SEMINAR:

CBL-
COMMON GENETIC DEFECTS

-
Genetic Disorder
Faiqah, Ummi, Alia, Woo, Vanida
 Outline
1. Introduction to genetic diseases
2. Types of genetic disorder
a. Single gene disease
b. Chromosomal Disorders
c. Multifactorial Disorders
d. Mitochondrial Disorders
e. Cancer genetics
3. Diagnosis of Genetic disease
 Terminologies
Introduction to Gene Variation
Pathogenesis
Genetic Diseases Types of Inheritence
Birth defects

National Institutes of Health (US); Biological Sciences Curriculum Study. NIH Curriculum Supplement Series [Internet].
Bethesda (MD): National Institutes of Health (US); 2007. Understanding Human Genetic Variation.Available from:
https://www.ncbi.nlm.nih.gov/books/NBK20363/
Mohammad Saad Zaghloul Salem, Pathogenetics. An introductory review, Egyptian Journal of Medical Human
Genetics, Volume 17, Issue 1, 2016, Pages 1-23, ISSN 1110-8630, https://doi.org/10.1016/j.ejmhg.2015.07.002.
 Terminologies
Terms Definition

Gene Genes are made up of sequences of DNA and are arranged, one after
another, at specific locations on chromosomes in the nucleus of cells.

Chromosome A structure found inside the nucleus of a cell. A chromosome is made up of

proteins and DNA organized into genes. Each cell normally contains 23
pairs of chromosomes.

DNA DNA is made up of a double-stranded helix held together by weak

hydrogen bonds between purine-pyrimidine nucleotide base pairs: adenine
(A) paired with thymine (T), and guanine (G) paired with cytosine (C).

Genome The complete set of DNA (genetic material) in an organism.

Eg. haploid 44XX/ 44XY in a normal human being
 Gene variations
- a term used to describe the variation in the DNA sequence in
each of our genomes

- Single nucleotide polymorphisms (SNPs) are the most

common type of genetic variation, including

- Each single nucleotide polymorphism represents a difference

in a single DNA base (A, C, G or T), in a person’s DNA,
producing different alleles, which exhibits different
phenotypes in human beings, eg different eye colours

- Significant examples:
- Sickle cell anemia is resistant to malaria
- Mutation in CCR5 gene lowers risk to HIV
- Cystic fibrosis
- Duchenne muscular dystrophy
Gene variations - SNPs
Pathogenesis of Genetic Abnormalities
(1) Deletion or loss of part of a gene, one or many genes, part of a chromosome, one or
more chromosomes, one or more of mitochondrial genes, or even a whole genome.
(2) Duplication/rearrangement of the genetic material.
(3) Deficient/defective transcription of mRNA.
(4) Deficient/defective post-transcriptional modifications of mRNA.
(5) Deficient/defective translation of mRNA leading to deficient/defective production
of gene products.
(6) Deficient/defective post-translational modifications/ trafficking of synthesized proteins.
(7) Deficient/defective synthesis of genetic regulatory components that include
transcription nucleoproteins, transcription factors, microRNA, etc.
Pathogenesis of Genetic Abnormalities
(1) Deletion or loss of part of a gene, one or many genes, part of a chromosome, one or
more chromosomes, one or more of mitochondrial genes, or even a whole genome.
(2) Duplication/rearrangement of the genetic material.
(3) Deficient/defective transcription of mRNA.
(4) Deficient/defective post-transcriptional modifications of mRNA.
(5) Deficient/defective translation of mRNA leading to deficient/defective production
of gene products.
(6) Deficient/defective post-translational modifications/ trafficking of synthesized proteins.
(7) Deficient/defective synthesis of genetic regulatory components that include
transcription nucleoproteins, transcription factors, microRNA, etc.
 Pathogenesis of Genetic Abnormalities
Types Description Examples

Inherited Happens in germline cells (ovum & sperm) passed down from
parents
- Due to direct inheritance

Acquired Happens in somatic cells (developing embryo) not inherited from - Skin cancer
parents - Colon cancer
- d/t environmental factors: UV light, irradiation, certain viruses

De novo Not inherited from parents but spontaneously occurred in germline - cri-du-chat syndrome,
cells - 1p36 deletion syndrome,
- genetic cancer
A genetic alteration that is present for the first time in one family syndromes (FAP, MEN2,
member as a result of a variant (or mutation) in a germ cell (egg or Hereditary
sperm) of one of the parents, or a variant that arises in the Retinoblastoma)
fertilized egg itself during early embryogenesis
 Types of Inheritance of genetic diseases
1. Mendelian Inheritance
a. Autosomal dominant
b. Pseudodominant inheritance
c. Autosomal recessive
d. X-linked
2. Y linked inheritance
3. Digenic inheritance
4. Pseudogenic Inheritance & Familial Clustering
5. Non-traditional Inheritance
a. Mitochondrial Inheritance
b. Triple Repeat Exapansion
c. Genetic Imprinting
6. Multifactorial & Polygenic Inheritance
 Types of Inheritance - Mendelian Inheritance
Types of Mendelian Inheritance Description

