Sex-linked and Mendelian Disorders in Humans

 

Sex-linked and Mendelian Disorders in Humans

1. Human Genetic Disorders

Human genetic disorders are diseases caused by abnormalities in genes or chromosomes.

Genetic disorders are divided into:

1. Mendelian disorders (Single gene disorders)
2. Chromosomal disorders

2. Mendelian Disorders

Definition

Mendelian disorders are genetic diseases caused by mutation in a single gene.

These disorders follow Mendel's laws of inheritance. Their inheritance can be studied using pedigree analysis.

Examples include:

• Haemophilia
• Colour blindness
• Sickle-cell anaemia
• Thalassaemia
• Phenylketonuria
• Cystic fibrosis (Sathee)

3. Classification of Mendelian Disorders

Type	Examples
Autosomal Dominant	Huntington disease, Myotonic dystrophy
Autosomal Recessive	Sickle-cell anaemia, Thalassaemia, PKU
X-linked Dominant	Rare (Vitamin D resistant rickets)
X-linked Recessive	Haemophilia, Colour blindness
Y-linked (Holandric)	Hairy pinna (classical textbook example)

4. Sex-linked Inheritance

Definition

Sex-linked inheritance refers to inheritance of genes located on the sex chromosomes (X or Y).

Most sex-linked diseases are X-linked because:

• X chromosome contains more than 800 genes.
• Y chromosome contains very few genes.

Therefore:

• Males (XY) possess only one X chromosome.
• Females (XX) possess two X chromosomes.

This is why recessive X-linked disorders occur much more frequently in males.

5. Why are males more commonly affected?

Male genotype: XY

Female genotype: XX

If defective allele = Xʰ

Male: XʰY

No normal allele is present. Disease develops.

Female: XᴴXʰ

Normal allele masks defective allele. Female becomes carrier.

Hence: Males are hemizygous for X chromosome.

6. Characteristics of X-linked Recessive Inheritance

These disorders show:

✔ More males affected

✔ Females usually carriers

✔ No father-to-son transmission

✔ Trait may skip generations

✔ Carrier mother transmits disease to sons

✔ Affected father transmits defective X chromosome to daughters only

7. Haemophilia

Definition

Haemophilia is an X-linked recessive disorder affecting blood clotting. It results from mutation in genes coding clotting factors.

Most common types:

• Haemophilia A → Factor VIII deficiency
• Haemophilia B → Factor IX deficiency

Cause

Mutation in X chromosome

↓

Deficiency of clotting factor

↓

Blood clot cannot form properly

↓

Continuous bleeding

Symptoms

• Prolonged bleeding
• Internal bleeding
• Joint bleeding
• Bruising
• Delayed clot formation

Inheritance

Carrier female: XᴴXʰ

Normal male: XᴴY

Punnett square

	Xᴴ	Y
Xᴴ	Normal daughter	Normal son
Xʰ	Carrier daughter	Haemophilic son

Probability

• 25% normal daughter
• 25% carrier daughter
• 25% normal son
• 25% haemophilic son

i.e.  Among sons: 50% affected, Among daughters: 50% carriers

Why haemophilic females are rare?

Because: Mother must be carrier AND Father must be haemophilic. Hence extremely rare.

Queen Victoria

One of the most famous historical carriers. Disease spread among several European royal families.

8. Colour Blindness

Definition

Colour blindness is an X-linked recessive disorder.

It results from mutation in genes coding red or green cone pigments. Affected persons cannot distinguish: Red and green colours (Most common)

Cause

Mutation in X chromosome

↓

Abnormal cone pigment

↓

Defective colour perception

Incidence

Approximately:

• 8% males
• 0.4% females

Because males possess only one X chromosome. (Sathee)

Inheritance

Carrier female: XᴺXᶜ

Normal male: XᴺY

Children:

·       25% normal daughter

·       25% carrier daughter

·       25% normal son

·       25% colour blind son

Colour blind daughter

Occurs only when: Carrier mother × Colour blind father

9. Comparison: Haemophilia vs Colour Blindness

Character	Haemophilia	Colour Blindness
Inheritance	X-linked recessive	X-linked recessive
Gene affected	Clotting factor	Cone pigment
Main symptom	Continuous bleeding	Red-green colour defect
More common in	Males	Males
Female affected?	Very rare	Rare

10. Autosomal Mendelian Disorders

These are caused by mutation in autosomal genes. Both males and females affected equally.

