In general, genetic disorders can either be problems with whole or part of a chromosome, or problems at the level of the gene. The latter group divides into the autosomal and sex chromosome disorders.
There are 44 autosomes in Man comprising 22 homologous pairs of chromosomes. Upon each chromosome, the genes have a strict order, each gene occupying a distinct locus in unison with its counterpart of maternal or paternal origin.
Alleles are alternative forms of genes which arise by mutation, normal types being referred to as 'wild'. If both members of a gene pair are identical then the individual is described as being homozygous, whereas if they are different, they are said to be heterozygous.
Gene-specified characteristics are termed traits. There are three types of disorder depending on the expression of traits:
autosomal dominant: trait is seen in the heterozygote
autosomal recessive: trait is seen only in homozygote
autosomal codominant: effect of both alleles seen in heterozygote
types of autosomal inheritance
Autosomal dominant inheritance is characterised by manifestation of the disorder in either the homozygote or the heterozygote that carries the allele.
There would be expected to be a segregation ratio of 1:1 in the offspring of an affected heterozygote and a normal partner. Hence, more offspring tend to be affected than in autosomal recessive disorders.
As with autosomal recessive disorders, both sexes may be affected, but, there may be different degrees of severity - variable expression - between individuals.
Rarely, an individual with a mutant gene may have a normal phenotype. This is termed 'non-penetrance'. The gene and trait may still be transmitted to the individual's offspring.
About 2200 autosomal dominant traits are known to date. They tend to be defects of carrier, structural or receptor proteins. The most common autosomal dominant diseases are:
disorder incidence/1000 births
autosomal recessive disorders
A list of some diseases that are associated with autosomal recessive inheritance is presented below:
endemic goitrous cretinism
familial amaurotic idiocy
glycogen storage disease
dominant otosclerosis 3
familial hypercholesterolaemia 2
adult polycystic kidney disease 1
multiple exostoses 0.5
Huntington's disease 0.5
myotonic dystrophy 0.2
congenital spherocytosis 0.2
polyposis coli 0.1
dominant blindness 0.1
dominant congenital deafness 0.1
autosomal codominant inheritance
Autosomal codominant inheritance is defined by the ability to detect either or both of two alleles in an individual. The two fragments can also be followed through the family pedigree. Hence, the pedigree pattern of human codominant traits resembles that of autosomal dominant inheritance except that both alleles can be distinguished.
Some examples of human codominant traits include:
blood groups: ABO, Duffy, Kell, Kidd, MNS, Rhesus
red cell enzymes: acid phosphatase, adenylate kinase
serum proteins: haptoglobulins
cell surface antigen: human leucocyte antigen (HLA)
If mutations of genetic material are large enough to be seen under the light microscope, they are called chromosomal aberrations.
They can be divided into structural and numerical abnormalities.
The smallest visible alteration to a chromosome that is visible is approximately four million base pairs.
Chromosomal disorders are very common, affecting 7.5% of all conceptions, yet, due to spontaneous miscarriage, their livebirth frequency is only 0.6%. Hence, amongst spontaneous early miscarriages, 60% have a chromosomal abnormality, usually that of trisomy, 45,X, or triploidy.
Disorders of this kind may result from germ cell mutations in the parent that have been passed on to sex chromosomes or autosomes in the affected individual. Alternatively, chromosomal aberrations may arise out of somatic mutation in the generation affected.
Generally, autosomal chromosomal disruptions are more severe than sex chromosome abnormalities. Similarly, deletions are more deliterious than duplications
types of chromosomal disorder
Chromosomal disorders may be numerical, structural or more complex
A chromosomal number that is an exact multiple of the haploid number of 23 chromosomes in humans, and exceeds the diploid number of 46 chromosomes is called polyploidy. A state with a chromosomal number not an exact multiple of haploid's is called aneuploidy.
Examples of numerical disorders are:
92, XXYY tetraploidy
69, XXY triploidy
47, XX, (21) trisomy 21
47, XY, (1 trisomy 18
47, XX, (16) trisomy 16
47, XX, (13) trisomy 13
47, XXY Klinefelter's syndrome
47, XXX Trisomy X
45, X Turner's Syndrome
49, XXXXY Klinefelter's variant
Structural abnormalities are a consequence of chromosomal breakage. Once broken, there is the possibility that repair may join two unrelated sections of chromosome. The spontaneous mutation rate is 1 per 1000 gametes. Breakage is facilitated by ionizing radiation, mutatogenic chemicals and some rare inherited conditions.
A number of types of structural aberration are recognized:
translocation - the transfer of chromosomal material between chromosomes. Three subtypes are recognized according to which region of the chromosomes swap. Often, the carrier with a 'balanced translocation' is not affected, but offspring are affected.
deletion - where this occurs at both ends of a chromosome, a ring chromosome can result.
duplication - the presence of two copies of a segment of chromosome, often with little harmful consequences.
inversion - breakage at two ends of a chromosome with a rotation and rejoining of the part inbetween so that it lies the wrong way around. There is an increased risk of chromosomally imbalanced offspring. Carriers may appear normal.
isochrome - a chromosome which has deletion of one arm and duplication of the other.
centric fragments - small, remaining material left after translocations
Sex linked disorders are due to alterations in the normal sex chromosomes of the sufferer.
