTR Function Manifestations of Cystic Fibrosis

< 1% Classic disease

< Progressive pulmonary disease
4.5%
Clinically demonstrable sweat abnormality
< 5%
Congenital absence of the vas deferens
< 10% (male infertility)
10–49% No known abnormality
50–100% No known abnormality
(asymptomatic carriers)
Source: Adapted from www.cysticfibrosismedicine.com.

Gunder L.M. & Martin, S.A. (2011),Essentials of Medical Genetics for Health Professionals.
Autosomal recessive
 Thalassaemia
Alpha -Chr16
Beta -Chr11

 Sickle cell anemia

HbS -Chr11

 Cystic fibrosis
CFTR -Chr7
Fragile X Syndrome
Symptoms:
• Chromosome instability
• Intellectual disabilities such as ADHD
Aetiology:
• Expansion and methylation of CGG
repeat in FMR1 5’ UTR, promoter
methylation

Cummings, M.R. (2010) Human Heredity: Principles and issues.

X-linked dominant
 Fragile X Syndrome

FMR1 5’ UTR,
promoter methylation
Hemophilia
• F8 mutation resulting in a factor VIII deficiency manifests as hemophilia A or “classic
hemophilia”
• F9 mutation causes a factor IX deficiency and is designated as hemophilia B or
“Christmas
• disease”
• Both F8 and F9 mutations are inherited in an X-linked recessive pattern, with mostly males being
affected
• Both types of hemophilia occur worldwide across all races
• Approximately 1 in 4000 males is affected with hemophilia A
• Hemophilia B is not as common Intrinsic
and has an incidence of approximately
Extrinsic 1 in 20,000 males.
XII XIIa VIIa
VII

Damaged Trauma
XI XIa Tissue
surface
factor
IX IXa + VIII

X Xa + V Ca2+ PF3
Pro- Thrombin
thrombin
Fibrinogen Fibrin

XIII XIIIa Stable

fibrin clot
Common

Gunder L.M. & Martin, S.A. (2011),Essentials of Medical Genetics for Health Professionals.
Mutant allele for hemophilia in the Pedigree of Queen Victoria, Great Britain

I
King George III

II
Duke of Edward Duke of Duke of
Saxe-Coburg Gotha Duke of Kent Cambridge
Clarence
III Prince Queen

Albert Victoria
IV
Victoria King Alice
Empress Edward of Beatrice
VII Hesse
Leopold,
Fredrick
Duke
of
Albany

To English To Russian To Spanish

royal family royal family royal family

Cummings, M.R. (2010) Human Heredity: Principles and issues.

Classification of Hemophilia A & B by normal
coagulation factor activity (Factor VIII & Factor IX)

Percent Normal
Classification Factor Activity* Associated Clinical Findings

Severe < 1% Spontaneous joint and muscle bleeding; post-

trauma and postoperative bleeding
Moderate 1% to 5% Bleeding in joints and muscles due to minor trauma;
postoperative bleeding
Mild 5% to 40% Postoperative and mild trauma bleeding

Gunder L.M. & Martin, S.A. (2011),Essentials of Medical Genetics for Health Professionals.
Glucose-6-phosphate
dehydrogenase (G6PD)
is located at
chromosome Xq28

Gómez-Manzo S. et. al. (2016) Int. J. Mol. Sci. 17, 2069

G6PD
deficiency is
X-linked
recessive
inheritance

https://en.wikipedia.org/wiki/X-linked_recessive_inheritance
Major types of mutation that cause G6PD deficiency
Type of mutation Number

Single missense 111

Double or triple missense 8
Small in frame deletions 8
Splice site 3’ intron 10 1
(G6PD Vansdorf)
Nonsense (female heterozygote) 1
(G6PD Georgia 1284 CA)
Total 129
Note: Maternally transmitted severe G6PD deficiency is
embryonic lethal.

Longo L. et. al. (2002) EMBO J 16: 4229 – 4239.