Autosomal dominant -Vertical transmission (from parent-to-child)

-An affected individual has a 50% (1 in 2) chance of passing on the
deleterious gene in each pregnancy
- male-to-male transmission essentially confirms autosomal dominant
inheritance (although not characteristic-per-se, this differentiates from
X-linked transmission & Y linked inheritance is rare )
- Incomplete penetrance (not all who carry the mutation has phenotypic
manifestations)
- Skipped generation
@?*
>@
Autosomal recessive - Horizontal transmission (multiple affected family members in the same
generation, but not affected from different genrations)
- Consanguity is a risk factor

X-linked - Males are more commonly affected

- Female carriers are not affected, has 25% to affect son & daugther
 Types of Inheritance - Mendelian Inheritance
Pseudodominant Inheritance

Definition:

- The observation of apparent dominant

vertical transmission of a known
autosomal recessive disorder
- This occurs when a homozygous
affected individual has a partner who is
a heterozygous carrier, and it is most
likely to occur for relatively common
traits,
- Eg. Sickle cell anemia
 Types of Inheritance - Y-linked Inheritance
- Only demonstrates male-to-male transmission
- Most Y-linked genes are related to male sex
determination and reproduction and are associated
with infertility.
- Therefore, it is rare to see familial transmission of
a Y-linked disorder.
 Types of Inheritance - Digenic Inheritance

- Example: Retinitis pigmentosa

Both parents have normal vision, as would be

expected, but their offspring who are double
heterozygotes, having inherited both mutations
develop RP.

Digenic pedigrees can exhibit characteristics of

both autosomal dominant (vertical trans-
mission) and autosomal recessive inheritance (1
in 4 recurrence risk).
Types of Inheritance - Pseudogenic Inheritance & Familial Clustering

- Sometimes non-genetic reasons for the occurrence of a particular disease in multiple

family members can produce a pattern that mimics genetic transmission.
- Non-genetic factors:
- Identifiable factors: environmental factors, teratogenic exposures
- Eg. asthma 2ndary to smoke exposure
- Eg. FTT, developmental delay 2ndary to alcohol exposure
- Non-identifiable factors
- In some cases the disease is sufficiently common in the general population
that some familial clustering occurs simply by chance.
- Eg. breast cancer can occur in the whole family
 Types of Inheritance - Non-Traditional Inheritance
Types of Non-Traditional Description Examples
Inheritance

Mitochondrial inheritance Only maternal transmission (sperm does not - Discussed more
contain mitchondria, but ovum does) below
- Will be discussed more below

Triple Repeat Expansion Caused by expansion in the number of 3-bp /base pair) - Fragile X syndrome,
repeats. - Myotonic dystrophy,

&
&
-...
Eg. The fragile X gene, FMR1, normally has - Huntington disease,
Ab
5-40 CGG triplets. An error in replication can - Spinocerebellar
result in expansion of that number to a level in ataxias
the gray zone between 41 and 58 repeats, or to
a level referred to as premutation, which
comprises 59-200 repeats.
Types of Inheritance - Multifactorial & Polygenic Inheritance

Will be discussed later

Birth Defects
Definition: abnormal structural changes present at birth that can affect almost any part or parts of
the body that occurs during fetal development.
Types:
● Single primary anomalies:
○ Malformation sequence
○ Deformation sequence
○ Disruption sequence
○ Dysplasia sequence
○ Malformation syndrome
 ***
Types of Genetic
Disorder
Single Gene Disease Chromosomal Disorder

Multifactorial Disorder Mitochondrial Disorder

Cancer Genetic
● Single gene disorders are caused by DNA changes in one particular gene, and often have
predictable inheritance patterns.
● The mutated version of the gene responsible for the disorder is known as a mutant, or
diseased allele
● Since only a single gene is involved, these disorders can be easily tracked through families
and the risk of them occurring in later generations can be predicted.
● Can be divided into different categories :
○ Autosomal dominant disorders
○ Autosomal recessive disorders
○ X-linked recessive
○ X-linked dominant
 AUTOSOMAL DOMINANT DISORDERS
● A single copy of a gene bearing a
mutation is sufficient to cause disease
and that gene is not one of the sex
chromosomes
● Each child of an affected parent has a
50 % chance of inherited the mutated
gene
● Affect both males & females equally
● Ex : achondroplasia, Neurofibromatosis
1, Neurofibromatosis 2, Huntington
disease, Marfan Syndrome
 AUTOSOMAL RECESSIVE DISORDER
● Both copies of a gene pair located on a
non-sex chromosome have a mutation
● Children affected with autosomal recessive
disorder are usually born to unaffected
parents, each of whom carries one copy of the
mutation
● Each of their offspring has a 25 % chance of
being affected
● Affected : requires deleterious variants in both
copies of a gene to cause disease
● Carriers : if they have one normal copy of the
gene and one mutated copy of the gene.
Usually, they do not show symptoms of the
disorder
● Ex : Sickle cell disease, Tay- Sachs disease,
Thalassemia
 X - LINKED RECESSIVE
● An affected father transmits the
mutation to all his daughters, who are
a carriers, but not to his sons as they
having received their fatherʼs Y
chromosome
● No male to male transmission

