Genetic Diseases  

Chromosomal anomalies

These are genetic diseases that are due to an abnormal number or structure of the chromosomes. A frequent chromosome anomaly is Down syndrome.

Monogenic diseases
These are genetic diseases that are due to a mutation(s) in only 1 gen. They can be inherited in different ways: autosomal dominant, autosomal recessive, X-linked or Y-linked. Frequent monogenic diseases are cystic fibrosis, thalassemia and fragile X syndrome.

Metabolic diseases
These are monogenic that are due to the deficiency of a protein which is important in the metabolism. Examples of metabolic diseases are Phenylketonuria (PKU) and Gaucher disease.

Multifactorial diseases
These are diseases with a small genetic component. They are due to an interaction between environmental factors and several hereditary factors.
Examples of multifactorial diseases are spina bifida, and diabetes.

Specific diseases
Specific information on genetic diseases can be found on these websites.



Chromosomal anomalies


A. Deviations of the number of chromosomes (aneuploidy)
Each individual has 46 chromosomes in every cell of the body. Individuals with too many or too few chromosomes have a chromosome anomaly referred to as a numerical chromosome anomaly or aneuploidy. Since there are 46 chromosomes there exist chromosome anomalies. In most of the cases the patients suffer from serious physical and mental handicaps. The most well-known example of a chromosome anomaly is down syndrome. In 1866 Doctor Langdon Down described this chromosome anomaly for the first time in the medical literature. In genetics, and in medicine in general, it is quite common to call diseases after the doctor that described them for the first time.
A syndrome is a disease with anomalies of several organs, such as the eyes, brain and the heart. Many syndromes are due to a genetic anomaly.


Down syndrome is caused by an extra (third) chromosome 21. These individuals have therefore not 46, but 47 chromosomes. Whereas everyone has two chromosomes 21, they have 3. Therefore, Down syndrome is also called trisomy 21. The trisomy is usually due to an abnormality of the egg of the mother: normally all reproductive cells (eggs and sperms) carry only 23 chromosomes (one of each). At fertilisation the 23 chromosomes from the female egg than join the 23 chromosomes from the male sperm to form a fertilised egg or zygote with the normal 46 chromosomes. When one of the reproductive cells has an extra chromosome 21, the fertilised egg has 47 chromosomes with 3 chromosomes 21, resulting in Down syndrome.


With the age of the mother, particularly  from 36 year on, increases the risk that the egg contains 2 instead of 1 chromosome 21. Therefore, also the risk on a child with Down syndrome steadily increases with maternal age. For this reason pregnant woman with a certain age (frequently from the age of 36 years) have prenatal tests to exclude Down syndrome. An average couple has risk of approximately 1 on 200 on a child with a chromosome anomaly, and 1 on 600 for trisomy 21.



Other numerical chromosome anomalies are trisomy 13 (Patau syndrome), and trisomy 18 (Edwards syndrome).

Trisomy 13 is a very severe chromosome anomaly with early death. The trisomy 13 babies frequently have cleft lip and palate, and congenital heart malformations.


Also trisomy 18 or Edwards syndrome is a serious syndrome where the babies generally die in the first life year. The babies have malformations of many organs.


The numerical chromosome anomalies of the sex chromosomes, the X and Y chromosome, are less severe. Girls with Turner syndrome have 1 instead of 2 X chromosomes (monosomy X): they are small, have no menstruation and are sterile. Frequently also there exists a broad neck (webbed neck). The intellectual development is normal or slightly behind.


When the mother of a child with a numerical chromosome anomaly is pregnant again, there is a slightly increased risk on a second child with a chromosome anomaly (1-2% on top of the risk defined by the maternal age). The risk in other family members is not increased. The numerical chromosome anomalies are therefore in fact not hereditary in the sense of transmission to the progeny, but still they are anomalies of our hereditary material.



