NCERT grounding
NCERT Class 12 Biology, Chapter 4, places this material in section 4.8.2. The text states that genetic disorders fall into two categories — Mendelian disorders and chromosomal disorders — and that Mendelian disorders are "mainly determined by alteration or mutation in the single gene." Because the defect lies in one gene, the disorder is "transmitted to the offspring on the same lines as we have studied in the principle of inheritance," and its pattern can be traced in a family through pedigree analysis.
The named examples in NCERT are Haemophilia, Cystic fibrosis, Sickle-cell anaemia, Colour blindness, Phenylketonuria and Thalassaemia. The text is explicit that such disorders "may be dominant or recessive" and that the trait may also be linked to the sex chromosome, as in haemophilia. That single sentence is the backbone of every NEET question on this topic: the examiner wants you to attach the correct label — autosomal or X-linked, dominant or recessive — to each disease.
"Thalassemia differs from sickle-cell anaemia in that the former is a quantitative problem of synthesising too few globin molecules while the latter is a qualitative problem of synthesising an incorrectly functioning globin." — NCERT Biology, Class 12, §4.8.2
The five Mendelian disorders
All five disorders in this subtopic are recessive single-gene conditions. Two of them — haemophilia and colour blindness — sit on the X chromosome, so they are X-linked recessive and follow criss-cross inheritance. The other three — sickle-cell anaemia, thalassaemia and phenylketonuria — sit on autosomes, so they are autosomal recessive and need a defective allele from each parent for the disease to appear. Holding this two-axis grid (autosome vs. X chromosome; the disease appears only in the homozygous or hemizygous state) in mind is the fastest route through any NEET item here.
| Disorder | Inheritance | Gene / chromosome | Core defect |
|---|---|---|---|
| Haemophilia | X-linked recessive | Clotting-factor gene on X | A clotting-cascade protein is defective; non-stop bleeding from a small cut |
| Colour blindness | X-linked recessive | Genes on X chromosome | Defect in red or green cone; failure to discriminate red from green |
| Sickle-cell anaemia | Autosomal recessive | HBB β-globin gene | Qualitative — abnormal HbS; RBC sickles under low O₂ |
| Thalassaemia | Autosomal recessive | HBA1/HBA2 (chr 16) or HBB (chr 11) | Quantitative — too little α or β globin synthesised |
| Phenylketonuria | Autosomal recessive | Phenylalanine hydroxylase gene | Phenylalanine not converted to tyrosine; toxic build-up |
Haemophilia — X-linked recessive, criss-cross inheritance
Haemophilia is described by NCERT as a "sex linked recessive disease, which shows its transmission from unaffected carrier female to some of the male progeny." In an affected individual a single protein that is part of the cascade of proteins involved in the clotting of blood is defective. The clinical consequence is stark: a simple cut results in non-stop bleeding, because the clot cannot form.
Because the gene lies on the X chromosome and is recessive, a heterozygous female is a carrier — she is not herself haemophilic, since her second X carries a dominant normal allele that masks the defect. She can, however, transmit the disease to her sons, each of whom has a 50 per cent chance of receiving the defective X. NCERT notes that the possibility of a female actually being haemophilic is "extremely rare," because for that to happen her mother must be at least a carrier and her father must be haemophilic — and a haemophilic male is described as unviable in the later stage of life. The famous family pedigree of Queen Victoria, a carrier, shows a number of haemophilic descendants and is the textbook illustration of this pattern.
Figure 1. A carrier mother (X Xʼ) crossed with a normal father (X Y). Half her sons inherit the defective X and are affected; half her daughters become carriers. No daughter is affected here, because every daughter receives a normal X from her father — the criss-cross signature.
Colour blindness — X-linked recessive, an 8% vs 0.4% split
Red-green colour blindness is, in NCERT's words, "a sex-linked recessive disorder due to defect in either red or green cone of eye resulting in failure to discriminate between red and green colour." The defect is due to mutation in certain genes present on the X chromosome. Its mode of inheritance is exactly the same as haemophilia — criss-cross transmission from a carrier mother to her sons.
Males colour blind
A male has only one X chromosome, so a single defective allele expresses the trait — he is hemizygous.
Females colour blind
A female has two X chromosomes, so she must inherit a defective allele on both — far less probable.
NCERT spells out the inheritance arithmetic precisely. The son of a woman who carries the gene has a 50 per cent chance of being colour blind. The mother is not herself colour blind, because the gene is recessive and its effect is suppressed by her matching dominant normal gene. A daughter will not normally be colour blind "unless her mother is a carrier and her father is colour blind" — the only cross that delivers a defective X to a daughter from both sides. This is why the disorder is roughly twenty times more frequent in males than in females.
Sickle-cell anaemia — the qualitative defect
Sickle-cell anaemia is an autosome-linked recessive trait. NCERT states it "can be transmitted from parents to the offspring when both the partners are carrier for the gene (or heterozygous)." The disease is controlled by a single pair of alleles, HbA and HbS. Out of the three possible genotypes, only individuals homozygous for HbS — that is, HbS HbS — show the diseased phenotype. Heterozygotes (HbA HbS) are carriers of the disease; they appear healthy but exhibit sickle-cell trait, and there is a 50 per cent probability of transmitting the mutant gene to the progeny.
