Mendelian Disorders: Haemophilia, Sickle Cell, Thalassemia

Mendelian disorders are diseases caused by a mutation in a single gene, passed down in clear dominant or recessive patterns. Four well-studied examples are haemophilia (blood cannot clot), sickle cell anaemia (red blood cells bend into sickles), thalassemia (too little haemoglobin) and cystic fibrosis (thick mucus blocks lungs and gut).

These disorders affect millions of people, especially thalassemia and sickle cell disease in India, Africa and the Mediterranean. Because their inheritance is predictable, carrier screening and early treatment can prevent much suffering.

Key Concepts

• Haemophilia: X-linked recessive; clotting factor VIII (type A) or IX (type B) missing; mostly males affected
• Sickle cell anaemia: autosomal recessive; a single base change in the beta-globin gene (GAG → GTG) replaces glutamic acid with valine at position 6
• Thalassemia: autosomal recessive; reduced production of alpha or beta globin chains; alpha-thalassemia often from gene deletions on chromosome 16
• Cystic fibrosis: autosomal recessive; faulty CFTR chloride channel gene on chromosome 7
• Carrier: a heterozygote with one mutant allele — healthy but can pass it on

How It Works

Step 1: For autosomal recessive disorders, two carrier parents (Aa × Aa) have, on average, 25% affected (aa), 50% carrier (Aa) and 25% normal (AA) children. Step 2: For haemophilia, the gene sits on the X chromosome, so carrier mothers pass it to 50% of their sons, who are affected. Step 3: The mutant protein causes the symptoms — sickle haemoglobin sticks together in low oxygen and bends the cell, blocking tiny blood vessels and causing pain and organ damage. Step 4: Carriers of sickle cell (HbAHbS) are mostly healthy and, importantly, gain protection against malaria.

Worked Example

Both parents are carriers of thalassemia (genotype Aa). They plan three children. What is the chance that all three will be free of the disease (not aa)?

Step 1: For one child, P(affected, aa) = 1/4 and P(not affected) = 3/4.

Step 2: The children are independent, so multiply for three children: 3/4 × 3/4 × 3/4 = 27/64.

Step 3: 27/64 ≈ 42%. There is about a 42% chance all three avoid the disease — and still a 25% risk with each single pregnancy, which is why doctors offer prenatal testing.

Common Misconceptions

• Misconception: Carriers are sick people. Correction: Carriers of these recessive disorders are generally healthy; that is why the allele hides in populations.
• Misconception: Haemophilia affects only males, so females need not be tested. Correction: Females can be carriers (and rarely affected), and carrier testing of mothers and sisters is essential.
• Misconception: Sickle cell disease is 'bad' in every way. Correction: In the carrier state it protects against malaria — a balanced polymorphism that natural selection keeps in malaria regions.

Real-World Applications

Premarital and antenatal carrier screening for thalassemia is promoted across India to reduce births of affected children. Newborn screening detects cystic fibrosis early so treatment starts before lung damage. Haemophilia patients now receive recombinant clotting factor and, in recent years, approved gene therapies. Sickle cell patients benefit from hydroxyurea tablets and curative bone-marrow transplants. Chorionic villus sampling lets doctors test a fetus's DNA during pregnancy.

Four diseases, four lessons in how one gene rules health — and why knowing your carrier status is real power for a family.