Structure of Glucose-6-phosphate dehydrogenase (G6PD)

Adopted from Ma, S.K. (2003) Presentation in HKU

Distribution of G6PD mutations in Southern China

Mutant Number (total n =20)

Canton 1376 GT 10

Kaiping (Anant) 1388 GA 5
Gaohe 95 AG 2
Viangchan 871 GA 2
Fushan 1004 CA 1

Zuo L. et. al. (1990) Blood 76: 51a (suppl)

Global Distribution of X
Chromosome
G6PD gene

G6PD mutations G6PD Gene

Variants
Cairo Cassano Cosenza Mahidol Union
A−
Aures Canton Coimbra Kaiping Mediterranean Viangchan

Global
Distribution

Countries where
favism has
beenreporte
d

Figure 4. Global Genetic Heterogeneity of G6PD Deficiency Underlying Favism.

Countries where favism has been reported are shown in light blue. The symbols indicate areas where individual G6PD variants are
poly- morphic in the population and have been shown to be associated with favism. The map is no doubt incomplete because it is
based on published reports. Also, the information shown is general rather than specific. (For example, favism has been reported in
Russia but probably does not occur in large parts of Russia, and it has been reported in the United States but probably does not
occur in Alaska.) Because variant A− is one of the most common worldwide, it is shown in areas where favism is unknown (tropical
Africa) and in areas where it is very rare (South America, where favism has been reported only in Chile78).
Luzzatto L. & Arese P. (2018)N Engl J Med. 378:60-71.
Prevalence of G6PD deficiency on neonatal screening in Hong Kong

Males 4.47% (n = 223,696)

Female 0.27% (n – 208,457)
s

Lo K.K. et. al. (1996) In: Neonatal and Perinatal Screening-the Asian Perspective (Lam STS, Pang CCD eds), 33-35.
G6PD deficiency in Chinese males (in QMH, HK cohort)
• Case accrued from 1996 - 2002 Amplification-refractory mutation
• Based on dubious or abnormal FST system (ARMS) analysis of point
(fluorescent spot test) mutations

• Mutation detection: ARMS  sequencing

• Among 139 samples collected

 G6PD Kaiping (1388) 46 (33%)

 G6PD Canton (1376) 40 (29%)
 G6PD Goahe (95) 14 (10%)
 G6PD Viangchan (871) 9 (6.5%)
 G6PD Chinese-4 (392) 7 (5%)
 G6PD Union (1360) 4 (3%)
 G6PD Chinese-5 (1024) 2 (1.5%)
 Unknown 9 (6.5%)
 Poor DNA quality 8 (5.5%)
Ma, S.K. et. al. (2003) Unpublished data
Glucose-6-phosphate dehydrogenase (G6PD) deficiency effects

G6PD Deficiency is a hereditary

abnormality in the activity of an
erythrocyte (red blood cell) enzyme.
This enzyme, glucose-6-phosphate
dehydrogenase (G-6-PD), is essential
for assuring a normal life span for
red blood cells, and for oxidizing
processes. This enzyme deficiency
may provoke the sudden destruction
of red blood cells and lead to
hemolytic anemia with jaundice
following the intake of fava beans,
certain legumes and various drugs

http://www.stepwards.com/wp-content/uploads/2015/12/m40-142B4E4875F2F2A75BE.jpg
Acute haemolysis in G6PD deficiency

Spherocyte

Blister
Nucleated cells
red cell

Hemighost
Irregularly
c
ontracted
red cell
Figure 2. Blood Specimen from a 3-Year-
Old Boy with a Severe Attack of Favism.