● Ex X-linked recessive : Duchenne

Muscular Dystrophy
 X - LINKED DOMINANT

● Both males and females are

affected
● But females have less severe
symptoms due to X
chromosome inactivation
● Some X - linked dominant
disorders are lethal in males,
with death occurring before
death
● Ex : X - linked vitamin D
resistant rickets, Incontinentia
pigmenti, Rett Syndrome
2) Chromosomal
Disorder
Trisomies
- Down Syndrome (Trisomy 21)
- Edward Syndrome (Trisomy 18)
- Patau Syndrome (Trisomy 13)
- Klinefelter Syndrome (XXY)

Monosomies
- Turner Syndrome (XO)

Chromosomal deletions
- Cri Du Chat Syndrome
 Trisomy 21 (Down Syndrome)
● Most common abnormality of
chromosome number

● It occurs in 1 of every 1000 births

● Risk Factors :
➔ Increased maternal age
➔ Family history of Down Syndrome
● Most cases (92.5%) are due to
nondisjunction

● In 68%, the nondisjunction event

occurs in maternal meiosis phase I

● As a result of nondisjunction, there

are three copies of chromosome
21 (trisomy 21); using standard
cytogenetic nomenclature, trisomy
21 is designated 47,XX,+21 or
47,XY,+21
 Clinical features of Down Syndrome
Typical Craniofacial Appearance
● Round face
● Flat nasal bridge
● Upslanted palpebral fissures
● Epicanthic folds
● Almond shaped eyes
● Brushfields spots in iris
● Small mouth & protruding tongue
● Low set, small ears
● Flat occiput

Others
● Short neck
● Single palmar crease
● Incurved fifth fingers & wide sandal gap between toes
● Short stature
● Excess skin at nape of neck
 Medical problems in Down Syndrome
Newborn - Cardiac defects (50% ): AVSD [most common], VSD, ASD, TOF
or PDA.
- Gastrointestinal (12%): duodenal atresia [commonest], pyloric
stenosis, anorectal malformation, tracheoesophageal fistula,
and Hirschsprung disease.
- Vision: congenital cataracts (3%), glaucoma.
- Hypotonia and joint laxity.
- Feeding problems. Usually resolves after a few weeks.
- Congenital hypothyroidism (1%).
- Congenital dislocation of the hips
Infancy and - Delayed developmental milestones
childhood - Mild to severe intellectual impairment (IQ 30-70)
- Autistic spectrum disorder and attention deficit hyperactivity disorder
- Maladaptive behaviour such as using social distraction to avoid a given task
and stubbornness
- Seizure disorder (6%)
- Recurrent respiratory infections
- Hearing loss (>60%) due to secretory otitis media, sensorineural deafness, or
both
- Visual Impairment – squint (50%), cataract (3%), nystagmus (35%), glaucoma,
refractive errors (70%)
- Sleep related upper airway obstruction. Often multifactorial
- Leukaemia (relative risk: 15 to 20 times). Incidence 1%
- Atlantoaxial instability. Symptoms of spinal cord compression include neck
pain, change in gait, unusual posturing of the head and neck (torticollis), loss of
upper body strength, abnormal neurological reflexes, and change in
bowel/bladder functioning
- Hypothyroidism (10%). Prevalence increases with age.
- Short stature – congenital heart disease, sleep related upper airway obstruction,
coeliac disease, nutritional inadequacy due to feeding problems and thyroid.
Hormone deficiency may contribute to this.
- Over/underweight
Adolescent and - Puberty:
adulthood - In Girls menarche is only slightly delayed. Fertility
presumed.
- Boys are usually inferile due to low testosterone levels
- Obstructive sleep apnoea is common.
- May have internalizing symptoms such as social withdrawal
and depression
- Increased risk of dementia /Alzheimer disease in adult life
- Shorter life expectancy.
 Trisomy 18 (Edward Syndrome)

● Trisomy 18 (47,XX+18 or 47,XY+18)