B. Deviations of the structure of the chromosomes (structural chromosome anomalies)
Beside the number of chromosomes also the structure of a chromosome can be abnormal: this is called a structural chromosome anomaly. Structural chromosome anomalies can be transmitted to the progeny in contrast to numerical chromosome anomalies.
There exists a large number of structural chromosome anomalies:

B1. Deletions
Sometimes there is a piece of chromosome missing: this is called a deletion. Persons with a deletion nearly always show serious mental handicap and different physical anomalies. Examples of chromosome deletions are Angelman syndrome (deletion of part of chromosome 15) and Shprintzen syndrome (deletion of part of chromosome 22).

B2. Insertions
Sometimes there is a piece of chromosome too much: this is called an insertion.

B3. Inversions
When part of a chromosome turns 180° around its centre, one speaks of an inversion. Usually an inversion does not lead to symptoms unless one of the breakpoints of the inversion disrupts an important gene.

B4. Translocations
Sometimes there is part of one chromosome attached to another chromosome: this is a translocation. In general structural chromosome anomalies only cause a syndrome when there is an abnormal amount of part of a chromosome: this is sometimes referred to as unbalanced chromosomes, and it can be a partial trisomy or a partial monosomy. Frequently one of the parents of a child with unbalanced translocation has a balanced translocation. This parent shows no physical anomalies, but has an increased risk on children with deviations. A prenatal chromosome analysis after amniocentesis or chorion villi sampling is advised in these cases. Moreover, chromosome analysis of the nearest family members is indicated because these can have a balanced chromosome translocation, and thus an increased risk on children with unbalanced chromosome anomalies with a syndrome as a consequence.



Monogenic diseases

When a hereditary disease is caused by an anomaly in a single gene one speaks of a monogenic disease. When a disease it is caused by an interaction between several genes and environmental factors, one speaks of a multifactorial disease.
Below monogenic diseases and their inheritance are discussed.
Monogenic diseases are caused by an anomaly in a single gene called mutations. When the mutation occurs in an autosomal gene, the mode of inheritance is autosomal. When the mutation is located in a gene on the X or Y chromosome, the disease is called X-linked or Y-linked.
Therefore, the mode of inheritance of a monogenic disease is defined by the position of the mutated gene. On the other hand one can also derive the mode of inheritance of the disease by studying the transmission within the family. The geneticist or genetic counseler therefore makes a family pedigree. In such pedigree the women are indicated with a round symbol, and the men with a square. The older generations are shown on top, and the younger generations below. Coloured persons are the family members who have the hereditary disease, and empty symbols are the healthy individuals.



A. Autosomal dominant diseases
Autosomal dominant diseases are hereditary diseases where a mutation in one copy of an autosomal gene causes the disease. A person with such a disease therefore has 1 mutated and 1 normal copy of the disease gene. On the other hand the mutation can also arise in the patient as a new mutation (referred to as de novo mutation). Each patient with an autosomal dominant disease has a risk of 1 on 2 on a child with the same syndrome, although the severity of the syndrome can change from person to person, even within the same family.


Autosomal dominant diseases are frequently inherited from generation to generation. When a generation is skipped, one says that the disease has incomplete penetrance.



Some examples of autosomal dominant disease are Huntington ‘s disease, and some forms of breast cancer, colorectal cancer, and Alzheimer’s dementia.
A lot of these dominant diseases only show symptoms at a later age. Molecular testing before symptoms appear is called predictive testing.



B. Autosomal recessive diseases
Autosomal recessive diseases are hereditary diseases with a mutation in both copies of the gene. The patients have therefore 2 mutant genes and no normal gene. A family member with a recessive mutation in 1 copy and a normal second copy is a carrier or heterozygote. Both parents of a patient with an autosomal recessive disease are always carriers. Usually the parents do not know they are carriers until the birth of the first affected. The risk on future children with the disease (recurrence risk) is 1 on 4 for each child. The children of an affected patient are all carriers, but there exists only a small risk that the children of a patient also show the disease. Healthy brothers and sisters of a patient have a chance of being a carrier of 2 on 3. Related (consanguineous) parents have an increased risk on autosomal recessive diseases because the risk that they are both carrier of the same recessive mutation is increased as compared to unrelated couples.