Ma, S.K. et. al. (2003) Unpublished data

Genetic Screening for G6PDD
Glucose-6-Phosphate
• Since 1984, the Genetic Screening Unit, Dehydrogenase Deficiency
Department of Health, Hong Kong providing (G6PD Deficiency)
free-of-charge cord blood screening service
for glucose-6-phosphate dehydrogenase
(G6PD) deficiency.
• It is to provide early diagnosis and treatment,
so as to prevent adverse outcome on the
health and development of those babies
affected by these diseases.
衞 生 署
• Parents of confirmed G6PD-deficient babies
Department of Health
will receive notification from the hospital
where their babies were born, or the Genetic
Screening Unit, Department of Health,
HKSAR. Please scan QR code for
video on this disease

http: //www.cgs.dh.gov.hk
Avoid the following Drugs for G6PD deficiency individuals

Avoid these Chinese herbal medicines

No prescriptions on following drugs Rhizoma Coptidis
Flos Lonicerae
(Jin Yin Hua)
(Huang Lian)
- Certain antipyretics
- Antibiotics such as:
- Nitrofurantoin
- Nalidixic acid Flos Chimonanthi Praecocis Calculus Bovis
- Sulfamethoxazole (La Mei Hua) (Niu Huang)

- Antimalarials such as: Primaquine

- Antispasmodics such as:
Phenazopyridine
Margaritas (Pearl powder)
(e.g. Over-the-counter drugs
such as Bo Ying Compound
which contains Margaritas)

http: //www.cgs.dh.gov.hk
Avoid the following foods and substances in daily life for
G6PD deficiency individuals
Avoid eating fava or broad Avoid close contact with mothballs
beans and their products (Naphthalene) and naphthalene-containing
(Example of assorted
products
beans with broad beans)

B
r
o
a
d

b
e
a
n
s

(Example of vermicelli
made of broad beans)

http: //www.cgs.dh.gov.hk

Pay attention to
the food labelling
 Duchenne Muscular Dystrophy ( 杜興⽒肌⾁萎縮
症)

• X-linked genetic disorder

• approximately 1 in
5000–6000 boys

Podkalicka P. et. al. (2019) Cellular and Molecular Life Sciences. 76:1507–1528.
Dystrophin defective protein products in Duchenne Muscular Dystrophy

Dystrophin is a crucial component

of the dystrophin-associated
protein complex, responsible for the
connection of the sarcolemma and
extracellular matrix (ECM) to the
actin cytoskeleton within skeletal
myofibers and cardiomyocytes

Podkalicka P. et. al. (2019) Cellular and Molecular Life Sciences. 76:1507–1528.
Duchenne Muscular Dystrophy in Hong Kong

• Data collected in 2011 and 2012 from all Pediatric Neurology Units in Hong
Kong.

• Ninety patients with dystrophinopathy were identified, and 83% has

Duchenne muscular dystrophy (~75 patients).

• The overall prevalence of dystrophinopathy in Hong Kong in 2010 is 1.03 per

10 000 males aged 0 to 24 years.

• Among the Duchenne group, a higher percentage (40.6%) of point

mutations with a lower percentage (45.3%) of exon deletions in the Hong
Kong patient cohort when compared with overseas studies.

Chan S.H.S. et. al. (2015) Child Neurol Open. 2(2): 2329048X15585345.
Total Number and Percentages of Patients With Duchenne Muscular Dystrophy Undergoing the
Diagnostic Procedures and the Different Interventions

Patients With Duchenne (%)

Muscular Dystrophy No. of
Cases (75)

Age <15 37 (49)

Age >15 38 (51)
Muscle biopsy done 49 (65)
Genetic mutation 64 (85)
study
Steroid treatment 19 (25)
Scoliosis surgery 14 (19)
Cardiac treatment 23 (31)
Noninvasive 19 (25)
ventilation
Gastrostomy 2 (3)

Chan S.H.S. et. al. (2015) Child Neurol Open. 2(2): 2329048X15585345.
Mutation Analysis Result Comparison Between Patients With DMD

Distribution of Duchenne Muscular Dystrophy

Mutation No. of Cases % of Cases (95% CI)
Exon deletion 29 45.3
(33.7-57.4)
Exon duplication 6 9.4
(4.4-18.9)
Point mutation/small 26 40.6
rearrangement (29.5-52.9)
No mutation found 3 4.7
(1.6-12.9)
Total 64 100