● Second most common autosomal trisomy
about 1/7500 births
● 95% of children die in the 1st year
● Most infants with trisomy 18 are small for
gestational age
 Clinical features of Edward Syndrome
- Low birth weight
- Intellectual disability
- Microcephaly
- Hypertelorism
- Malformed/ low set ears
- Prominent occiput
- Micrognathia
- Overlapping fingers
- Clenched fist
- Short sternum
- Rocker bottom feet
 Trisomy 13 (Patau Syndrome)

- Incidence ~1:7400 live births

- Prognosis: Infants usually die before the
age of 1, only approx. 11% of infants
survive past 12 months of age
- Survivors have significant
neurodevelopmental delay
 Clinical features of Patau Syndrome
- Structural defects of brain
- Scalp defects (cutis aplasia)
- Small eyes (microphthalmia)
and other eye defects
- Cleft lip and palate
- Polydactyly
- Capillary hemangioma
- Cardiac and renal
malformations
 XXY (Klinefelter Syndrome)
● Occurs in 1 in 500 live-born males.
● Not inherited, but d/t random error during
cell division.
● Most common genetic cause of hypogonadism
& infertility in males
● Male phenotypes
● Usually normal throughout childhood, remains
undiagnosed until adolescence
● Affect testicular growth, long limbs, sparse
hair, failure to reach secondary sex
characteristics
● Low testosterone will cause increase in two other hormones, follicle stimulating hormone (FSH) and
luteinizing hormone (LH).
● LH stimulates testosterone production from the interstitial cells of the testes (Leydig cells). FSH stimulates
testicular growth and enhances the production of an androgen-binding protein by the Sertoli cells, which are
a component of the testicular tubule necessary for sustaining the maturing sperm cell
● The increased amount of FSH and LH cause hyalinization and fibrosis, the growth of excess fibrous tissue, in
the seminiferous tubules, where the sperm are normally located. As a result, the testicles appear smaller and
firmer than normal.
 Clinical features of Klinefelter Syndrome
● Infertility – most common presentation
● Hypogonadism with small testes
● Pubertal development may appear normal (some
males benefit from testosterone therapy)
● Gynaecomastia in adolescence
● Tall stature
● Intelligence usually in the normal range, but some
have educational and psychological problems
● Hypergonadotrophic hypogonadism
 Management of Klinefelter Syndrome
a. Testosterone replacement therapy under endocrinologist
b. Occupational therapies
i. Many klinefelter patients have speech problems as such may cause difficulty in daily life
ii. Other physical therapies
c. Long term complication
i. Insulin resistance disorder (DMT2,thromboembolism,dyslipidemia,PVD,fatty liver disease)
ii. Bone mineral density (negatively impacted by hypogonadism)
iii. Increase risk of certain malignancies
 Turner Syndrome (45, XO)
● The most common aneuploidy which the occurring is in 1
in 3200 lived-born female (45,XO)
● In about 50% of girls with Turner syndrome, there are 45
chromosomes, with only one X chromosome.
● The other cases have a deletion of the short arm of one X
chromosome, an isochromosome that has two long arms
but no short arm, or a variety of other structural defects of
one of the X chromosomes.
● Turner Syndrome is not associated with advanced
maternal age
● In 75% of patients, the lost of sex chromosome is paternal
origin
● 99% of embryos with 45,X are spontaneously aborted
 Diagnosis and Treatment of Turner Syndrome
● Prenatal dx: If U/S shows IUGR, fetal edema, coarctation of aorta, cystic hygroma,
then can do chorionic villi sampling/amniocentesis with karyotyping, monocular
testing, blood

● Postnatal Dx: Karyotype/Array Comparative Genomic Hybridization (ACGH)

Treatment:
Screening: Echocardiogram & Renal u/s
Follow up : Thyroid function test,eye examination, scoliosis
Hormonal: Estrogen & progesterone replacement therapy - tablet/patch, growth
hormone.
Chromosomal Deletion (Cri Du Chat Syndrome)
● Loss of the tip of the short arm of chromosome 5, hence
the name 5p deletion syndrome, 5p minus.

● 80-85% de novo deletion ( Occur without being inherited)

● 10% Deletion inherited from a parent with a balanced
translocation.
● Affected babies have a high-pitched cat like cry during
infancy
● Clinical severity depends on the size of deletion. Larger
deletions associated with more severe expression
Clinical features of Cri Du Chat Syndrome
● Craniofacial disproportion
● Microcephaly
● Round face
● Flattened nose
● Dysplastic low set ears
● Downward slant of the palpebral fissure
(anti-mongoloid)
● Hypertelorism
● Micrognathia
● Cat cry (due to narrow larynx, due to the vocal
cords are approximated anteriorly, leaving a
narrow opening posteriorly) – disappears as infant
grows
 Diagnosis and Treatment of Cri Du Chat Syndrome
Diagnosis:
● Suspected by high pitched crying and accompanying physical problems.
● Confirm by karyotyping. If high clinical suspicion but karyotyping negative (canʼt detect very
small deletion), Fluorescence in situ hybridization (FISH) can be used.