Normally, the female complement is two X sex chromosomes. One is derived from each parent and one of the pair is also randomly inactivated by a process called lyonization at an early developmental stage.
In contrast, a male has the XY sex chromosome constitution and so has only one copy of each X-linked gene. The Y chromosome contains important male determinants.
The family pedigree of sex-linked disorders depends on which sex chromosome carries the mutant gene, and whether the trait is dominant or recessive. Some autosomal traits may mimic sex-linked diseases.
types of sex-linked disorder
Sex-linked disorders can be dominant or recessive; in the former they will be present in women as well as men; in the latter their occurrence in women is rare.
X-linked recessive disorders
Some features of X-linked recessive inheritance are:
only males are affected
there is no variation in expression, the disorder always follows a typical course
heterozygous females are clinically unaffected but carry the mutant gene
only rarely will a female manifest the signs of an X-linked disease; this is usually due to atypical lyonization, a new mutation in the other X chromosome, a carrier with Turner's syndrome, or X-autosome translocation
milder signs of X-linked disorders may evolve in the female due to normal lyonization
Approximately 290 X-linked recessive conditions are known, the following are the most frequently encountered:
red-green colour blindness
fragile X-linked mental retardation
non-specific X-linked mental retardation
Duchenne muscular dystrophy
Becker muscular dystrophy
Haemophilia A (factor VIII)
Haemophilia B (factor IX)
X-linked dominant disorders
X-linked dominant disorders are characterised by:
expression in both sexes, but with a greater incidence in females due to the greater number of X chromosomes
the female may be homozygous or heterozygous for the affected gene - this can only be elucidated from the family pedigree - while the male can only be heterozygous
the pedigree mirroring that of autosomal dominance. The only difference is that a positive father will give the condition to all of his daughters, but not his sons, whereas a positive female will transmit the trait to half of her sons and half of her daughters
affected males having a uniform severity of disorder, while females are affected to different degrees
Presently, there only a few known human X-linked dominant traits. With the exception of the Xg blood group, all are rare. Examples are:
Xg blood group
vitamin D resistant rickets
Pseudohypoparathyroidism represents one of the difficulties in determining linkage; the apparent lack of transmission from male to male is now thought to be secondary to male hypofertility, and the disease has been reclassified as autosomal dominant.
Pedigree patterns do not permit the diagnosis of a multifactorial trait as the phenotype is dictated by the action of multiple genetic loci and the environment.
Autosomal or sex-linked single gene conditions generally produce distinct phenotypes, said to be discontinuous: the individual either has the trait or does not. Multifactorial traits, alternatively, may be discontinuous or continuous.
With multifactorial discontinuous traits, the risk in the affected family is elevated relative to the rest of the population, but falls with more distant relationship to the affected individual within the family.
Continuous multifactorial traits present as a spectrum of gradation of the trait within a population: this is how normal human characteristics are determined.
Twin concordance and family correlation studies are required if multifactorial inheritance is suspected.
A prime example of multifactorial inheritance is spina bifida. Geographical differences within the UK have suggested a genetic influence related to Celtic descent. Seasonal variation in incidence, and the greater incidence in lower social classes, suggest that an environmental influence is also acting
continuous multifactorial traits
Continuous multifactorial traits determine the vast majority of usual human characteristics. By definition, these traits have a continuously graded distribution.
Typically the distribution of the trait is Gaussian, the majority of individuals having values around the mean value.
There is a tendency for siblings to have gradations of these traits that are 0.71 correlated, due to the influence of genetic loci, with their mid-parents' value. Hence, the value of an individual's trait over successive generations regresses towards the mean.
Examples of continuous multifactorial traits include height, weight, skin colour, IQ, red cell size and blood pressure.
discontinuous multifactorial traits
Discontinuous multifactorial traits are dependent on the balance of gene interactions. Once a certain number of genes have become underactive, a threshold level is passed and the trait, usually a congenital malformation, will become evident. Beyond the threshold, the greater the frequency of underactive genes, the greater will be the severity of the trait.
The further the relationship of relatives from an affected individual, the lesser will be the proportion of underactive genes, and the lesser the probability that the threshold for trait manifestation will have been exceeded.
Some multifactorial traits show an overt sex bias. This is accounted for by a different threshold for disease appearance in only one sex. For example, pyloric stenosis affects 5 in 1000 males and only 1 in 1000 females.
Common examples of discontinuous multifactorial traits are:
cleft lip and palate
congenital right heart disease
neural tube defects
common adult diseases:
In digenic disorders two genes interact to produce a disease phenotype.
Often the main mode of inheritance is simple Mendelian with another gene modulating the severity of the disease. A good example is the variability of cystic fibrosis in patients with the same deletion mutation at position 508 in the CFTR gene.
The first true digenic disease may be some forms of limb-girdle muscular dystrophy.