Dr Maite Tome, consultant cardiologist at the Heart Hospital in London, talks about the genetics of the cardiomyopathies
We look like our parents:sometimes even we can identify unique features from our grandparents in ourselves. So we all know about transmission and inheritance.
However, scientific knowledge about how the transmission of the information happens in the human body is only recent.
The discipline of genetics was born with the discovering of the basic structure of the genetic code, the DNA (desoxyribose nucleic acid) in 1953 by Watson and Creek. Fifty years later in 2003 the first high quality genetic code was completed.
Basic concepts in genetics
The human body is composed of trillions of cells. Each cell is a basic component of all living structure. The central part of the cell is the nucleus. The nucleus contains the control centre, sending information for the cell to mature, divide, grow or die. It also houses the cell's hereditary material, the DNA.
Most of the hereditary material is the nucleus, but there is also some outside in some structures (organelles) called mitochondrias. Mitochondrias are complex organelles. They are crucial as they transform nutrients in energy for cell functioning. They are the respiratory part of the cells, they have their own genetic material and can divide themselves.
The genetic information is stored in the DNA as a code. This code is based on four chemical bases, called Adenine (A), Guanine (G), Cytosine (C) and Thymine (T). Human DNA contains three billion bases, most of them are identical in all human beings.
The sequence of those bases determine the information to function and to create a new body, for example, in the same way that letters in an alphabet form words with different meanings.
Spatially, the bases pair A-T and C-G form a structure like a twised ladder called a double helix. This particular distribution is essential as it allows the DNA to be copied and therefore to be passed on to the next cell generation.
The genetic material is packed in the nucleus in units called chromosomes. Human cells have 46 chromosomes, arranged in pairs. Twenty two of them contai information for body functioning, autosomas, and one pair contains information about the sex-sex chromosomes. Esch pair of chromospmes contains information for the same characteristic by duplicate - one copy from our mother and one from our father.
The basic unit of hereditary is called a gene. Genes are made of DNA and they range in size from a few bases to more than two million bases. The information contained in a gene serves to create proteins.
Only one per cent of our genes are different from human to human and small variations between genes make the unique physical differences in all of us.
What is mutation and how does it occur
A gene mutation is a permanent change in the structure of the DNA sequence that makes a gene.
Comparing the genetic code to an alphabet, a mutation is a spelling mistake. The size of the mutation can range from a few bases to a large segment of a chromosome.
Spelling mistakes can be either inherited from a parent or acquired. Mutations that are inherited from parents are called germline mutations and affect all cells in the body during the life time of the individual.
Mutations affecting only the egg or sperm are called 'de novo' mutations. They can explain how a child gets a disease from a mutation that does not exist in the family.
Acquired mutations are those affecting individual cells during a person's lifetime. Unless they affect the eggs or sperm, they cannot be possed on to the next generation.
Spelling mistakes of this type occurring early in the embryo can lead to what we call mosaicism - that is some cells have genetic defecters and others do not in the same body.
Some genetic defects are very rare and others are very frequent. Frequent genetic defects are called polymorphism and are responsible for human diversity such as different eye colours.
Most genetic material is not in use. Therefore having a mutation does not mean a person will suffer from a disease or experience change in any way. Penetrance is the percentage of individuals affected with the disease compared with those carrying the defect.
Patterns of inheritance
For every new individual there are four genetic possible combinations. This is because each of our patents will give us one copy of the two they have. There are certain ways of transmitting a defect. We could say that transmission follows different laws.
We need to remember that for every gene we have two copies - one from our mother and one from our father. Unless the mutations are linked to the sex chromosomes, the transmission is not sex dependent.
Dominant pattern of inheritance
We say dominant trait when only one copy of the defect is required for the condition to develop. So only one parent needs to have the defective gene. This is the way that hypertrophic cardiomyopathy (HCM), and most forms of dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) are transmitted to the descendants. The chances of inherited this way are two in four (or one in two).
Recessive pattern of inheritance
For the disease to occur both compies of the gene must have the mutation. These are causes of rare diseases. Both parents need to have a least one defective copy of the gene. The chances of inheriting in this way are one in four. Some forms of ARVC and DCM are transmitted in this way.
Inheritance linked to the sex chromosomes
Women have two XX sex chromosomes while men have XY ones. Some characters are linked to the X chromosome. Diseases like Anderson Fabry disease, Barth syndrome, Danon's syndrome and some forms of DCM are transmitted in this way.
Females carry the defect only in one X chromosome, so they are either not affected, are a carrier or are affected later in life. The woman's descendants will have a one in two chance of carrying the same genetic defect, while all the men will inherit the defect and will suffer the condition.
From an affected man, there is no possible male to male transmission, while all the woman's descendants will carry the defect.
Research and gene mutations
As outlined before, gene mutations are common in nature. Since a mutation is not equal to any visible or functionasl consequence (they can be part of the normal variations between human beings), how do we know a mutation is responsbile for a disease?
Genetic research is based on clinical observation and family screening. Experimental confirmation is required sometimes to confim the genetic findings.
The future
We are still at the beginning of our understanding of genetic conditions. For some diseases, for example Anderson Fabry disease, the understanding of genetics has lead to a possible treatment. For others the genetic confirmation allows the identifications of people at risk.
Dedicated to Damian McLoughlin, who died age 20 of cardiomyopathy. This site is supported by Damian's family and friends.
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