Genetics, revised edition. Karen Vipond
3.6 Estimation of risk from two homozygote parents
Offspring have a:
• 1 in 1 chance or 100 per cent risk of being affected.
Affected individuals who are homozygous recessive are usually the offspring of one of the above three matings.
There are thousands of autosomal monogenic recessive conditions. Table 3.1 contains a few examples of the most common conditions.
Table 3.1 Common autosomal monogenic recessive conditions
| Condition | Chromosome | Gene | Effect |
| Adenosine Deaminase Deficiency | 20q | ADA | Severe combined immunodeficiency |
| Batten Disease | 16p | CLN3 | Progressive disorder resulting in neuronal death within the brain |
| Congenital deafness | 11p | USH1C | Deafness |
| Cystic Fibrosis | 7q | CFTR | Defective chloride ion transport leading to thickened mucus production |
| Galactosaemia | 9p | GALT | Developmental delay as a result of inefficient metabolism of galactose |
| Gaucher Disease | 1q | GBA | Build-up of fatty deposits on liver, spleen, lungs and brain; anaemia and joint problems |
| Hereditary Haemochromatosis | 6p | HFE | Iron overload due to too much iron being absorbed from the small intestine |
| Maple syrup urine disease | 7q | DLD | Metabolic disorder leading to seizures, failure to thrive and developmental delay |
| Oculocutaneous Albinism | 11q | TYR | Lack of pigment in hair, skin and eyes |
| PKU | 12q | PAH | Increased levels of phenylalanine leading to brain damage |
| Sickle Cell Anaemia | 11p | HBB | Abnormal haemoglobin. Sickle-shaped red blood cells, which lead to the blocking of small blood vessels |
| Spinal Muscular Atrophy | 5q1120 | SMN1IGHMBP2VAPB | Progressive loss of function of motor neurones leading to atrophy of muscles |
| Tay-Sachs | 15q | HEXA | Build-up of fatty deposits in the central nervous system, leading to death |
Additional risks
Everyone carries several ‘faulty’ recessive genes that have no impact on their health. There are many different forms of faulty genes within a population but, because genes are inherited from parents and grandparents, family members will have more similarity within their genes and shared ‘faulty’ genes.
Consanguinity
The risk of developing an autosomal recessive genetic condition is increased in offspring of consanguineous relationships. The term consanguinity derives from the Latin prefix con-, meaning ‘together’, and the word sanguis which means ‘blood’. It describes the marital relationship between two individuals who share a common ancestor. The most common form of consanguinity is the marriage between first cousins, which is encouraged in some cultures.
The children of unrelated parents are at low risk of inheriting two copies of the same faulty or altered allele. The risk of having a child with a birth defect is between 2 and 3 per cent, some of which will be due to a genetic condition. Children of parents who are blood relatives have an increased risk of having a genetic defect. The risk is doubled for parents who are cousins (5 to 6 per cent). The risk of inheriting the same faulty gene from both parents is increased the closer the relationship is between the parents (i.e. the more genes that they have in common) (see Table 3.2).
Table 3.2 Relationships between blood relatives
| Relationship to each ot her | Brothers/sisters Parent/child | Uncles/aunts Nephews/niecesGrandparentsHalf-brothersHalf-sisters | First cousins Half-unclesHalf-auntsHalf-nephewsHalf-nieces |
| Relationship type | First-degree relatives | Second degree | Third degree |
| Proportion of genes that they have in common | Half 50 per cent | Quarter 25 per cent | Eighth 12.5 per cent |
The risk of having an affected child is much higher than 5 to 6 per cent in some families, because parents who are first cousins might also have grandparents who are themselves related.
| ACTIVITY 3.1 |
a. A child who has a recessive genetic condition has two unaffected parents. If the child’s genotype for this disorder is bb, what are the genotypes of the parents?
b. Why do recessive conditions appear to ‘skip’ generations?
AUTOSOMAL DOMINANT INHERITANCE
Autosomal dominant single gene disorders occur in individuals who have a single altered copy of the disease-associated allele. An alteration in only one of the alleles within a gene is enough to cause the disorder. The mutated disease-causing allele can be inherited from either parent.
Alleles encode for the production of a specific protein. When one allele is altered, in that the specific protein is no longer produced, the remaining functioning allele will still continue to encode for the specific protein. In autosomal dominant disorders, the amount of protein being encoded for by the functioning allele is not enough for the body to function normally. In these cases the faulty allele causes a problem for the individual as it is dominant in its effect over the functioning normal allele.
In individuals who possess both alleles in an altered form (homozygous dominant), the disease symptoms are generally more severe. Dominant disease allele homozygotes are quite rare as many conditions appear lethal in the homozygous dominant form.
Rules of autosomal dominant inheritance
• Both males and females are equally affected, and can transmit to both sons and daughters.
• Most affected individuals will have an affected parent. The disease does not ‘skip’ generations.
• In affected families, where one parent is affected, the risk of transmitting the trait to the offspring is 50 per cent.
• If both parents are unaffected, none of the children will be affected.
Inheritance patterns
Affected individuals, who possess a dominant allele, are produced via one of three different types of mating.
1. Two homozygous dominant parents: AA x AA (both parents are affected) (see Figure 3.7).
Figure 3.7 Two homozygous dominant parents
Key: A = dominant affected allele, a = recessive normal allele.
The estimation of risk of an affected offspring is 100 per cent (see Figure 3.8).
Figure 3.8 Estimation of risk from two homozygous dominant parents
Offspring have a:
• 1 in 1 chance or 100 per cent risk of being affected.
2. Two heterozygous parents: Aa x Aa (both parents are affected) (see Figure 3.9).
Figure 3.9