Concise Genetics Notes: I MBBS

Prepared by Dr Deepa Bhat

AN73.1: "Describe the structure of chromosomes with classification." This is suitable for
undergraduate medical education.
Definition of a Chromosome
Chromosomes are thread-like structures located in the nucleus of eukaryotic cells. They are
made of DNA tightly coiled around histone proteins, and carry the genetic information essential
for inheritance, growth, and function.
Structure of a Chromosome
1. Chromatid: Each chromosome consists of two identical halves called sister chromatids
(in the metaphase stage).
2. Centromere: Constricted region that divides the chromosome into two arms – the short
arm (p) and the long arm (q).
3. Telomeres: Repetitive DNA sequences at the ends of chromosomes that protect them
from degradation.
4. Chromatin Types:
o Euchromatin: Loosely packed, transcriptionally active.
o Heterochromatin: Densely packed, transcriptionally inactive.
5. Kinetochore: Protein complex at the centromere where spindle fibers attach during cell
division.
Chemical Composition

Component Percentage

DNA ~40%

Histone Proteins ~40%

Non-histone Proteins ~10%

RNA ~10%

Classification of Chromosomes
A. Based on Position of Centromere

Type Description Example

Metacentric Centromere in the middle; p = q arms Chromosome 1

Submetacentric Centromere slightly off-center; unequal arms Chromosome 4

Chromosome 13, 14, 15, 21,

Acrocentric Centromere near one end; p arm very short
22

1
Type Description Example

Centromere at the terminal end (not found in

Telocentric Seen in mice
humans)

B. Based on Function
• Autosomes: Chromosomes that do not determine sex (22 pairs in humans).
• Sex Chromosomes: Determine the sex of the individual (XX in females, XY in males).
C. Based on Size
• Human chromosomes are numbered 1 to 22, from largest to smallest (excluding sex
chromosomes).
Karyotyping and Chromosome Grouping
In karyotyping, human chromosomes are grouped into 7 groups (A–G) based on size and
centromere position:

Group Chromosomes Description

A 1–3 Large, metacentric

B 4–5 Large, submetacentric

C 6–12, X Medium, submetacentric

D 13–15 Medium, acrocentric

E 16–18 Short, submetacentric

F 19–20 Short, metacentric

G 21–22, Y Very short, acrocentric

Conclusion
Chromosomes are fundamental units of genetic material. Their structure and classification
provide insight into genetic organization and abnormalities, which is crucial in cytogenetics,
prenatal diagnosis, and cancer genetics.

2
AN73.2 – Technique of Karyotyping and Its Applications
Definition
Karyotyping is a cytogenetic technique used to examine the number and structure of
chromosomes in metaphase cells. It helps in diagnosing chromosomal abnormalities and
genetic disorders. This can be done only in living cells.
Detailed Steps in the Karyotyping Procedure

Step Details

- Peripheral blood is the most commonly used source (especially in

postnatal cases). - Other sources: Amniotic fluid (for prenatal diagnosis),
1. Sample
chorionic villus samples, bone marrow aspirate (for hematologic
Collection
malignancies), and tissue biopsies. - Collected in a heparinized tube (Green
top) to prevent clotting.

- The sample is inoculated into a sterile culture medium such as RPMI 1640.
- Supplemented with fetal bovine serum and antibiotics to prevent
2. Cell Culture contamination. - Mitogen (typically phytohemagglutinin or PHA) is added
to stimulate T-lymphocytes in blood to divide. - Incubation is carried out at
37°C in a CO₂ incubator for 72 hours (standard protocol for blood samples).

- After 72 hours, colchicine (or colcemid) is added 1–2 hours before

3. Mitotic Arrest harvesting. - Colchicine binds to tubulin and disrupts the mitotic spindle,
(Colchicine arresting cells in metaphase, the ideal stage for chromosome visualization.
Treatment) - Metaphase chromosomes are short and condensed, allowing clearer
analysis.

- Cells are exposed to a hypotonic solution (commonly 0.075 M potassium

4. Hypotonic chloride). - This causes the cells to swell, spreading the chromosomes apart
Treatment to avoid overlapping. - Time: Typically 15–30 minutes at 37°C. - Critical for
optimal chromosome spread.

- Cells are fixed with a mixture of methanol and glacial acetic acid in a 3:1
ratio. - Fixative dehydrates the cells and hardens cellular structures for
5. Fixation
preservation. - Multiple changes of fixative are done to ensure complete
removal of hypotonic solution.