The molecular basis is the most heavily examined fact in the whole subtopic. The defect is caused by the substitution of glutamic acid (Glu) by valine (Val) at the sixth position of the beta-globin chain of the haemoglobin molecule. This amino acid substitution arises from a single base substitution at the sixth codon of the beta-globin gene — the codon changes from GAG to GUG. The mutant haemoglobin then undergoes polymerisation under low oxygen tension, which changes the shape of the RBC from a biconcave disc to an elongated, sickle-like structure. This is the classic example of a point mutation.
Figure 2. A single base substitution at the sixth codon of the beta-globin gene (GAG → GUG) swaps glutamic acid for valine at position six of the beta-globin chain. The mutant HbS polymerises under low oxygen tension, sickling the RBC.
Thalassaemia — the quantitative defect
Thalassaemia is also an autosome-linked recessive blood disease, transmitted from parents to offspring when both partners are unaffected carriers (heterozygous) for the gene. The defect "could be due to either mutation or deletion which ultimately results in reduced rate of synthesis of one of the globin chains (α and β chains) that make up haemoglobin." This causes the formation of abnormal haemoglobin molecules and the anaemia that defines the disease.
Thalassaemia is classified by which globin chain is affected. In α-thalassaemia, the production of the α-globin chain is affected; it is controlled by two closely linked genes, HBA1 and HBA2 on chromosome 16 of each parent, and severity depends on how many of the four genes are mutated or deleted — the more genes affected, the less alpha-globin produced. In β-thalassaemia, the production of the β-globin chain is affected; it is controlled by a single gene, HBB, on chromosome 11 of each parent and occurs due to mutation of one or both genes.
Sickle-cell anaemia
Qualitative
Wrong globin is made
- Normal amount of globin synthesised
- Globin is structurally abnormal (HbS)
- Caused by a point mutation: GAG → GUG
- Glu replaced by Val at position 6 of β-chain
Thalassaemia
Quantitative
Too little globin is made
- Globin chains are normal in structure
- Reduced rate of synthesis of α or β chain
- Caused by mutation or deletion of globin genes
- α: HBA1/HBA2 on chr 16; β: HBB on chr 11
NCERT compresses this comparison into one sentence worth memorising verbatim: thalassaemia is a quantitative problem of synthesising too few globin molecules, while sickle-cell anaemia is a qualitative problem of synthesising an incorrectly functioning globin. Both are autosomal recessive; the difference is what goes wrong with the globin, not where the gene sits.
Phenylketonuria — an inborn error of metabolism
Phenylketonuria (PKU) is, in NCERT's phrasing, an inborn error of metabolism inherited as an autosomal recessive trait. The affected individual lacks the enzyme that converts the amino acid phenylalanine into tyrosine. Elsewhere in the chapter, NCERT identifies this enzyme as phenylalanine hydroxylase and notes that the disease is caused by a single-gene mutation that illustrates pleiotropy.
Metabolic block in phenylketonuria
-
Step 1
Enzyme missing
Mutation disables phenylalanine hydroxylase.
-
Step 2
Conversion fails
Phenylalanine is not converted to tyrosine.
-
Step 3
Toxic build-up
Phenylalanine accumulates, forming phenylpyruvic acid and derivatives.
-
Step 4
Phenotype
Brain accumulation causes mental retardation; derivatives excreted in urine.
Because phenylalanine cannot move down the normal pathway, it accumulates and is converted into phenylpyruvic acid and other derivatives. Their accumulation in the brain causes mental retardation, and these derivatives are also excreted in the urine because of their poor absorption by the kidney. The same single mutation also reduces hair and skin pigmentation — one gene driving several phenotypic effects, a textbook case of pleiotropy.
Worked examples
A colour-blind man marries a woman who is homozygous normal for colour vision. What is the colour-vision status of their sons and daughters?
The man is XʼY; the woman is XX. Sons receive the Y from the father and an X from the mother — every son is X Y and has normal colour vision. Daughters receive the Xʼ from the father and a normal X from the mother — every daughter is X Xʼ, a carrier with normal vision. So all children have normal colour vision: sons are non-carriers, daughters are carriers. The defective X has crossed from father to daughter, the criss-cross signature.
Two phenotypically healthy parents are each carriers for sickle-cell anaemia. What fraction of their children are expected to be diseased, and what fraction are carriers?
Both parents are heterozygous, HbA HbS. The cross HbA HbS × HbA HbS gives offspring in the ratio 1 HbA HbA : 2 HbA HbS : 1 HbS HbS. Only the homozygous HbS HbS individual shows the diseased phenotype, so 1/4 (25%) of the children are diseased. The HbA HbS individuals — 2/4 (50%) — are carriers with sickle-cell trait, and 1/4 are completely normal.
A patient produces structurally normal beta-globin chains but in sharply reduced amounts. Which disorder is this, and why is it not sickle-cell anaemia?
This is β-thalassaemia. The diagnostic phrase is "structurally normal but reduced amount" — a quantitative defect. Sickle-cell anaemia is a qualitative defect: the globin is made in normal quantity but is structurally abnormal because glutamic acid has been replaced by valine. Both are autosomal recessive blood disorders, so the inheritance label cannot distinguish them — only the qualitative-versus-quantitative test can.
Common confusion & NEET traps
The single most frequent error on this subtopic is mislabelling the inheritance mode. Students routinely tag sickle-cell anaemia as X-linked because they associate "blood disorder" with haemophilia. NCERT is unambiguous: sickle-cell anaemia and thalassaemia are autosome-linked recessive; only haemophilia and colour blindness are X-linked. A second cluster of confusion surrounds the qualitative-versus-quantitative distinction and the exact molecular detail of the sickle-cell mutation.