These disorders manifest only when an individual is homozygous for the disease allele, i.e. both chromosomes carry the mutated gene. In this case the parents are generally unaffected healthy carriers (heterozygous for the disease allele). There is usually no family history, although the defective gene is passed from generation to generation. The offspring of an affected person will be healthy heterozygotes unless the other parent is also a carrier. If carriers marry, the offspring have a 1 : 4 chance of being homozygous and affected; a 1 : 2 chance of being a carrier; and a 1 : 4 chance of being genetically normal. Consanguinity increases the risk of two carriers having a child who has a 25% chance of being affected. The clinical features of autosomal recessive disorders are usually severe; patients often present in the first few years of life and have a high mortality.
Many inborn errors of metabolism are recessive diseases. The commonest recessive disease in the UK is cystic fibrosisnd. The overall incidence of autosomal recessive disorders is about 2.5 per 1000 live births in the UK. Worldwide, diseases such as thalassaemia and sickle cell disease are very common; the frequency of these diseases may be as high as 20 per 1000 births in some populations. Prenatal diagnosis for recessive disorders may be possible by analysing the DNA of the fetus for mutations known in the parents. lists some autosomal dominant and autosomal recessive genetic diseases with their chromosomal localization. Some diseases show a racial or geographical prevalence. Thalassaemia is seen mainly in Greeks, South East Asians and Italians, porphyria variegata occurs more frequently in the South African white population, and Tay-Sachs disease particularly occurs in Ashkenazi Jews.
Genes carried on the X chromosome are said to be Xlinked and can be dominant or recessive in the same way as autosomal genes (Table 2.7). As females have two X chromosomes they will be unaffected carriers of X-linked recessive diseases. However as males have just one X chromosome, any deleterious mutation in an X-linked gene will manifest itself as no second copy of the gene is present.
X-LINKED DOMINANT DISORDERS. These are rare. Vitamin D-resistant rickets is the best known example. Females who are heterozygous for the mutant gene and males who have one copy of the mutant gene on their single X chromosome will manifest the disease. Half the male or female offspring of an affected mother and all the female offspring of an affected man will have the disease. Affected males tend to have the disease more severely than the heterozygous female.
X-LINKED RECESSIVE DISORDERS. These disorders always present in males and only present in (usually rare) homozygous females. X-linked recessive diseases are transmitted by healthy female carriers or affected males if they survive to reproduce. An example of an X-linked recessive disorder is haemophilia A, which is caused by mutation in the X-linked gene for the essential clottin factor, factor VIII. It has recently been shown that in 50 of cases there is an intrachromosomal rearrangement (inversion) of the tip of the long arm of the X chromosome (one break point being within intron 22 of the factor VIII gene).
Of the offspring from a carrier female and a normal male, 50% of the girls will be carriers as they inherit a mutant allele from their mother and the normal allele from their father; 50% of the girls inherit two normal alleles and are themselves normal; 50% of the boys will have haemophilia as they inherit the mutant allele from their mother (and the Y chromosome from their father); 50% of the boys will be normal as they inherit the normal allele from their mother (and the Y chromosome from their father).
The male offspring of a male with haemophilia and a normal female will not have the disease as they do not inherit his X chromosome. However all the female offspring will be carriers as they all inherit his X chromosome. Genes carried on the Y chromosome are said to be Ylinked and only males can be affected. However, there are no known exam pies of Y-linked single-gene disorders which are transmitted.
Occasionally a gene can be carried on an autosome but manifests itself only in one sex. For example, frontal baldness is an autosomal dominant disorder in males but behaves as a recessive disorder in females. Other single gene disorders These are disorders which may be due to mutations in single genes but which do not manifest as simple monogenic disorders. They can arise from a variety of mechanisms including:
TRIPLET REPEAT MUTATIONS: in some genetic diseases, for example myotonic dystrophy, the severity of the disease (such as age of onset) increases down through the generations. This phenomenon is known as ‘anticipation’. In the allele which is mutated and gives rise to myotonic dystrophy it was found that in the 3′ UTR of the gene was a region in which three nucleotides, GeT, were repeated up to about 35 times.
In families with myotonic dystrophy, people with the late onset form of the disease had 20-40 copies of the repeat, but their children and grandchildren who presented with the disease from birth have vast increases in the number of repeats, up to 2000 copies. It is thought that some mechanism during meiosis causes this ‘triplet repeat expansion’ so that the offspring inherit an increased number of triplets. The number of triplets affects mRNA and protein function (although these repeats are not in the coding region of the gene). Diseases such as Huntington’s disease are due to massive triplet repeat expansions which are inherited through the generations.
IPRINTlNG: it is known that normal humans need a diploid number of chromosomes, 46. However the maternal and paternal contributions are different and, in some way which is not yet clear, the fetus can distinguish between the chromosomes inherited from the mother and the chromosomes inherited from the father, although both give 23 chromosomes. In some way the chromosomes are ‘imprinted’ so that the maternal and paternal contributions are different. Imprinting is relevant to human genetic disease because different phenotypes may result depending on whether the mutant chromosome is maternally or paternally inherited. A deletion of part of the long arm of chromosome 15 will give rise to the Prader-Willi syndrome (PWS) if it is paternally inherited. A deletion of a similar region of the chromosome gives rise to Angelman syndrome (AS) if it is maternally inherited. (Probably two different genes are involved in PWS and AS.)
Multifactorial and polygenic inheritance
Characteristics resulting from a combination of genetic and environmental factors are said to be multifactorial; those involving multiple genes can also be said to be polygenic. Measurements of most biological traits, for example height, show a variation between individuals in a population and a unimodal, symmetrical (Gaussian) frequency distribution curve can be drawn. This variability is due to variation in genetic factors and environmental factors. Environmental factors may play an important part in determining some characteristics, such as weight, whilst other characteristics such as height may be largely genetically determined. This genetic component is thought to be due to the additive effects of a number of alleles at a number of loci, many of which can be individually identified using molecular biological techniques, for example studying identical twins in different environments. One such condition that has been studied is congenital pyloric stenosis. This is more common in boys but if it occurs in girls the latter have a larger number of affected relatives. This difference suggests that a larger number of the relevant genes are required to produce the disease in girls than in boys. Most of the important human diseases, such as heart disease, diabetes, and common mental disorders are multifactorial traits.