- Fixed cell suspension is dropped onto clean glass slides from a height (~1
6. Slide foot). - Air drying helps in spreading chromosomes evenly. - Environmental
Preparation conditions (temperature, humidity) are controlled for good metaphase
spread.

- Giemsa staining is the most common technique (G-banding). -

Chromosomes are treated with trypsin before staining to partially digest
7. Staining
proteins. - Results in alternating light and dark bands, unique to each
(Banding)
chromosome. - Other banding methods: Q-banding (fluorescent), C-banding
(centromeres), R-banding (reverse of G), and high-resolution banding.

8. Microscopic - Slides are examined under a light microscope at 1000× magnification

Analysis using oil immersion. - Well-spread metaphase plates are photographed or

3
Step Details

digitally captured. - Chromosomes are arranged in descending order of size,

paired based on banding patterns and centromere position.

- A karyotype (karyogram) is constructed showing chromosomes in 22

9. Karyogram autosomal pairs and one sex chromosome pair (XX or XY). - Software like
Preparation CytoVision or MetaSystems is used in digital labs. - Any deviations in number
or structure are noted.

Normal Karyotype
• Total chromosomes: 46
o 44 autosomes (22 pairs)
o 2 sex chromosomes (XX or XY)
Applications of Karyotyping
1. Clinical Genetics
• Diagnosis of numerical abnormalities:
o Down syndrome (Trisomy 21)
o Turner syndrome (45,X)
o Klinefelter syndrome (47,XXY)
• Detection of structural abnormalities:
o Translocations (e.g., Robertsonian)
o Inversions, deletions, duplications, ring chromosomes
2. Prenatal Diagnosis
• Indicated in advanced maternal age, abnormal serum screening, or family history
• Sample types: amniotic fluid, chorionic villus sampling
3. Infertility & Recurrent Pregnancy Loss
• Detection of balanced translocations, mosaicism, or sex chromosome anomalies
4. Oncology
• Certain cancers exhibit characteristic chromosomal abnormalities:
o Philadelphia chromosome (t(9;22)) in CML
o t(8;14) in Burkitt lymphoma
o Helps guide prognosis and treatment
5. Congenital Anomalies and Intellectual Disability
• Identifies syndromic causes (e.g., Cri du Chat syndrome)

4
6. Ambiguous Genitalia / DSD Evaluation
• Determines chromosomal sex in intersex conditions
7. Bone Marrow Disorders
• In aplastic anemia, MDS, leukemias, chromosomal abnormalities help define subtypes
Conclusion
Karyotyping is a cornerstone technique in cytogenetics. It enables visualization of chromosomal
number and structure, with wide applications in medical genetics, reproductive health, oncology,
and prenatal screening. Despite newer technologies like microarrays and sequencing,
karyotyping remains essential for first-line assessment of many chromosomal conditions.

5
AN73.3 – Lyon’s Hypothesis (X-Chromosome Inactivation)
Definition
Lyon’s Hypothesis was proposed by Mary Lyon in 1961, and it explains the mechanism of X-
chromosome inactivation in female mammals.
According to the hypothesis:
One of the two X chromosomes in every somatic cell of a female is randomly inactivated
during early embryonic development to compensate for dosage differences between XX
females and XY males.
This process is also known as dosage compensation.
Key Features of Lyon’s Hypothesis

Feature Explanation

Random In each cell, either the maternal or paternal X chromosome is randomly

Inactivation inactivated.

Early Inactivation occurs during the blastocyst stage (around day 5–7 post-
Embryogenesis fertilization).

Once an X chromosome is inactivated in a cell, all its daughter cells retain

Clonality
the same X chromosome inactivated — leading to mosaicism in females.

Barr Body The inactivated X chromosome becomes a condensed, heterochromatic

Formation structure called a Barr body, visible in interphase nuclei.

Incomplete About 15% of genes on the inactivated X escape silencing, particularly in

Inactivation the pseudoautosomal regions.

Males Since males have only one X chromosome, inactivation is not necessary.

