The following points highlight the three main types of inheritance with its characteristics. The types are: 1. Autosomal Dominant Inheritance 2. Autosomal Recessive Inheritance 3. Polygenic Disorders and Multifactorial Inheritance.
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Type # 1. Autosomal Dominant Inheritance:
Farabee in 1905 gave the first description of a pedigree showing brachydactyly (short fingers and toes), an autosomal dominant trait. Some more examples are porphyria, Huntington’s chorea (a degenerative disease of nerve cells), Polydactyly, retinoblastoma (a malignant eye tumour of children) and others. The dominant transmission of a trait is also called manifest inheritance because whenever a gene is present its effect is produced.
Characteristics of Autosomal Dominant Inheritance:
a. The trait appears in every generation.
b. An affected child must have at least one affected parent.
c. About one half of the offspring of an affected person are affected; the recurrence risk is 50% at each conception.
d. Both male and female persons are affected.
e. Individuals who appear normal do not transmit the trait to their offsprings.
Penetrance and Expressivity in Dominant Traits:
Penetrance is a quantitative term and denotes the fraction of individuals carrying a gene that show the specific phenotype. Sometimes a pedigree shows absence of an affected person expected in a generation. The trait has skipped a generation because a heterozygous person is showing the normal phenotype.
The gene though present was not penetrant. A gene is said to have low penetrance when it does not manifest in a large fraction of the individuals. In other cases of dominant inheritance the gene may manifest in all the heterozygotes, but the degree of clinical manifestation may be different. This is called variable expressivity.
Sex-Linked Dominant Inheritance:
The X-linked dominant trait shows itself in hemizygous males and heterozygous females. All the daughters of an affected male also show the trait. An affected mother produces normal and affected children, both male and female in the ratio 1:1.
In X-linked dominant inheritance the males are affected more severely than females. For example dermal hypoplasia is apparently lethal in males. In females it produces characteristics like cutaneous pigmentation and papillomas, a few more skin defects and atrophy. Hypophosphatemia is also an X-linked dominant disease.
Characteristics of X-Linked Dominant Inheritance:
a. The affected male transmits the trait to all his daughters but not to the sons.
b. When affected females are homozygous, they transmit the trait to all their children of both sexes.
c. When affected females are heterozygous, only 50% of their children of both sexes have a chance of being affected.
d. Affected females transmit the trait to their progeny in a manner similar to that in autosomal dominant inheritance.
Type # 2. Autosomal Recessive Inheritance:
In recessive inheritance the offspring inherits a trait from both parents. An albino offspring is born to parents who are normal in appearance, but each carries an albino gene (heterozygous Aa). If each person had married a normal (AA) person, no albino would appear in their progeny.
Abnormal recessive genes are thus transmitted for many generations through heterozygotes. Their existence is found out only when two heterozygotes marry and the homozygote appears, the ratio 1 normal: 1 affected.
The rare recessive conditions are more easily detected through consanguineous marriages which involve matings between blood relatives. In some parts of India consanguineous marriages are common, and the incidence of rare recessive disorders is also high. Microcephaly (small head), phenylketonuria, galactosemia and others are due to recessive genes.
Children affected with galactosemia are not able to metabolise galactose, which is a component of the milk sugar lactose. Normally, galactose is converted into glucose phosphate by the enzyme phospho-galactose uridyl transferase present in the liver. Homozygous children lack this transferase enzyme.
The heterozygotes have an enzyme level intermediate between that of the normal and affected homozygotes. Affected babies have severe vomiting and diarrhoea, and consequently suffer from undernourishment and fail to grow normally.
The condition can be treated if after birth the babies are kept on a lactose- and galactose-free diet, and are given specially formulated milk substitutes. Untreated children accumulate toxic amount of galactose- 1-phosphate which lead to cataract in the lens of the eye, damage to liver and kidney tubules and some mental retardation.