Management:
● Maximizing development of babies
● There is no cure for cri du chat syndrome. Treatment aims to stimulate the child and help
them to reach their full potential and can include:
➔ physiotherapy to improve poor muscle tone
➔ speech therapy
➔ communication alternatives, such as sign language, since speech is usually delayed,
often severely
➔ occupational therapy to teach coping strategies and new skills.
 3) Multifactorial Disorder
● The commonest genetic disorders, accounting for 20% of children with congenital
malformations
● Also known as complex disorders or polygenic inheritance
● It represents the sum of the simultaneous effect of many different genes interacting with
environmental factors and lifestyle such as diet.
● Does not follow mendelian inheritance
● Risk of occurrence higher in 1st degree relatives than in more distant relatives who are likely
to have inherited fewer high liability genes
● Examples include hypertension, arthritis, cleft palate, diabetes
 4) Mitochondrial
⑧
)
!]⑤
- Introduction
- Pathogenesis

Disorder -
-
Examples
Inheritance

Chinnery PF. Primary Mitochondrial Disorders Overview. 2000 Jun 8 [Updated 2021 Jul 29]. In: Adam MP, Mirzaa GM,
Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available
from: https://www.ncbi.nlm.nih.gov/books/NBK1224/#

Alston CL, Rocha MC, Lax NZ, Turnbull DM, Taylor RW. The genetics and pathology of mitochondrial disease. J Pathol. 2017
Jan;241(2):236-250. doi: 10.1002/path.4809. Epub 2016 Nov 2. PMID: 27659608; PMCID: PMC5215404.
Clinical features in MtDNA Disorders
Neuro VS Non-Neuro
 Clinical Syndromes of MtDNA Disorders
Disorder Primary Feature Additional Features

Chronic Progressive External ● External ophthalmoplegia ● Mild proximal myopathy

Ophthalmoplegia (CPEO) ● Bilateral ptosis

Kearns-Sayre syndrome (KSS) ● PEO onset age <20 yrs ● Bilateral deafness
● Pigmentary retinopathy ● Myopathy
● One of the following: CSF protein >1 g/L, ● Dysphagia
cerebellar ataxia, heart block ● Diabetes mellitus
● Hypoparathyroidism
● Dementia

Pearson syndrome ● Sideroblastic anemia of childhood ● Renal tubular defects

● Pancytopenia
● Exocrine pancreatic failure

Leigh syndrome ● Subacute relapsing encephalopathy ● Basal ganglia lucencies

● Cerebellar & brain stem signs ● Maternal history of neurologic
● Infantile onset disease or Leigh syndrome
 Clinical Syndromes of MtDNA Disorders
Disorder Clinical features Additional features
Neurogenic weakness with ataxia ● Late-childhood or adult-onset peripheral ● Basal ganglia lucencies
and retinitis pigmentosa (NARP) neuropathy ● Abnormal electroretinogram
● Ataxia ● Sensorimotor neuropathy
● Pigmentary retinopathy

Mitochondrial encephalomyopathy ● Stroke-like episodes at age <40 yrs ● Diabetes mellitus

with lactic acidosis and stroke-like ● Seizures &/or dementia ● Cardiomyopathy (initially hypertrophic; later dilated)
episodes (MELAS) ● Ragged-red fibers &/or lactic acidosis ● Bilateral deafness
● Pigmentary retinopathy
● Cerebellar ataxia

Myoclonic epilepsy with ragged-red ● Myoclonus ● Dementia

fibers; (MERRF) ● Seizures ● Optic atrophy
● Cerebellar ataxia ● Bilateral deafness
● Myopathy ● Peripheral neuropathy
● Spasticity
● Multiple lipomata

Leber hereditary optic neuropathy ● Subacute painless bilateral visual failure ● Dystonia
(LHON) ● Males:females ~4:1 ● Cardiac pre-excitation syndromes
● Median age of onset 24 yrs
 Classification of nDNA Disorders
Genetic cause Disorders