Turner Syndrome
No inactivation occurs due to the presence of only one X chromosome.
(45,X)

Molecular Mechanism
Inactivation is initiated at the X-inactivation center (XIC) on the X chromosome.
• The gene XIST (X-inactive specific transcript) plays a central role by producing RNA that
coats the X chromosome and induces silencing.
• Epigenetic modifications like DNA methylation and histone deacetylation help
maintain the inactivated state.
Examples and Clinical Implications

6
Condition Relevance to Lyon’s Hypothesis

Different patches of fur color represent X-inactivation mosaicism

Calico cats
(coat color genes on X chromosome).

May show variable expression depending on which X is

Females heterozygous for
inactivated (e.g., G6PD deficiency, Duchenne muscular
X-linked disorders
dystrophy carriers).

The normal X is preferentially inactivated to preserve

X-autosome translocations
autosomal gene expression.

Absence of a second X leads to clinical features — confirms that

Turner Syndrome (45,X)
one active X is necessary.

Conclusion
Lyon’s Hypothesis explains how females, despite having two X chromosomes, express genes
from only one, ensuring dosage balance with males. This process of random X-chromosome
inactivation is essential for normal development and explains the mosaic nature of X-linked
traits in females.

7
AN74.1 – Modes of Inheritance: Description and Examples
What is Inheritance?
Inheritance refers to the transmission of genetic information (traits or disorders) from parents to
offspring via genes. The pattern by which a trait or disease is passed down is called the mode of
inheritance.
I. Mendelian (Monogenic) Inheritance
Mendelian inheritance follows predictable patterns described by Gregor Mendel. These traits are
typically caused by mutations in a single gene.
1. Autosomal Dominant (AD)

Feature Description

Chromosome involved Autosomes (non-sex chromosomes)

Number of alleles needed Only one mutant allele is needed to express the trait

Inheritance risk 50% chance if one parent is affected

Transmission Vertical (seen in every generation)

Examples:
• Marfan syndrome
• Achondroplasia
• Huntington’s disease
• Familial hypercholesterolemia
2. Autosomal Recessive (AR)

Feature Description

Chromosome involved Autosomes

Number of alleles needed Two mutant alleles required (homozygous)

Inheritance risk 25% affected, 50% carrier if both parents are carriers

Transmission Often seen in siblings, not in every generation

Examples:
• Sickle cell anemia
• Cystic fibrosis
• Thalassemia
• Phenylketonuria (PKU)
3. X-linked Recessive (XLR)

8
Feature Description

Chromosome involved X chromosome

Affected individuals Mostly males (XY); females are usually carriers

Inheritance pattern No male-to-male transmission; carrier mothers → affected sons

Examples:
• Hemophilia A & B
• Duchenne muscular dystrophy
• G6PD deficiency
• Color blindness
4. X-linked Dominant (XLD)

Feature Description

Affected individuals Both sexes, but females more commonly affected

Inheritance pattern Affected fathers → all daughters affected, no sons

Severity Often more severe in males; may be lethal prenatally in males

Examples:
• Rett syndrome
• Fragile X syndrome
• Vitamin D–resistant rickets
5. Y-linked (Holandric) Inheritance

Feature Description

Chromosome involved Y chromosome

Affected individuals Only males, passed from father to son

Traits affected Often related to male sexual development

Examples:
• Y-chromosome infertility
• Some cases of Swyer syndrome
II. Non-Mendelian Inheritance
6. Mitochondrial (Maternal) Inheritance

9
Feature Description

Inheritance From mother to all offspring

Affected individuals Both males and females can be affected, but only females transmit

Involves** Mitochondrial DNA (mtDNA), not nuclear chromosomes

Examples:
• Leber’s hereditary optic neuropathy (LHON)
• MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like episodes)
7. Multifactorial (Polygenic) Inheritance

Feature Description

Cause Interaction of multiple genes and environmental factors

Inheritance pattern Does not follow simple Mendelian ratios

Recurrence risk Increases with number of affected family members and severity

Examples:
• Hypertension
• Diabetes mellitus
• Neural tube defects
• Cleft lip and palate
8. Other Atypical Patterns

Type Description Examples

Disorder appears at an earlier age or with Myotonic dystrophy,

Anticipation
increased severity in successive generations Huntington’s disease

Genomic Expression depends on whether gene is inherited Prader-Willi vs. Angelman

imprinting from the mother or father syndrome

Presence of two or more genetically distinct cell Turner mosaic, somatic

Mosaicism
lines in one individual mosaicism in NF1

Summary Table

Mode of Inheritance Key Feature Example

Autosomal Dominant One copy sufficient Marfan syndrome

Autosomal Recessive Two copies needed Sickle cell anemia

10
Mode of Inheritance Key Feature Example

X-linked Recessive Males mostly affected Hemophilia A

X-linked Dominant Affects both sexes Rett syndrome

Y-linked Only males affected Y-chromosome infertility

Mitochondrial Maternal inheritance MELAS

Multifactorial Polygenic + environment Diabetes, Cleft palate

Conclusion
Understanding modes of inheritance is crucial for diagnosing genetic disorders, counseling
families, predicting recurrence risks, and planning interventions or genetic testing.