Characteristics of Autosomal Recessive Inheritance:
a. The trait is visible only in sibs, but not in their parents or other relatives.
b. The parents of an affected person may have been blood relatives (consanguineous).
c. About one fourths of the children of such parents are affected; the recurrence risk at each birth is 25%.
d. Both male and female children have equal chance of being affected.
Sex-Linked Recessive Inheritance:
This type of inheritance is mostly X-linked and predominantly males are affected (due to hemizygous condition). Heterozygous females are carriers and are expected to produce affected and normal sons in the ratio 1: 1.
An affected male never produces an affected son. A famous example is haemophilia, the gene for which was passed on to the descendants of Queen Victoria. Some other examples are red green colour blindness, G6PD, Lesch-Nyhan syndrome and muscular dystrophy.
In haemophilia or bleeding disease, as it has been known for centuries, the blood is not able to clot within 4 to 8 minutes like the normal blood. Instead it takes an hour or more to clot. Failure to clot is due to the absence of a coagulation factor which is present in normal blood. Two different X-linked loci are involved in haemophilia.
One causing the more prevalent haemophilia A, the other giving rise to haemophilia B or Christmas disease (so called because it was first noted in a person named Christmas). The coagulation factor which is absent in the A form of haemophilia is called antihaemophilic globulin (AHG), while in the B form the deficient factor is called plasma thromboplastin component (PTC).
The affected individuals rarely live beyond the first decade, although with treatments available now they may live longer. The survivors still have problems due to internal bleeding in the joints. Being an X-linked recessive disorder, males are more frequently affected.
Haemophilia seems to have started in Britain’s royal family through a mutation in one of Queen Victoria’s parents. One of Victoria’s four sons was affected and produced a carrier daughter. Out of the two sons of this daughter, only one was a haemophiliac, the other was normal. Out of the 5 daughters of Victoria, two turned out to be carriers and produced in all 3 carrier daughters and 3 affected sons. The 3 carrier daughters further produced 6 carrier daughters and 5 haemophiliac sons.
Characteristics of X-linked Recessive Inheritance:
a. Males are affected more frequently than females.
b. When the female parent is carrying the trait then 50% of her sons have a chance of being affected, and 50 % of the daughters would be carriers but phenotypically normal.
c. The trait is transmitted through several generations by carrier females.
d. The affected male parent cannot transmit the trait directly to his sons.
Type # 3. Polygenic Disorders and Multifactorial Inheritance:
Some normal traits like height and intelligence, and disorders like cleft lip/palate, club foot, some allergies, diabetes mellitus, hydrocephalus, pyloric stenosis and others are inherited through polygenes and may be influenced by extraneous factors including drugs.
The polygenes have small additive effects. The clinical features are due to cumulative effects of all the polygenes as well as other factors. For this reason the term multifactorial inheritance is preferred. In most cases the exact number of genes involved is not known.
The congenital conditions of cleft lip (CL) as well as of cleft lip with cleft palate (CLP) are found to be associated with a large number of syndromes (listed in Nora and Fraser, 1974). Some of these are related to chromosomal aberrations, a few are caused by mutant genes, the rest appear to be multifactorially determined.
An individual may have a cleft lip (Fig. 21.4) due to defective closure of the primary palate in embryological development, or a cleft palate, due to faulty closure of the secondary palate; or both cleft lip and cleft palate (CLP) may be present in the same person.
Studies on families have shown that cleft lip ± cleft palate are frequently associated with syndromes which are inherited as autosomal dominant, autosomal recessive, or X-linked conditions. It has also been revealed that some genes will cause cleft lip and cleft palate in some individuals, while in some other individuals they cause cleft palate.
The combined influence of genetic and environmental factors have established multifactorial inheritance for CLP. More males than females are affected by CLP. The recurrence risk is higher in sibs of female pro-bands. The condition is more common among Orientals. Rarely cleft palate occurs in absence of cleft lip. This is more common in females than males, and in children of older mothers.