nDNA disorders of ● Leigh syndrome w/complex I deficiency

the mt respiratory ● Leigh syndrome w/complex II deficiency
chain nDNA genes encoding ● Leukodystrophy w/complex II deficiency
structural subunits 1 ● Cardiomyopathy & encephalopathy (complex I deficiency)
● Optic atrophy & ataxia (complex II deficiency)
● Hypokalemia & lactic acidosis (complex III deficiency)
● Leigh syndrome
● Hepatopathy & ketoacidosis
● Cardiomyopathy & encephalopathy
nDNA genes encoding
● Leukodystrophy & renal tubulopathy
assembly factors 1
● Hypertrophic cardiomyopathy
● Encephalopathy, liver failure, renal tubulopathy (w/complex III deficiency)
● Encephalopathy (w/complex V deficiency)
● Leigh syndrome, liver failure, & lactic acidosis
● Lactic acidosis, developmental failure, & dysmorphism
nDNA genes encoding
● Myopathy & sideroblastic anemia
translation factors 1
● Leukodystrophy & polymicrogyria
● Leigh syndrome & optic atrophy w/COX deficiency
 Classification of nDNA Disorders
Genetic cause Disorders
● Autosomal progressive external ophthalmoplegia
● Mitochondrial neurogastrointestinal encephalomyopathy
● Alpers-Huttenlocher syndrome
● Ataxia neuropathy syndromes 2
● Infantile myopathy / spinal muscular atrophy
nDNA disorders assoc w/multiple mtDNA deletions or ● Encephalomyopathy & liver failure
mtDNA depletion ● Hypotonia, movement disorder, &/or Leigh syndrome
w/methylmalonic aciduria
● Hypotonia, encephalopathy, renal tubulopathy, lactic acidosis
● Mitochondrial encephalomyopathy w/combined RC deficiency
● Reversible hepatopathy
● Myopathy w/cataract & combined RC deficiency
● Coenzyme Q10 deficiency
● Barth syndrome
Disorders of the mt membrane
● Cardiomyopathy & lactic acidosis (mitochondrial phosphate carrier
deficiency)
 Inheritance of Mitochondrial Disorders
1. Simplex case: Only 1 family member is known to be affected, consider:
● Autosomal dominant inheritance
● A single occurrence of an autosomal recessive, X-linked, or maternally inherited disorder
● An acquired (non-genetic) cause

2. Multiple affected family members

● Mitochondrial inheritance: Sperm has no mitochondria, hence only females transmit
the disease to offsprings, both male & female offsprings are equally affected
● Autosomal recessive inheritance: Horizontal inheritance
● Autosomal dominant inheritance: Vertical inheritance
● X-linked inheritance: Only males affected

Conclusion:
- MtDNA disorders: maternal inheritance
- nDNA disorders: Mendellian inheritance (more common in paeds)
5) Cancer genetics Categories of cancer genetics
Pathogenesis

Noralane M. Lindor and others, The Concise Handbook of Family Cancer Syndromes, JNCI: Journal of the
National Cancer Institute, Volume 90, Issue 14, 15 July 1998, Pages 1039–1071,
https://doi.org/10.1093/jnci/90.14.1039

Saletta F, Dalla Pozza L, Byrne JA. Genetic causes of cancer predisposition in children and
adolescents. Transl Pediatr. 2015 Apr;4(2):67-75. doi: 10.3978/j.issn.2224-4336.2015.04.08.
PMID: 26835363; PMCID: PMC4729088.
 Categories of cancer genetics
Categories Details Examples

1. Acquired Caused by somatic mutation EBV - Hodgkin lymphoma,

- Lifestyle factors: EBV - Burkitt’s lymphoma
smoking, obesity, alcohol HPV - cervical cancer
- Exposure to radiation HSV - Kaposi’s sarcoma
- Viral infection HBV - Hepatocellular carcinoma
- Chemo/radiotherapy Other types of cancer

2. Family Inheritance of germline mutation Hereditary breast & ovarian cancer

cancer - Strong family history of cancer, (BRCA1 & BRCA2)
syndrome - esp 1st degree relatives, Lynch syndrome
- Multiple cancer of the same type, Li Fraumeni syndrome
- cancer from the same side of Cowden syndrome
family, Peutz jegher syndrome
- Same type of rare cancer MEN
- Consanguinuity Multiple mole melanoma syndrome
- Early onset
 Cancer predeposition in Childhood/Adolescent
Disorders Gene affected Associated features

Fanconi Anemia counts 16 potentially Congenital abnormalities, bone marrow failure, and a
mutated genes higher risk of developing myeloid and solid malignancies:
(including BRCA2, SCC, HCC
previously known as
FANCD1

Xeroderma pigmentosum XP nucleotide excision Increased sensitivity to UV light, and neurodegeneration,

repair genes leading to elevated risk of non-melanoma skin cancer,
including melanoma

Retinoblastoma RB1 tumour suppressor Retinoblastoma

Li-Fraumeni Syndrome TP53 Osteosarcoma (bone cancer), soft tissue sarcoma, acute
leukemia, breast cancer, brain cancer, and adrenal cortical
tumors
 Cancer predeposition in Childhood/Adolescent
Disorders Gene affected Associated features