11
AN74.3 – Multifactorial Inheritance: Description and Examples
Definition
Multifactorial inheritance refers to the transmission of traits or disorders that result from the
combined influence of:
• Multiple genes (polygenic)
• Environmental factors
Unlike Mendelian (monogenic) inheritance, these traits do not follow a simple dominant or
recessive pattern, and the risk of recurrence increases with the number of affected relatives
and severity of the condition.
Key Features of Multifactorial Inheritance

Feature Description

Genetic Basis Involves many genes, each contributing a small additive effect

Environment Influences gene expression (e.g., nutrition, infections, toxins, lifestyle)

No clear pattern Does not follow Mendel’s laws; seen in families but not in every generation

Threshold
A trait is expressed only when genetic liability exceeds a certain threshold
model

Higher if: multiple family members affected, one severely affected, or close
Recurrence risk
relative affected

Types of Multifactorial Traits

A. Congenital Disorders (Structural)
• Neural tube defects (e.g., spina bifida, anencephaly)
• Cleft lip and/or palate
• Congenital heart defects
• Pyloric stenosis
• Clubfoot
• Hypospadias
B. Adult-Onset Common Diseases
• Hypertension
• Type 2 diabetes mellitus
• Coronary artery disease
• Obesity
• Osteoarthritis

12
 • Psychiatric disorders (schizophrenia, bipolar disorder)
Multifactorial Inheritance vs. Mendelian Inheritance

Feature Multifactorial Inheritance Mendelian Inheritance

Number of genes Multiple (polygenic) Single gene

Environmental influence Significant Often minimal

Inheritance pattern No clear pattern Dominant/recessive/X-linked

Recurrence risk Variable Predictable (e.g., 25%, 50%)

Example Diabetes, cleft lip Thalassemia, Marfan syndrome

Examples of Environmental Factors

Trait Environmental Triggers

Neural tube defects Folic acid deficiency

Type 2 diabetes Obesity, sedentary lifestyle

Coronary artery disease High-fat diet, smoking, stress

Schizophrenia Prenatal infections, substance use

Recurrence Risk (General Estimate)

Scenario Risk

One 1st-degree relative affected 2–5%

Two 1st-degree relatives affected 10–15%

Parent and one child affected 15–20%

More severe or early-onset cases Higher risk

Risk is higher if the affected person is of the less commonly affected sex (e.g., pyloric stenosis
in females).
Conclusion
Multifactorial inheritance is the most common mode underlying complex diseases and birth
defects. Understanding this model is crucial for genetic counseling, prevention (e.g., folic acid
supplementation), and managing recurrence risk in families.

13
AN74.4 – Genetic Basis & Clinical Features of Common Genetic Disorders
1. Achondroplasia

Category Details

- Autosomal dominant inheritance- Caused by mutation in FGFR3 gene

Genetic Basis (Fibroblast Growth Factor Receptor 3)- Most common mutation: G380R
substitution

FGFR3 mutation leads to inhibition of endochondral bone growth,

Pathophysiology
especially in long bones

- Short stature (disproportionate dwarfism)- Rhizomelic limb shortening

Clinical
(proximal)- Large head with frontal bossing- Midface hypoplasia- Lumbar
Features
lordosis- Normal intelligence

2. Cystic Fibrosis (CF)

Category Details

- Autosomal recessive inheritance- Mutation in CFTR gene (Cystic Fibrosis

Genetic Basis Transmembrane Conductance Regulator) on chromosome 7- Common
mutation: ΔF508

Defective chloride channel leads to thick, viscous secretions in lungs,

Pathophysiology
pancreas, and other organs

- Recurrent respiratory infections and chronic cough- Pancreatic

Clinical insufficiency → steatorrhea, malabsorption- Meconium ileus (in newborns)-
Features Infertility in males (absent vas deferens)- Failure to thrive- Salty sweat
(positive sweat chloride test)

