Types of Disorders and the Conditions Caused

Due to the complex nature of genetics and heredity, there are thousands of possible combinations of genetic mutation and therefore many different conditions and diseases that may result from a genetic mutation.

However, the types of genetic disorder broadly fall into three categories.

• Monogenic disorders
• Multifactorial disorders
• Chromosomal disorders

Monogenic disorders

When a mutation occurs within a single gene present within all cells of the body, this is known as a monogenic disorder (single-gene disorder). This mutation can be present in a single chromosome or both chromosomes inherited from each parent.

Current estimates suggest that more than 10,000 human diseases are known as monogenic diseases and according to the World Health Organisation, the global occurrence of single-cell diseases at birth is approximately 1 in every 100.

Monogenic disorders typically affect the quality and lifespan of the individual and most commonly cause birth defects and intellectual, sensory or motor disability. They affect millions of people across the globe today.

Some of the most common monogenic disorders include:

• Sickle Cell Disease
• Cystic Fibrosis
• Polycystic Kidney Disease
• Tay-Sachs Disease
• Thalassaemia Haemophilia
• Huntington’s Disease
• Congential (present at birth) deafness
• Duchenne muscular dystrophy

Every human is made from two sets of the same gene one from the mother and one from the father. They sit at the same point in the DNA molecules and are known as alleles. The type of disease which develops is determined by the function that the modified or damaged gene performs.

The three main classifications of genetic disease broadly refer to the way the mutation is transmitted.

Dominant disease
Dominant diseases (also known as autosomnal dominant diseases) are monogenic disorders in which damage occurs to a single copy of a gene. One parent will have the damaged gene and so the chances of the child inheriting the disease will be 50%.

Recessive disease
A monogenic disorder in which both copies of a particular gene are damaged in both parents. The chance of the child being born with an autosomnal recessive disease is 25%.

X-linked genetic disorders
When a defective gene is located on the X chromosome (the sex chromosome) it may create an X-linked monogenic disorder. X-linked alleles can be dominant or recessive. Males are more likely to be affected by X-linked recessive disorders because they have X and Y sex chromosomes. Whereas females have two X chromosomes and it is far less likely that two altered copies of the gene will be present.

Multifactorial disorders

Multifactorial disorders (also known as complex genetic disorders) arise when gene mutations combine with environmental factors. These mutations occur in more than one gene in all cells of the human body. Disease occurs when the small inherited differences in genes act together with external factors such as chemical exposure, dietary influences, certain medications, and alcohol or drug use.

These include but are not limited to:

• Heart disease
• Diabetes
• Late-onset Alzheimer’s disease
• Spina bifida
• Coronary artery disease
• Autism spectrum disorder
• Arthritis
• Many cancers

Because conditions such as diabetes, heart disease and obesity are multifactorial, i.e. a combination of inherited genes and environment, clinicians agree that this is an important area for study so that a greater understanding of why and how these diseases develop can be gained as well as how they can be prevented.

The different types of gene mutations

Genetic mutations can be categorised into seven types whether they occur in a single gene or across a number of genes.

Insertion: When the number of DNA bases in a gene changes this is known as insertion and occurs when a piece of DNA is added to the DNA code. This can cause proteins to malfunction.

Duplication: If a short sequence of DNA is copied (once or more than once), this is referred to as duplication and can change the function of the subsequent protein.

Repeat Expansion: Short DNA sequences that repeat a number of times in a row are known as nucleotide repeats. Examples of repeat expansion are named according to the number of times a DNA sequence is repeated. For example, a trinucleotide consists of 3-base-pair sequences and a tetranucleotide repeat is made from 4-base-pair sequences. Once again, a mutation of this type can cause the resulting protein to function incorrectly.

Deletion: When a DNA base is changed because a piece of DNA is removed, this is known as a deletion and can also have an impact on the function of a resulting protein. Small deletions can take away a single base pair or a few base pairs in a gene. Larger deletions may remove a whole gene or a number of neighbouring genes.

Frameshift mutation: This occurs when the addition or loss of a DNA base changes a gene’s reading frame. The reading frame is made of three bases which provide code for one amino acid. If the grouping of these bases is shifted, then changes can occur to the code of the amino acids, leading to the resulting protein functioning incorrectly.

Missense mutation: When an amino acid is substituted for another in one DNA base pair to make a protein, this change is known as a missense mutation. It can completely or partially alter the function of the protein within the cell.

Nonsense mutation: When a change occurs in one DNA base pair and creates a signal to stop creating a protein, this is called a nonsense mutation. The result is a shortened protein which may not work properly and sometimes not at all.

Chromosomal disorders

Chromosome abnormalities occur when a portion of chromosomal DNA is missing, additional or structurally irregular.

Missing or extra DNA:
People have two copies of each gene which they inherit one from the mother and one from the father. Whenever there is an excess or deficiency of genes on a chromosome it is known as a Copy Number Variation (CNV).

If part of a chromosome is missing or deleted it may result in conditions such as Prada-Willi syndrome or Wolf-Hirschhorn syndrome. The first is caused by an absence or non-expression of particular genes in chromosome 15, and the second is caused by a partial deletion located in chromosome 4.

When a person loses one complete copy of a chromosome from a pair, this is known as monosomy (related to conditions such as Turner syndrome). Partial monosomy refers to cells possessing one chromosome from a pair as well as part of the second chromosome.

Chromosome duplication: 
Duplication causes excess genetic material to be created. Down’s Syndrome occurs as a result of an extra copy of chromosome 21. This creates a genetic abnormality despite the fact that no individual genes on the chromosome are unusual.

Such genetic mutations are known as trisomy disorders i.e. there are three copies of a chromosome rather than two. Alongside Down’s syndrome, Patau syndrome and Edward syndrome are two of the most common forms of trisomy

DNA structural changes without loss of material: 
When one part of a chromosome is transferred to another chromosome, this is called translocation. A reciprocal translocation is when two parts of two different chromosomes swap over. A Robertsonian translocation refers to what occurs when a complete chromosome attaches to another one (at the centromere – the point at which a chromosome appears constricted and where the cell’s spindle fibres attach). When a chromosomal translocation causes parts of chromosomes 9 and 22 to swap, this may cause chronic myeloid leukaemia.

If a chromosome breaks away, becomes inverted and then reattaches, it is called an inversion. Chromosome 9 is the most common place where this happens in humans. Although it is generally considered to have no harmful effects, it can increase the risk of miscarriage and infertility for some people.

Structural changes with loss of genetic material: 
When two chromosome pieces fuse abnormally (including the centromere) this results in dicentric chromosomes. These structures are unstable, often having lost genetic material. Dicentric chromosomes are often present in sufferers of malignant diseases such as myelodysplasia and acute myeloid leukaemia.

Rings:
Rings occur when part of a chromosome breaks off and forms a circle or ring. This can happen either with or without the loss of genetic material. Epilepsy is caused when a ring forms with one copy of chromosome 20. When rings occur with chromosomes 14 or 13, this may cause mental retardation and unusual facial features. Ring chromosome 15 is linked to mental retardation, dwarfism and microcephaly.

When a chromosome loses an arm but it is replaced with an exact copy of the other arm, this is known as an isochromosome. One example is Pallister-Killian mosaic syndrome which is caused when an additional chromosome formulates out of two copies of the shorter arm of chromosome 12. This means there are four copies of this part of chromosome 12 within these cells instead of the normal two.