C. X-linked diseases
X-linked diseases are hereditary diseases with a single mutation in an X-linked gene. Most of the X-linked diseases are more serious in men than in women because men have only 1 X chromosome, whereas women have 2. Frequently female members are carriers of the mutation, but have no symptoms of the disease. Exclusion of carriership in these female family members of affected men is very important because they a risk to transmit the disease to affected sons. The risk that a carrier female has an affected son is 1 on 4. The mutation also arise in the patient as a new mutation (de novo mutation). The risk that an affected man transmits an X-linked disease to his sons is not increased as he transmits his Y and not his X chromosome to his sons. However, each of his daughters will be a carrier with possibly mild symptoms of the disorder.




D. Y-linked diseases
These diseases arise by a mutation in a gene on the Y chromosome. The human Y chromosome however contains very few genes; therefore there is only a limited amount of Y-linked diseases, mainly involving male fertility. Mutations in Y-linked genes thus frequently cause male fertility. Consequently, these mutations are not transmitted to progeny, unless assisted fertility procedures such as ICSI are used.



E. Characteristics of monogenic diseases
The most important characteristics of monogenic diseases are summarised in the table below.

  Autosomal
Dominant
Autosomal
R
ecessive
X-linked
Number of mutations in patients 1 2 1
Sex of patients both both mainly boys
Risk* of children with the disease 1 on 2
small small
Risk* of grandchildren with the disease 1 on 4 small 1 on 8
Risk* of an affected sib A. small if none of the parents is affected
B. 1 on 2 if one of the parents is also affected
1 on 4 A. small if the mother is no carrier
B. 1 on 4 if the mother is a carrier

* = Risks apply to the patient which has the genetic disease.



Metabolic diseases

Metabolic diseases are hereditary diseases of the metabolism, also referred to as inborn errors or metabolism. They arise by gene mutations, which lead to a deficiency of a particular enzyme. Enzymes are proteins that convert certain substances into our body into other substances. A person with a metabolic disease has therefore a deficiency of a particular enzyme leading to an abnormal metabolism of specific metabolites (an excess of some metabolites, and a shortage of other metabolites). Metabolic diseases have a recessive inheritance (autosomal recessive or X-linked recessive).
There exist more than 100 metabolic diseases. These can be detected by assay of the activity of the deficient enzyme in blood or skin cells. Also determination of metabolites in blood or urine is possible to detect these diseases. Molecular testing of the gene which is mutated in the disease, can confirm the diagnosis.
Some well-known inborn errors or metabolism are phenylketonuria (PKU) and Tay-Sachs disease.



Multifactorial diseases


Multifactorial diseases are caused by an interaction of multiple factors. These can be genetic factors and/or environmental factors. Multifactorial diseases are more frequent than chromosome anomalies or monogenic diseases, which each have a frequency of approximately 1%.
Congenital multifactorial disorders, including defects such as neural tube defects (spina bifida) or cleft lip/palate affects approximately 3% of the babies. Multifactorial disorders, which manifest themselves on a later age are much more frequent, and most individuals develop one or several multifactorial disorders, including diseases such as diabetes, hypertension, or cardiovascular disease. For most of the multifactorial disorders it is still unknown which genes and/or environmental factors play a role. Also the inheritance is frequently unclear, and the risk depends on a number of factors: the more serious the disease , the higher the risk is; the more family members affected, the higher the risk is; the closer related the affected family members is, the higher the risk. Much is not yet known concerning the environmental factors, which contribute to multifactorial syndromes. Our diet clearly contributes to cardiovascular disease; smoking certainly  in combination with oral contraceptives contributes to thrombosis, folic acid taken during the pregnancy reduces the risk  on neural tube defects.



Specific diseases

Specific information on genetic diseases can be found on the following websites:






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