3. Vitamin D–Resistant Rickets (Hypophosphatemic Rickets)

Category Details

- X-linked dominant inheritance- Mutation in PHEX gene (Phosphate-

Genetic Basis
regulating gene) on X chromosome

Impaired renal tubular reabsorption of phosphate leads to

Pathophysiology
hypophosphatemia, resulting in defective bone mineralization

- Bowing of legs (genu varum)- Short stature- Delayed walking- Dental

Clinical
abscesses- Hypophosphatemia with normal calcium and vitamin D levels-
Features
Poor response to regular vitamin D supplementation

4. Haemophilia A & B

14
Category Details

- X-linked recessive inheritance- Hemophilia A: mutation in F8 gene (Factor

Genetic Basis
VIII)- Hemophilia B: mutation in F9 gene (Factor IX)

Pathophysiology Deficiency in clotting factor VIII or IX → prolonged bleeding

- Easy bruising- Spontaneous bleeding into joints (hemarthrosis)- Muscle

Clinical
hematomas- Prolonged bleeding after injury/surgery- More severe in males;
Features
females are carriers

5. Duchenne Muscular Dystrophy (DMD)

Category Details

- X-linked recessive inheritance- Mutation in DMD gene → absence of

Genetic Basis
dystrophin protein- Frameshift or nonsense mutations

Dystrophin stabilizes muscle membrane. Its absence leads to muscle fiber

Pathophysiology
degeneration

- Onset: ~2–5 years of age- Progressive proximal muscle weakness- Gower’s

Clinical sign (using hands to stand up)- Pseudohypertrophy of calves- Loss of
Features ambulation by ~12 years- Cardiomyopathy, respiratory failure later in life-
Elevated serum creatine kinase (CK)

6. Sickle Cell Anaemia

Category Details

- Autosomal recessive inheritance- Mutation in HBB gene (β-globin gene)-

Genetic Basis
Missense mutation: Glu6Val substitution (GAG → GTG)

Abnormal hemoglobin (HbS) polymerizes under low oxygen → sickling of

Pathophysiology
RBCs, vaso-occlusion, hemolysis

- Chronic hemolytic anemia- Painful vaso-occlusive crises- Dactylitis in

Clinical infants- Splenomegaly early, then autosplenectomy- Increased risk of
Features infections (e.g., pneumococcus)- Avascular necrosis, stroke, leg ulcers-
Triggered by hypoxia, dehydration, infection

Summary Table

Disorder Inheritance Gene Key Feature

Achondroplasia Autosomal dominant FGFR3 Short-limbed dwarfism

Cystic Fibrosis Autosomal recessive CFTR Respiratory & pancreatic involvement

15
Disorder Inheritance Gene Key Feature

Vit D–Resistant Rickets X-linked dominant PHEX Hypophosphatemia, bow legs

Haemophilia A/B X-linked recessive F8 / F9 Bleeding tendency

Duchenne MD X-linked recessive DMD Muscle weakness, Gower’s sign

Sickle Cell Anemia Autosomal recessive HBB Vaso-occlusive crisis, hemolysis

16
AN75.1 – Structural and Numerical Chromosomal Aberrations
What are Chromosomal Aberrations?
Chromosomal aberrations are abnormalities in the number or structure of chromosomes. They
can lead to congenital anomalies, developmental delay, intellectual disability, and various
syndromes or malignancies.
1. Numerical Chromosomal Aberrations (Aneuploidy & Polyploidy)
These involve a change in the number of chromosomes.
A. Aneuploidy
• Definition: Gain or loss of one or more chromosomes, but not a complete set.
• Caused by nondisjunction during meiosis or mitosis.

Type Description Example

One extra chromosome - Trisomy 21 (Down syndrome) - Trisomy 18

Trisomy
(2n + 1) (Edwards) - Trisomy 13 (Patau)

One chromosome
Monosomy - Monosomy X (Turner syndrome – 45,X)
missing (2n - 1)

Tetrasomy/Double
Two extra chromosomes - Rare, e.g., 48,XXYY
trisomy

B. Polyploidy
• Definition: Whole extra sets of chromosomes (3n, 4n, etc.)
• Usually incompatible with life

Type Description Example

Triploidy (3n) 69 chromosomes Spontaneous abortion

Tetraploidy (4n) 92 chromosomes Rare, usually lethal

2. Structural Chromosomal Aberrations

These involve alterations in chromosome structure due to breakage and incorrect rejoining.

