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Inherited causes of disease in populations

Genetics: Inherited causes of disease in populations

GENES AND DISEASE IN POPULATIONS

Some 4000 inherited diseases are known to be associated with mutations in single genes. These diseases are known as single-gene or Mendelian diseases because they show recognisable patterns of inheritance consistent with those discovered by Mendel (see next section).

Some genetic diseases are caused not by mutations in single genes but by larger-scale alterations involving whole chromosomes or large pieces of chromosomes. Perhaps the best known of these chromosomal disorders is Down syndrome, which is caused by the presence of an extra copy of chromosome 21 (trisomy 21). Chromosomal disorders usually arise as a result of mistakes that occur during the cell divisions that give rise to sperm and egg cells.

Individually, 'genetic diseases' caused by chromosomal alterations or single-gene mutations are rare, but collectively these disorders are relatively common (table 1), with a combined birth prevalence of around 1-2%. It has been estimated that a district with a population of 250,000 will have about 1000 living patients suffering from such diseases.

Table 1: Numbers of people with some single-gene and chromosomal diseases (excluding non-recurrent diseases such as Down's Syndrome).

Numbers are based on a typical primary care organisation area with 3,000 births annually and a total population of 250,000; Non-recurrent genetic diseases such as Down syndrome are not included.

Condition

Birth frequency

New cases per year in district

No. living patients in district

No. unrelated families

No. relatives at > 1 in 10 risk of being affected or carriers

Autosomal dominant disorders

Huntington's chorea

1/3,000

1.0

18

14

162

Familial polyposis coli

1/8,000

0.4

8

6

50

Adult polycystic disease of kidneys

1/1.000

3.0

55

43

330

Familial hypercholesterolemia

1/500

6.0

394

355

2360

Tuberous sclerosis

1/12,000

0.25

19

12

70

Neurofibromatosis

1/2,500

1.2

69

30

280

Von-Hippel Lindau disease

1/100,000

0.03

1.3

0.8

10

Retinitis pigmentosa

1/5,000

1.6

36

32

220

Bilateral retinoblastoma

1/30,000

0.1

8

5

230

Myotonic dystrophy

1/7,000

 

 

 

 

Autosomal recessive disorders

Cystic fibrosis

1/2,000

1.5

25

20

50

Adrenal hyperplasia

1/10,000

0.3

23

20

46

Friedreich's ataxia

1/54,000

0.06

2

1.7

4

Spinal muscular atrophy

1/10,000

0.3

3

2

46

Phenylketonuria

1/13,000

0.2

18

15

36

Usher's syndrome

1/27,000

0.1

9

6

18

Sickle cell disease in Afro-Caribbeans

1/250

Estimates: actual figures depend on ethnic characteristics of the population and uptake of screening and offer of prenatal diagnosis

Thalassaemia

 

in Cypriots

1/140

in Indians

1/1,000

in Pakistanis

1/300

X-linked recessive disease

Duchenne/Becker muscular dystrophy

1/9,000

0.3

8

7

78

Haemophilia A and B

1/20,000

0.15

11

7

66

X-linked retinitis pigmentosa

1/7,000

0.43

23

14

70

Other X-linked eye disorders

1/7,000

0.43

23

14

70

Fragile-X syndrome

1/4,000

0.75

52

49

360

Other forms of X-L mental disorders

1/4,000

0.75

52

49

360

Chromosomal disorders

Unbalanced translocations

1/2,000

1.5

16

16

60

TOTAL

1/144

20.8

987

730

5056

Notes
Birth frequency: many of these birth frequencies are changing, and those listed here refer to the most recent figures. For example, the birth frequency of Duchenne muscular dystrophy has fallen from 1 in 6,000 to 1 in 9,000 as a result of genetic counselling. The birth frequency of thalassaemia in Cypriots has fallen to 0, as a result of antenatal screening, prenatal diagnosis and the offer of selective termination of pregnancy.

Data taken from: Royal College of Physicians of London. Purchasers' guidelines to genetic services in the NHS. An aid to assessing the genetic services required by the resident population of an average health district. London Royal College of Physicians 1991.

In addition, susceptibility to the common diseases of middle and later life is known to have a genetic component. Here, the association between gene variants and disease is less clear-cut: several genes are involved and the genes interact in complex ways with each other and with environmental and lifestyle factors to determine whether disease will develop. Such diseases are often termed 'multifactorial'.

Sometimes, however, there are families in which several members are affected by the same common disease, often at any early age, and the disease shows a Mendelian inheritance pattern, suggesting the existence of a single mutation that confers a high risk of disease in that family. These Mendelian subsets of common disease include conditions such as familial hypercholesterolaemia, a dominantly inherited condition that is characterised by a build-up of cholesterol and a high risk of premature cardiovascular disease. The disease is caused by mutations in a gene encoding a cell-surface receptor for a blood lipoprotein. About 1 in 500 people are thought to carry the mutant gene. In the population as a whole, fewer than 1 in 20 of people who develop atherosclerosis carry a strongly predisposing single-gene mutation; in general, single-gene subsets of common diseases account for a maximum of about 5% of the total burden of disease.

Cancer
Cancer is often described as a 'genetic disease', in the sense that it is caused by genetic alterations. It occurs when the DNA instructions in a cell are damaged or altered in such a way that the cell escapes the normal regulatory mechanisms that should control its behaviour (figure 8). Such cells may multiply unchecked to form tumours, and acquire the ability to migrate to, lodge and grow in distant sites of the body (metastasis). The genetic alterations that lead to cancerous behaviour are somatic alterations, however. That is, they occur in the somatic cells of the body and are not passed on to the next generation.

Cancer, like coronary heart disease or diabetes, is a multifactorial disease; that is, predisposition to cancer is affected both by inherited and environmental/lifestyle factors. Most of the common genetic variants that predispose to cancer are unknown. However, there are some germ-line mutations (that is, mutations that are present in all the cells of the body including the sex cells) that predispose people who carry them to developing cancer, and these are heritable. In people who inherit these mutations, all the cells of the body have essentially taken one step along the path to tumour formation, making eventual development of cancer more likely. Examples of strongly predisposing genes are the BRCA1 and BRCA2genes, which when mutant are associated with hereditary breast cancer. BRCA1 or BRCA2 mutations account for fewer than 5% of breast cancer cases.

© Public Health Genetics Unit 2006