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Phenotype—genotype relationships in monogenic disease: lessons from the thalassaemias

Key Points

  • The inherited disorders of haemoglobin are the commonest genetic diseases.

  • These diseases consist of the structural haemoglobin variants, such as sickle-cell haemoglobin, and the thalassaemias, which result in defective globin production.

  • The β-thalassaemias are causing an increasingly important public health problem throughout tropical countries.

  • The severity and clinical symptoms of the β-thalassaemias are extremely variable.

  • Much of the clinical variability of the β-thalassaemias can be accounted for by the complex interactions of the primary thalassaemia mutations, with various secondary and tertiary genetic modifiers and with environmental factors.

  • A better understanding of the mechanisms that underlie the phenotypic diversity of this disease offers hope for improved genetic counselling and ways towards new treatment strategies.

  • Furthering our understanding of the clinically diverse monogenic disorders should help inform future experimental approaches to unravelling the genetics and pathophysiology of the more common complex diseases.

Abstract

The remarkable phenotypic diversity of the β-thalassaemias reflects the heterogeneity of mutations at the β-globin locus, the action of many secondary and tertiary modifiers, and a wide range of environmental factors. It is likely that phenotype–genotype relationships will be equally complex in the case of many monogenic diseases. These findings highlight the problems that might be encountered in defining the relationship between the genome and the environment in multifactorial disorders, in which the degree of heritability might be relatively low and several environmental agents are involved. They also emphasize the value of an understanding of phenotype–genotype relationships in designing approaches to gene therapy.

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Figure 1: The α-globin gene cluster on chromosome 16 and the β-globin gene cluster on chromosome 11.
Figure 2: Human β-globin mutations.
Figure 3: The global distribution of the β-thalassaemia mutations.
Figure 4: Dominant β-thalassaemia.
Figure 5: The global distribution of the α-thalassaemias.
Figure 6: A summary of the main genetic mechanisms that contribute to the phenotypic diversity of the β-thalassaemias.

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Acknowledgements

This work was supported by the Medical Research Council (MRC) and the Wellcome Trust. I thank my former colleagues in the MRC Molecular Haematology Unit for their help and support.

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DATABASE LINKS

HbF

β-globin

hereditary persistence of fetal haemoglobin

HbE

α-globin

UGT1

HFE

vitamin D receptor

oestrogen receptor

P. falciparum

HLA-DR

TNF

ICAM1

sickle-cell anaemia

ENCYCLOPEDIA OF LIFE SCIENCES

Globin synthesis

Thalassaemias

Selection and common monogenic diseases

Glossary

THALASSAEMIA

Inherited disorder caused by the abnormal production of haemoglobin.

SPLENOMEGALY

Enlargement of the spleen that results in the pooling of red cells and in anaemia.

ANAEMIA

A reduction in the haemoglobin level or red-cell count, which leads to defective tissue oxygenation.

INTERCURRENT ILLNESS

An illness unrelated to the primary disease (for example, infection or malnutrition in a child with thalassaemia).

OSTEOPOROSIS

Reduction in the amount of bone without a change in its composition. Associated with bone pain and fractures.

HAEMOLYTIC ANAEMIA

Anaemia due to reduced red-cell survival.

ERYTHROPOIESIS

Differentiation and maturation of red blood cells.

BILIRUBIN

A principal metabolic product of haemoglobin breakdown.

HYPOGONADISM

Reduction in ovarian or testicular function. This might be primary, due to disease of the ovaries or testes, or secondary due to disease of the hypothalamic–pituitary axis.

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Weatherall, D. Phenotype—genotype relationships in monogenic disease: lessons from the thalassaemias . Nat Rev Genet 2, 245–255 (2001). https://doi.org/10.1038/35066048

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