Type Description Example

A. Deletion
• Loss of a segment of a chromosome
• Partial monosomy
Examples:
• Cri-du-chat syndrome (del 5p)

17
 • Wolf-Hirschhorn syndrome (del 4p)
B. Duplication
• A segment is present in two copies on the same or different chromosome
Examples:
• Charcot-Marie-Tooth disease type 1A (17p duplication)
C. Inversion
• A chromosome segment is reversed end to end

Subtype Description

Paracentric Does not include centromere

Pericentric Includes centromere

Usually balanced; may cause abnormal gametes if crossing over occurs.

D. Translocation
• Exchange of material between non-homologous chromosomes

Type Description Examples

Reciprocal Exchange between two chromosomes Often seen in cancers

Fusion of two acrocentric chromosomes at 14q21q translocation in familial

Robertsonian
the centromere Down syndrome

E. Ring Chromosome
• A chromosome forms a ring due to deletion of terminal ends and fusion of broken ends.
Example:
• Ring chromosome 14, 18
F. Isochromosome
• A chromosome with identical arms due to misdivision at the centromere.
Example:
• Isochromosome X in Turner syndrome (i(Xq))

Clinical Consequences of Chromosomal Aberrations

Feature Effect

Developmental delay Common in aneuploidy & large structural defects

18
Feature Effect

Congenital malformations Often seen in trisomies, deletions

Infertility or miscarriages Seen in translocations, mosaicism

Cancer Certain translocations (e.g., Philadelphia chromosome in CML)

Summary Table

Type Subtype Example

Numerical Trisomy Down syndrome (47,XX,+21)

Monosomy Turner syndrome (45,X)

Polyploidy Triploidy (69,XXX)

Structural Deletion Cri-du-chat syndrome (del 5p)

Duplication CMT type 1A

Inversion Paracentric inversion of chromosome 9

Translocation Robertsonian translocation (14;21)

Ring chromosome Ring chromosome 14

Isochromosome Isochromosome Xq in Turner syndrome

Conclusion
Chromosomal aberrations are important causes of genetic disorders. Understanding structural
and numerical abnormalities is essential for diagnosis, prognosis, prenatal screening, and
genetic counseling.

19
AN75.2 – Mosaics and Chimeras: Definitions and Examples
1. Mosaicism
Definition:
Mosaicism refers to the presence of two or more genetically different cell lines in an individual,
derived from a single zygote.
Mechanism:
• Caused by post-zygotic mutations (after fertilization) during early embryonic cell
divisions.
• Mutations may affect all or some tissues, depending on when the error occurred.
Types of Mosaicism:

Type Description Example

Somatic Mutation occurs in somatic cells; only

Segmental neurofibromatosis
Mosaicism some body cells are affected

Gonadal Mutation affects only germ cells;

Gonadal mosaicism in
(Germline) individual is unaffected but can pass
Duchenne muscular dystrophy
Mosaicism mutation to offspring

Somatic +
Both somatic and germline cells are Can result in milder forms of
Gonadal
affected genetic disorders
Mosaicism

Examples of Mosaicism:

Condition Mosaic Karyotype

Turner syndrome 45,X / 46,XX (some cells monosomic X, others normal)

Down syndrome 46,XX / 47,XX,+21 (some cells trisomy 21, others normal)

McCune-Albright syndrome Caused by post-zygotic GNAS mutation

2. Chimerism
Definition:
Chimerism is the presence of two or more genetically distinct cell lines in an individual that
are derived from different [Link]:
• Occurs due to fusion of two embryos (e.g., dizygotic twins) or cell exchange (e.g., via
placental circulation in twins).
• Very rare in humans.
Types of Chimerism:

20
Type Description Example

Dispermic Individual with both XX and XY

Fusion of two fertilized eggs (zygotes)
chimera cell lines

Occurs in fraternal twins due to exchange of Detected via mixed blood cell
Blood chimera
blood stem cells in utero types

Iatrogenic Recipient has donor’s

Result of bone marrow transplant
chimera hematopoietic cells

Examples of Chimerism:
• True hermaphroditism (46,XX/46,XY) in rare cases
• Microchimerism: Presence of a small number of cells from another individual (e.g., fetal
cells in maternal circulation)
Comparison Table: Mosaic vs Chimera