A. Sickle-cell Anaemia

Definition

Autosomal recessive disorder. Caused by mutation in β-globin gene.

Molecular Basis

Normal codon:

GAG

↓

Mutated codon:

GTG

DNA mutation:

A → T substitution

This changes

Glutamic acid

↓

Valine

at 6th position of β-chain.

This single amino acid substitution changes haemoglobin structure. (Sathee)

Normal Hb- HbA

Mutant Hb- HbS

Genotypes

HbAHbA- Normal

HbAHbS- Carrier (Sickle-cell trait)

HbSHbS- Disease

Symptoms

• Anaemia
• Fatigue
• Pain crises
• Sickle-shaped RBCs
• Reduced oxygen transport

Important Facts

Inheritance: Autosomal recessive

Carrier × Carrier

Results

25% diseased

50% carriers

25% normal

B. Thalassaemia

Definition

Autosomal recessive disorder. Characterized by decreased synthesis of globin chains.

Unlike sickle-cell anaemia: Here haemoglobin quantity decreases. it is a quantitative defect, whereas sickle-cell anaemia is a qualitative defect.

Types

α-thalassaemia

↓

Reduced α-globin synthesis

β-thalassaemia

↓

Reduced β-globin synthesis

Symptoms

• Severe anaemia
• Weakness
• Growth retardation
• Enlarged spleen

C. Phenylketonuria (PKU)

Definition

Autosomal recessive metabolic disorder. Caused by deficiency of Phenylalanine hydroxylase enzyme.

Normal pathway

Phenylalanine

↓

Tyrosine

Disease

Phenylalanine accumulates

↓

Brain damage

↓

Mental retardation (if untreated)

Symptoms

• Intellectual disability
• Seizures
• Fair skin
• Delayed development

D. Cystic Fibrosis

Definition

Autosomal recessive disorder. Caused by mutation in CFTR gene.

Symptoms

• Thick mucus
• Lung infections
• Pancreatic insufficiency
• Digestive problems

11. Pedigree Analysis

Definition

Pedigree analysis is the study of inheritance of a trait across generations.

Used to determine:

• Dominant or recessive
• Autosomal or sex-linked
• Carrier individuals

Pedigree analysis as a method to trace Mendelian disorders.

Standard Pedigree Symbols

Symbol	Meaning
□	Male
○	Female
■	Affected male
●	Affected female
◐	Carrier female
Horizontal line	Marriage
Vertical line	Offspring

12. How to Identify Inheritance Pattern

Autosomal Dominant

• Appears every generation
• Both sexes equally affected
• Father-to-son transmission possible

Autosomal Recessive

• Skips generations
• Parents usually normal carriers
• Both sexes equally affected

X-linked Recessive

• Mostly males
• No father-to-son transmission
• Carrier females common
• Trait may skip generations

Y-linked

• Only males
• Father → Son only

13. High-Yield Comparison Table

Disorder	Chromosome	Dominance	Defect
Haemophilia	X	Recessive	Clotting factor
Colour blindness	X	Recessive	Cone pigments
Sickle-cell anaemia	Autosome	Recessive	β-globin mutation
Thalassaemia	Autosome	Recessive	Reduced globin synthesis
Phenylketonuria	Autosome	Recessive	Phenylalanine hydroxylase deficiency
Cystic fibrosis	Autosome	Recessive	CFTR chloride channel

14. Summary

• Males are hemizygous for X chromosome.
• X-linked recessive disorders are more common in males.
• No father-to-son transmission in X-linked inheritance.
• Haemophilia and colour blindness are X-linked recessive.
• Sickle-cell anaemia and thalassaemia are autosomal recessive.
• Sickle-cell anaemia is a qualitative defect of haemoglobin.
• Thalassaemia is a quantitative defect of globin synthesis.
• Pedigree analysis helps determine inheritance patterns.
• Carrier mothers are central to transmission of X-linked recessive disorders.

15. Quick Revision Box

• Genetic disorders are of Mendelian and chromosomal types.
• Mendelian disorders result from mutation in a single gene.
• Haemophilia and colour blindness are X-linked recessive disorders.
• Sickle-cell anaemia, thalassaemia, phenylketonuria, and cystic fibrosis are classic Mendelian disorders.
• Males are affected more frequently by X-linked recessive disorders because they possess only one X chromosome.
• Pedigree analysis is used to trace the inheritance of Mendelian disorders in families.