Mendelian disorders in humans

A change in one gene

A Mendelian disorder is a disorder that is caused by a change, a mutation, in a single gene. Because one gene is involved, the disorder is passed on by the laws of Mendel. It can be dominant or recessive, and the gene can lie on an autosome or on the X chromosome.

• Haemophilia (X-linked recessive): one protein of the blood clotting cascade is faulty.
• Red-green colour blindness (X-linked recessive): a defect in the red or the green cone.
• Thalassaemia (autosomal recessive): too little of the alpha or the beta chain of haemoglobin is made.
• Sickle-cell anaemia (autosomal recessive): one amino acid of the beta chain is wrong, valine in place of glutamic acid.
• Phenylketonuria (autosomal recessive): an enzyme that changes phenylalanine to tyrosine is missing.
• Cystic fibrosis (autosomal recessive): a faulty channel protein makes the mucus thick and sticky.

Haemophilia and colour blindness were the subject of the last course. The NTA syllabus names thalassaemia among the Mendelian disorders. Sickle-cell anaemia, phenylketonuria and cystic fibrosis are in NCERT, and A-Level and IB ask about them, but the NTA text does not name them.

Thalassaemia

Thalassaemia is an autosomal recessive disorder. A person with two copies of the faulty allele makes too little of one of the globin chains of haemoglobin. Haemoglobin is built from four chains, two alpha and two beta.

• Alpha thalassaemia: the alpha chain is short. It is controlled by two closely linked genes, HBA1 and HBA2, on chromosome 16.
• Beta thalassaemia: the beta chain is short. It is controlled by one gene, HBB, on chromosome 11.

The red cells then carry too little oxygen, and the person is anaemic. Thalassaemia is a quantitative problem: the globin is normal, but there is too little of it. Sickle-cell anaemia is a qualitative problem: the globin is made in full amount, but one amino acid is wrong.

Sickle-cell anaemia

The gene for the beta chain has the alleles $Hb^A$ and $Hb^S$.

• $Hb^A Hb^A$ is normal. $Hb^A Hb^S$ is a carrier, who has the sickle-cell trait and is usually healthy. $Hb^S Hb^S$ has the disease.
• In $Hb^S$, the sixth amino acid of the beta chain is valine, where the normal chain has glutamic acid. When the oxygen level is low, the haemoglobin forms long fibres, and the red cell changes from a round disc into a sickle shape.

Phenylketonuria and cystic fibrosis

In phenylketonuria (PKU) the enzyme that changes the amino acid phenylalanine into tyrosine is missing. Phenylalanine builds up and is changed to phenylpyruvic acid. The excess damages the brain and leads to mental retardation. The acid is passed out in the urine.

Cystic fibrosis is caused by a faulty gene for a channel protein, which carries chloride ions. The mucus of the lungs and the gut becomes thick and sticky. It is also autosomal recessive.

Working out the risk

Two carriers (Aa) have children. The Punnett square gives AA, Aa, Aa and aa.

• The chance that a child is affected (aa) is $\tfrac{1}{4}$.
• The chance that a child is a carrier (Aa) is $\tfrac{1}{2}$.
• The chance that a child is normal and not a carrier (AA) is $\tfrac{1}{4}$.
• A child who is not affected has a chance of $\tfrac{2}{3}$ of being a carrier, because only three boxes are unaffected and two of them are Aa.

A carrier (Aa) and an affected person (aa) have a chance of $\tfrac{1}{2}$ for each child to be affected.

In the pedigree, the parents I-1 and I-2 look healthy, and so do their children II-1 and II-4. Yet II-2 has the disease. This is how two carriers show up in a family.

You should see that the chance for each child is always 1 in 4, but the chance that at least one child is affected grows as the family grows.

Dominant, recessive and X-linked: how a pedigree tells them apart

• Autosomal recessive: both sexes are affected equally. Two normal parents can have an affected child. The trait often skips a generation. Marriage of cousins raises the risk.
• Autosomal dominant: every affected person has an affected parent, and the trait appears in every generation. Huntington disease is an example that is taught at A-Level.
• X-linked recessive: more men are affected. A trait never passes from father to son.

Try it in Python

The program counts the children of two parents for an autosomal recessive disorder, and the chance that none of four children is affected.

Practise with new numbers

Common mistakes

• Saying that a carrier has the disease. A carrier has one copy of the allele and is healthy.
• Thinking that the next child is safe after an affected child. Each child has a chance of 1 in 4. Earlier children make no difference.
• Giving 1 in 3 for an unaffected child to be a carrier. The chance is 2 in 3, because the affected box is already out of the count.
• Mixing up thalassaemia and sickle-cell anaemia. In thalassaemia, there is too little globin. In sickle-cell anaemia, the globin has one wrong amino acid.

Remember these

• Mendelian disorders come from one gene: haemophilia, colour blindness, thalassaemia, sickle-cell anaemia, phenylketonuria and cystic fibrosis.
• Thalassaemia is autosomal recessive, with too little alpha or beta globin. Sickle-cell anaemia is autosomal recessive, with Glu changed to Val.
• Two carriers: $\tfrac{1}{4}$ affected, $\tfrac{1}{2}$ carriers, $\tfrac{1}{4}$ normal.

Check yourself

Try each one on your own first. If you are stuck, open a hint. Then check with Show the answer.

1. Two normal parents have a child with thalassaemia. What are the genotypes of the parents, and what is the chance that their next child is affected?

2. A woman has sickle-cell anaemia, and her husband is a carrier. What share of their children are expected to be affected?

3. What is the difference between a carrier of thalassaemia and a person with the disease?

4. Why is phenylketonuria described as an inborn error of metabolism?

5. An unaffected sister of a child with an autosomal recessive disorder wants to know whether she is a carrier. What is the chance?

References

• NCERT (2023). Biology, Textbook for Class XII, chapter 4, sections on Mendelian disorders and pedigree analysis.
• Clark M. A., Douglas M. and Choi J. (2018). Biology 2e, OpenStax, chapter 13.2 and chapter 12.