Feature Mosaic Chimera

Origin One zygote Two or more zygotes

Genetic
Post-zygotic mutation Fusion of embryos or cell exchange
change

Frequency More common Rare

Genetically different cells from one Genetically different cells from two
Cell types
fertilization event individuals

Example Turner mosaic (45,X/46,XX) Blood chimera in twins

Conclusion:
• Mosaicism results from mutations in early embryonic development and may cause
variable expression of genetic disorders.
• Chimerism involves fusion or coexistence of cells from two different zygotes and is rare
in humans.
• Both conditions challenge traditional definitions of genetic identity and have implications
in diagnosis, inheritance, and forensic analysis.

21
AN75.3 – Genetic Basis & Clinical Features of Selected Chromosomal Disorders
1. Prader–Willi Syndrome (PWS)

Aspect Details

- Caused by loss of function of paternally expressed genes on chromosome

Genetic
15q11–q13.- Mechanisms: ▫️ Paternal deletion (70%) ▫️ Maternal uniparental
Basis
disomy (25%) ▫️ Imprinting defect (1–5%)

Type of
Imprinting disorder
Disorder

Inheritance Mostly sporadic (rarely inherited)

- Neonatal hypotonia and poor feeding- Delayed milestones- Hyperphagia in

Clinical early childhood → obesity- Short stature, small hands and feet- Hypogonadism
Features (cryptorchidism, delayed puberty)- Mild to moderate intellectual disability-
Behavioral issues: tantrums, OCD traits

2. Edward Syndrome (Trisomy 18)

Aspect Details

Genetic - Trisomy 18: An extra copy of chromosome 18- Caused by nondisjunction

Basis during meiosis

Type of
Numerical chromosomal abnormality
Disorder

Karyotype 47,XX,+18 or 47,XY,+18

Inheritance Not inherited; sporadic

- Intrauterine growth restriction (IUGR)- Prominent occiput, low-set ears,

Clinical micrognathia- Clenched hands with overlapping fingers- Rocker-bottom
Features feet- Congenital heart defects (VSD, ASD)- Severe intellectual disability- Most
infants die within the first year (high mortality)

3. Patau Syndrome (Trisomy 13)

Aspect Details

Genetic - Trisomy 13: An extra copy of chromosome 13- Caused by meiotic

Basis nondisjunction

Type of
Numerical chromosomal abnormality
Disorder

Karyotype 47,XX,+13 or 47,XY,+13

22
Aspect Details

Inheritance Mostly sporadic; can occur due to Robertsonian translocation

- Midline facial defects: cleft lip/palate, cyclopia, holoprosencephaly-

Clinical Polydactyly- Microphthalmia- Congenital heart defects- Severe intellectual
Features disability- Rocker-bottom feet- Most affected infants die within days to weeks
after birth

Summary Table

Disorder Genetic Basis Type Key Clinical Features

Paternal deletion or
Prader–Willi Hypotonia, hyperphagia, obesity, short
maternal UPD of 15q11– Imprinting
Syndrome stature, hypogonadism
13

Edward Micrognathia, clenched fists, rocker-

Trisomy 18 Aneuploidy
Syndrome bottom feet, IUGR

Patau Facial clefts, polydactyly,

Trisomy 13 Aneuploidy
Syndrome microphthalmia, holoprosencephaly

Conclusion
These syndromes illustrate key principles of genomic imprinting and numerical chromosomal
abnormalities. Early diagnosis through prenatal screening, karyotyping, and genetic
counseling is critical due to their severe and often lethal outcomes.

23
AN75.4 – Genetic Basis of Variation: Polymorphism and Mutation

Genetic Variation: Overview

Genetic variation refers to the differences in DNA sequences among individuals in a population.
These variations are essential for:
• Biological diversity
• Evolution
• Individual traits (e.g., eye color, disease susceptibility)
There are two major types:
1. Polymorphism
2. Mutation
1. Polymorphism

Feature Description

Definition A genetic variation that is common in the population (occurs in >1% of individuals)

Effect Usually benign and does not cause disease

Location Can occur in coding or non-coding regions

- Single Nucleotide Polymorphisms (SNPs) – most common - Insertion/Deletion

Types
polymorphisms - VNTRs (Variable Number Tandem Repeats)