DICER1 syndrome germline DICER1 Pleuropulmonary blastoma and other rare tumors of
childhood, including cystic nephroma, ovarian Sertoli-Leydig
cell tumor, embryonal rhabdomyosarcoma, supratentorial
primitive neuroectodermal tumor and multinodular goiter

Neurofibromatosis NF1 NF1 is responsible for the regulation of cell division through
the inactivation of RAS-GTP, a fundamental step in the
regulation of the RAS and PI3K pathways.
Reduced inhibition from normal NF1 results in cell
proliferation and inhibited apoptosis

Down syndrome Trisomy 21 likely Transient myeloproleferative syndrome, AML, ALL

contributes to the
development of GATA1
mutations
Diagnosis of Genetic 1.
2.
History
Physical Examination
3. Investigations
Diseases 4. Genetic counselling
 Clinical Assessment

Physical Examination:
History:
● General examination
● History of presenting illness
● Growth assessment
● Past medical history
● Developmental assessment
● Paediatric history (antenatal,
● Systemic examination
intrapartum, postnatal)
● Detailed medical family history and
pedigree drawing
● Social history
● Drug / Dietary history
 Family History and Pedigree
➔ The family history taken is targeted to the condition of concern and includes at least
three (possibly four) generations
◆ Patientʼs parents
◆ Siblings
◆ Children
◆ Grandparents, grandchildrens
◆ Aunts and uncles
◆ Nieces and nephews
◆ First cousins
➔ Key component:
◆ Condition reported
◆ Consanguinity and other information about the family that could impact
genetic risk (increases the chance that a child will be born with a rare
autosomal recessive condition, as the mutated gene segregates through that
family)
◆ Age of family members at onset of condition
◆ Relevant information regarding unaffected individuals in the family
Pedigree

➔ A genetic representation of a family tree, minimum of three generations

➔ Diagrams the inheritance of a trait or disease through several generations
➔ Shows the relationships between family members and indicates which individual expresses
or silently carry the trait in question
➔ Use standardized symbols
➔ Allow calculation of risk of recurrence
 Antenatal History

➔ Maternal history of a chronic medical condition (seizure disorder,

diabetes)
➔ Medication used in pregnancy can be teratogenic
➔ Exposure to chemicals, radiation, use of alcohol, cigarettes or drugs
abuse
➔ Acute illnesses such as varicella, Lyme disease, and cytomegalovirus
expose the fetus to infectious agents that may cause birth defects
Prenatal Screening for Genetic disease / birth defect
● Prenatal screening : Maternal serum screening for a-fetoprotein
(AFP)
○ A protein secreted during fetal life by liver, GIT and yolk sac
○ AFP crosses placenta and enters maternal circulation
○ Low levels of AFP associated with fetal aneuploidy

● During 1st trimester- nuchal translucency 🡪measurement of a fluid

collection of the posterior neck of the developing fetus
○ An increase in the nuchal translucency is a marker for
chromosomal anomalies as well as genetic and structural
abnormalities in the fetus

● Testing for abnormalities with two first trimester analytes, free

β-HCG and PAPP-A (pregnancy associated plasma protein) has
enhanced first trimester screening to a detection rate of almost 90%

● Screening sonogram at 18 weeksʼ gestation

○ An anatomy scan is done to look for congenital anomalies
(brain, heart, kidneys, lungs, and spine are examined)
Chorionic Villi Sampling (CVS)
● Performed between 9 to 12 W of gestation but can be
performed as early as 8W of gestation
● CVS results have higher diagnostic uncertainty than
amniocentesis and the procedure may be less safe than
second trimester amniocentesis
● Indications:
○ Maternal age > 35 years
○ Previous child with a chromosome
abnormality/genetic disorder
○ Parent is a carrier of structural chromosome disorder
or monogenic (ie, single gene or Mendelian) disorder
○ Both parents are carriers of autosomal recessive
disease
○ Female parent is a carrier of a sex-linked disease
○ Congenital anomaly on first trimester ultrasound
examination
Amniocentesis
● A technique for withdrawing amniotic fluid (Cells
shed by the developing fetus) from the uterine
cavity using a needle via a transabdominal
approach.
● Technically possible at any gestational age after
approximately 11 weeks of gestation but is
optimally performed 15-17 weeks gestation.
● Indications:
○ Prenatal genetic studies
○ Assessment of fetal lung maturity
 Genetic Tests
1. Diagnostic testing: to confirm or exclude a genetic condition
2. Predictive testing: To detect specific later-onset monogenic disorder in healthy individual
(relative with Huntington disease)
3. Susceptibility testing (Risk profiling): Test for a marker or several genetic markers to detect an
increased or decreased risk for multifactorial condition in a healthy individual
4. Carrier testing: A genetic test that detects a gene mutation that will generally have limited or no
consequence to the health of that individual
5. Prenatal testing: A genetic test performed during a pregnancy, where there is increased risk for
certain condition in the fetus
6. Preimplantation genetic diagnosis: Testing the presence of mutation, linked haplotype or
chromosomal change in one or two cells of an embryo in a family with previously known risk for a
Mendelian or chromosomal disorder, in order to select the unaffected embryos to be implanted
7. Genetic screening: Testing where the target is not high-risk individuals or families, but where the
test is systematically offered to the general population or a specific group (newborn)
8. Direct to consumer genetic testing: Provides people access to their genetic information
without necessarily involving a healthcare provider or health insurance company in the process
(test kits bought online or in stores)
 Genetic Investigations
The type of test to be done will depend on the type of abnormality that is being
measured. Types that are available:

