Inheritance Patterns for monogenic genetic disorders

Explaining inheritance patterns for monogenic genetic disorders

Monogenic genetic disorders occur as a direct consequence of a single gene being defective. Such disorders are inherited (passed on from one generation to another) in a simple pattern according to Mendel's Laws. As such, these disorders are often referred to as Mendelian disorders. However, many disorders are not inherited in this pattern. These include disorders due to more than one gene (polygenic disorders), those caused by mutations in non-nuclear mitochondrial genes (such as Leber's atrophy) and nucleotide repeat disorders (such as myotonic dystrophy). 

You may want to consult the Introduction to Genetics page at this point before proceeding. The glossary may also be useful. 

Autosomal Dominant Inheritance 

Monogenic autosomal dominant disorders occur through the inheritance of a single copy of a defective gene found on a non-sex chromosome (remember, we each have two copies of each gene, one from each parent). The single defective copy is sufficient to over-ride the normal functioning copy, resulting in abnormal protein functioning or expression. Autosomal dominant disease include many of the serious and more common genetic disorders of adult life, such as polycystic kidney disease and Huntington's Disease.

In the diagram below, the disorder-causing allele (version of gene) is marked "D" and the normal copy "n". Observe how the father's single "D" causes the disorder to occur in him as well as 50% of his children (assuming the mother does not carry a copy of this gene). Note also that the occurrence of the disorder in his children is not affected by the sex of his children. 

 

Picture of dominate gene in family tree 

 

Autosomal Recessive Inheritance

A single gene also causes monogenic autosomal recessive disorders. But for the disorder to occur, both copies of the gene need to be defective. If just a single copy is inherited, the single functional copy is sufficient to over-ride the defective copy and the individual is not affected by the disorder, but is rather a carrier of the condition. Each of us, usually in ignorance of the fact, is a carrier for about six conditions. High frequencies of recessive disorders in a particular population are usually due to historical factors. Such is the case in sickle-cell anaemia, Tay-Sachs disease and cystic fibrosis, all of which are more common in some racial groups than in others. The origin of such variations is thought to lie in the relative benefits conferred by the carrier state in certain circumstances. For example, a single copy of the defective sickle-cell gene grants some protection against malaria, while a single copy of the cystic fibrosis gene offers some protection against cholera. 

In the diagram below, the disorder-causing allele (or version of gene) is marked "d" and the normal copy "N". Observe how both parents are carriers. In this example, the children have a one in four chance of inheriting both defective copies (and the disorder), a one in two chance of being a carrier (heterozygous for the defective gene) and a one in four chance of being neither affected nor a carrier. Note that the occurrence of the disorder is not affected by the sex of the child.

 

Picture of recessive gene family tree 

 

X-Linked Inheritance

X-linked disorders are those in which the defective gene lies on the X sex chromosome. We inherit the sex chromosomes along with the other 44 (22 pairs) of non-sex chromosomes from our parents. If we inherit two copies of the X chromosome, we're female; an X and a Y, and we're male. X-linked disorders are most common in males as there is no second X chromosome carrying the normal copy to compensate. In males therefore a recessive gene can cause a genetic disorder. Females are less likely to be affected as they have the non-affected X chromosome as well. However, as only one X chromosome is active in each female cell at a time (one is switched off due to a process called Lyonisation), patches of affected tissue or organs can occur in females.  Typical examples of X-linked disorders include haemophilia A, Duchenne muscular dystrophy. In such examples the sons of a non-carrier father and a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.

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