- SNP in APOE gene affects Alzheimer's risk- Blood group types (ABO) are
Example
polymorphic

Clinical Importance:
• Used in genome-wide association studies (GWAS)
• Helps in identifying disease susceptibility
• Basis for personalized medicine and pharmacogenomics
2. Mutation

Feature Description

A permanent change in the DNA sequence that is rare (<1% frequency in

Definition
population)

Effect May be deleterious, neutral, or beneficial

- Spontaneous errors in DNA replication - Radiation, chemicals, viruses - Inherited

Causes
germline mutations or acquired somatic mutations

24
Types (Based on DNA Change)
Point mutation: substitution of a single base (e.g., sickle cell disease: GAG → GTG)
• Insertions/deletions: can cause frameshift mutations
• Repeat expansions: trinucleotide repeats (e.g., Huntington’s disease)
| Types (Based on Effect on Protein) |
• Silent: no amino acid change
• Missense: change in one amino acid (e.g., SCD)
• Nonsense: introduces a stop codon (e.g., Duchenne muscular dystrophy)
Clinical Importance:
• Pathogenic mutations cause genetic disorders
• Used in molecular diagnostics
• Helps in carrier detection, prenatal diagnosis, gene therapy
Comparison Table: Polymorphism vs Mutation

Feature Polymorphism Mutation

Frequency in
>1% <1%
population

Effect Usually benign Can be harmful, neutral, or beneficial

Role Normal variation May cause disease

Inheritance Commonly inherited May be inherited or acquired

SNPs in drug metabolism Mutation in CFTR gene → cystic

Example
genes fibrosis

Conclusion
Both polymorphisms and mutations are forms of genetic variation. While polymorphisms
contribute to normal diversity, mutations may lead to genetic disorders. Understanding these
helps in diagnosis, treatment, and predicting genetic risk.

25
AN75.5 – Principles of Genetic Counselling
What is Genetic Counselling?
Genetic counselling is a communication process that helps individuals, couples, and families
understand and adapt to the medical, psychological, and familial implications of genetic
conditions. It includes:
• Understanding the genetic basis of diseases
• Risk assessment of recurrence
• Discussing testing options and results
• Supporting informed decision-making
• Providing psychosocial support
Core Principles of Genetic Counselling

Principle Description

1. Autonomy and Informed Decision-Making

• Respect the individual's right to make choices based on complete and unbiased
information.
• Provide accurate and understandable information about diagnosis, risk, and options.
• Do not impose decisions — non-directive counselling is key.
2. Confidentiality
• Maintain privacy of genetic information.
• Information should not be disclosed without consent, including to family members.
3. Accurate Risk Assessment and Communication
• Estimate the recurrence risk using tools like pedigree analysis, molecular data, or
population data.
• Clearly communicate the probability of disease occurrence or transmission in
understandable terms.
4. Non-directiveness
• Counsellors provide information and support but do not advise what decision should be
made.
• Especially important in prenatal diagnosis, termination decisions, or predictive
testing.
5. Respect for Cultural, Religious, and Personal Beliefs
• Recognize and respect the values of the individual or family.
• Tailor information and recommendations with cultural sensitivity.
6. Psychological Support
• Address emotional responses like anxiety, guilt, grief, or confusion.

26
 • Provide reassurance, referrals to mental health professionals if needed.
7. Family-Centered Approach
• Genetic disorders often affect multiple members.
• Consider the impact on and role of other family members (siblings, future offspring,
relatives).
8. Education
• Help clients understand basic genetic concepts, inheritance patterns, and implications
of test results.
• Promote genetic literacy for better decision-making.
9. Documentation and Follow-up
• Maintain detailed records of the counselling session and plan.
• Provide written summaries and arrange follow-up as necessary.
Scenarios Requiring Genetic Counselling
• Congenital anomalies or birth defects
• Recurrent miscarriages or infertility
• Family history of genetic disorders
• Carrier screening (e.g., thalassemia, hemophilia)
• Prenatal diagnosis (e.g., Down syndrome)
• Predictive testing (e.g., Huntington’s disease)
• Newborn screening abnormalities
• Consanguineous marriages
Conclusion
Genetic counselling is a cornerstone of medical genetics that combines science,
communication, and empathy. Adhering to its core principles ensures ethical, respectful, and
effective support for individuals and families facing genetic concerns.

27