❖ Cytogenetic
❖ Molecular

1. Cytogenetic studies
a. Involves the examination of whole chromosomes for abnormalities
b. Samples are obtained from
i. White blood cells
ii. Bone marrow (for leukemia)
iii. Amniotic fluid (prenatal diagnosis)
iv. Other tissue biopsies can also be cultured
c. Following several days of cell culture, chromosomes are fixed, spread on
microscope slides and then stained. The distinct bands of each chromosome
revealed by staining allow for analysis of chromosome structure.
 ● Used for scanning chromosome alterations that involve
both gains and/or losses, as well as rearrangements
Karyotype (conventional within and among the chromosomes
01 cytogenetic) ● Small and submicroscopic chromosomal abnormalities
remain undetected
● Difficult to detect microdeletions and duplications

● Fluorescent-labelled DNA probes to detect the

Fluorescence in situ presence, number and chromosomal location
02 hybridisation (FISH) of specific chromosomal sequences
● Useful for microdeletion

● New method to diagnose patients lacking an

apparent syndromic phenotype
Chromosomal Microarray
03 (CMA)
● Diagnosis of cognitive impairment, developmental
delay or autism in suspected patients are increased
by 20% using CMA
 FISH
CMA
Karyotyping
1. .
2. Molecular studies Molecular studies

Polymerase Chain Reaction DNA Sequencing

(PCR)

Sanger Sequencing Next Generation

● Amplification of a
(single gene) Sequencing (NGS)
specific target site
within the genome
which then permits the
conventional Sanger ● Gold standard for clinical ● Fast because they
sequencing of the DNA sequencing to look sequence millions of
amplified DNA at single genes or a few small DNA fragments in
genes at a time parallel ,at the same time
● Reliable, but can only ● Time and cost-effective
read one short section of ● Able to simultaneously
DNA at a time detect common and rare
genetic variation
 Next-generation sequencing (possible Molecular studies
to generate large volume of DNA
sequence data

Whole Genome Sequencing Whole Exome Targeted Gene

(WGS) Sequencing (WES) Sequencing

● Determines the order of the ● A laboratory process ● A rapid and

nucleotides in the entire that is used to determine cost-effective way to
genome that makes up an the nucleotide sequence detect known and novel
organism (including primarily of the exonic variants in selected sets
non-coding regions) regions of an individualʼs of genes or genomic
● To look for genetic aberrations genome and related regions
● Because the entire genome is sequences ● Gene sequencing can be
being sequenced, changes in accomplished using
the non-coding sections of several methods,
DNA within genes (introns) can depending on the scale
also be determined
 Genetic Counselling

Aim
1. To support and provide information for
individuals, couple and families
National Society of Genetic Counselors 2. Promoting informed decisions by
defined genetic counselling as the process involved family members
of helping people understand and adapt to 3. Clarifying the familyʼs options available
the medical, psychological and familial treatment and prognosis
implications of genetic contributions to 4. Explaining alternatives to reduce the
disease risk of genetic disorder
5. Decreasing the incidence of genetic
disorders
6. Reducing the impact of the disorders
Content of Genetic Counselling

1. Initial risk assessment

a. Conducted before the first genetic counselling session if sufficient information is
available
b. Once an initial risk figure has been determined, it is important to correlate it with
the patientʼs perception of the risk
2. Information and education
a. Initial visit: focuses on reviewing information, providing accurate risk assessment
information about personal and family risk and addressing psychosocial issues,
options for genetic testing are discussed along with possible outcomes
b. Subsequent visits: discussion on results of genetic testing and management
implications
 1. .
2. .
3. Informed consent for genetic testing
a. Ensuring patient fully understands and agrees to
the procedure (risks, benefits, limitations)
b. Potential results (inconclusive or unexpected)
should also be discussed
4. Psychosocial support
5. Risk modification
a. May involve more intensive screening, lifestyle or
dietary modifications, medical or surgical
interventions
b. In cases whereby there are no available risk
modification measures, ensure to provide guidance
on the importance of planning, supportive
treatment and implications for at-risk first-degree
relatives
THANK
YOU