Genetic disorders: pedigree and Mendelian disorders

Controlled crosses are impossible in humans, so inheritance of a trait is traced through a family tree over several generations; this is pedigree analysis, and it helps in genetic counselling.

Mendelian disorders are caused by a change in one gene and are inherited according to Mendel's rules. They can be autosomal or sex-linked, dominant or recessive; examples are colour blindness, haemophilia, sickle-cell anaemia, cystic fibrosis, thalassemia and phenylketonuria.

Haemophilia is sex-linked recessive: one protein of the clotting cascade is affected, so a small cut may bleed without stopping. A heterozygous (carrier) female can pass it to sons. An affected female is very rare, as her mother must be at least a carrier and her father haemophilic. Queen Victoria's family had many haemophilic descendants because she was a carrier.

Colour blindness, a sex-linked recessive disorder, results from a defect in the red or green cone cells of the eye. About 8 per cent of males have it, whereas among females the figure is only about 0.4 per cent, since a female is affected only if both her X chromosomes carry the allele.

Sickle-cell anaemia is autosomal recessive. Only HbˢHbˢ individuals show the disease; HbᴬHbˢ heterozygotes are unaffected carriers who can pass it on.

It is caused by a single base change in the codon, GAG → GUG, which puts valine (Val) in place of glutamic acid (Glu) at position six of the beta-globin chain. At low oxygen tension the altered haemoglobin polymerises, and the red cells become elongated and sickle-shaped.

Phenylketonuria is an autosomal recessive inborn error of metabolism. The affected person lacks the enzyme that converts phenylalanine to tyrosine, so phenylalanine builds up and is converted to phenylpyruvic acid and related compounds; their build-up in the brain causes mental retardation, and poor kidney absorption leads to their excretion in urine.

Thalassemia, an autosomal recessive blood disease, results from a mutation or deletion that lowers the synthesis of one of the globin chains, leading to abnormal haemoglobin and anaemia. In α-thalassemia the genes involved are HBA1 and HBA2, a closely linked pair on chromosome 16; β-thalassemia involves one gene, HBB, on chromosome 11.

Thalassemia is a quantitative problem (too few globin molecules are made), whereas sickle-cell anaemia is a qualitative problem (a globin that works incorrectly is made).