Chan S.H.S. et. al. (2015) Child Neurol Open. 2(2): 2329048X15585345.
X-linked recessive
 Hemophilia
haemophilia A
-clotting factor VIII
haemophilia B
-clotting factor IX

 G6PDD
G6PD gene-ChrXq28

 Duchenne Muscular Dystrophy

dystrophin gene –ChrXp21
Trinucleotide repeat expansions and their association with
several forms of neurodegenerative disease

• Huntington's disease (HTT/HD gene)

• Myotonic dystrophy (DMPK gene)
• Fragile X syndrome (FMR1 gene)
• Friedreich's ataxia (FRDA gene)
• Spinocerebellar ataxias (SCA1, SCA2, SCA3 & ATXN1 genes)

Chial, H. (2008) Nature Education 1 (1):192

Complex diseases

Complex diseases will be caused by unknown number of

multiple genes interacting with various environmental factors
https://www.nature.com/scitable/topicpage/complex-diseas
es-research-and-applications-748/

https://sapac.illumina.com/areas-of-interest/complex-diseas
e-genomics/polygenic-risk-scores.html
https://www.youtube.com/watch?v=3HjHSRjwiQk
https://www.youtube.com/watch?v=ykgOcAM6d_E
Color blindness is a sex-linked inheritance
Factors contribute variation in a trait
Human characteristics are controlled by multiple
genes with normal distribution
Multifactorial traits
Human disease spectrum from solo genetics to
environmental causation
Factors contribute variation in a trait
Dominant alleles (few)

• Von Willebrand disease (VWD) is the most common

hereditary blood-clotting disorder in humans
• It arises from a deficiency in the quality or quantity
of von Willebrand factor (VWF), a multimeric
protein that is required for platelet adhesion
• The three forms of VWD are hereditary, acquired,
and pseudo or platelet type
• The three types of hereditary VWD are VWD type 1,
VWD type 2, and VWD type 3
• von Willebrand disease types I and II are inherited
in an autosomal dominant pattern

• An acquired form can sometimes result from other

medical conditions
• Platelet type VWD is also an inherited condition
Epistasis

• Epistasis is a phenomenon in genetics in which the effect of a gene

mutation is dependent on the presence or absence of mutations in
one or more other genes, respectively termed modifier genes
• In other words, the effect of the mutation is dependent on the
genetic background in which it appears
• Epistatic mutations therefore have different effects on their own
than when they occur together
• Originally, the term epistasis specifically meant that the effect of a
gene variant is masked by that of a different gene
Genes with more than 2 alleles
Bombay In the ABO blood groups, A and B are
codominant. How can the person in this
phenotype pedigree be type O?
Epistasis

Suraci, N., & Mora, M. (2016). Bombay blood phenotype: Laboratory detection and
transfusions recommendations. Int J Blood Transfus Immunohematol, 6, 8-11.
Factors contribute variation in a trait
Radiation exposure is the source of mutation
Chemical modification of bases
Risk factors

Inherited risk factors are

passed down from parent to
child by way of genes.

Something that increases the

chance of developing a
disease.
Hypothetical liability curves in general
population and relatives for a hereditary
disorder
Recurrence risks
In genetics, the likelihood that a hereditary trait or
disorder present in one family member will occur again
in other family members.
Nucleotide Excision Repair Syndromes
Defects in nucleotide excision repair (NER) lead to at least three human syndromes
characterized by neurodegeneration and DNA repair; xeroderma pigmentosum, Cockayne
syndrome and Trichothiodystrophy
Diabetes Mellitus (DM)
Susceptible loci for type 2 diabetes
Genome-wide association study – stepwise
approach to gene discovery
Advancing the technology in PCR and DNA
sequencing
Human Genome Project
Free access to genes and genomes information
Mutation rates for selected genes

OMIM Number = Online Mendelian Inheritance in Man

Autosomal recessive disorders in different ethnic populations
Summary (I):

• Monogenic disorder involves single gene and likely follows

the “Mendelian” transmission patterns (recessive,
dominant or X-linked)

• Complex diseases will be caused by unknown number of

multiple genes interacting with various environmental
factors