Inheritance Patterns and Mechanisms Causing Genetic Disorders

The family pattern of affected people, the precise diagnosis or specific tests may confirm a particular genetic cause for a disorder. However, this may not be straightforward as the same genetic disorder may present differently in different family members. Disorders which are clinically similar may follow different patterns of inheritance in different families.

The most likely mode of inheritance or genetic mechanism responsible for a disease will be explained to the family during the clinic consultation. In this section we introduce the main categories of genetic disease and try to explain the underlying genetic mechanisms. It is likely that similar explanations and information will be given to your patients.

Types of Genetic Disease

Single gene (Mendelian) - Numerous though individually rare. Clear pattern of inheritance. High risk to relatives.


Multifactorial - Common disorders. No clear pattern of inheritance. Low or moderate risk to relatives.


Chromosomal - Mostly rare. No clear pattern of inheritance. Usually low risk to relatives.


Mitochondrial - Variable pattern of inheritance.


Mutations occurring in somatic cells - Associated with cancer, and mosaicism.

Incidence

1. Single gene    
Autosomal dominant   1%  
Autosomal recessive   0.2%   
X-linked recessive 0.2%
2. Multifactorial   
Major congenital malformations  2-3%   
Adult chronic diseases   10%   
3. Chromosomal  
Chromosomal  0.6%

1. Single Gene Disorders

Single gene disorders behave as though they are under the control of only one pair of genes. Although they occur in only about 1% of live births, they cause a high rate of morbidity and mortality, and have a high risk of recurrence in immediate family members.

2. Multifactorial Inheritance

Multifactorial inheritance accounts for many congenital malformations and common adult diseases.

Examples in children are:

• neural tube defects
• congenital heart disease
• cleft lip and palate
• congenital dislocation of hip
• pyloric stenosis.

Although these conditions tend to cluster in families they do not give a clear cut pedigree pattern.

Multifactorial conditions are considered to be determined by the summation of the effects of several genes at different loci, together with environmental factors. It is postulated that there is a liability threshold; people who are above this will manifest the disease.

The risk of recurrence for a multifactorial disorder within a family is highest for first degree relatives but is generally low. For most multifactorial conditions it is usual to use empiric risk figures - the observed recurrence risks for different relatives of an affected individual. These are obtained through population studies.

After a couple has had two children with a multifactorial condition, the recurrence risk rises. This is because couples with two affected children must either have a particularly high genetic susceptibility or suffer chronic environmental insult, or both.

3. Chromosomal

Humans have 46 chromosomes in their somatic cells, 22 pairs of autosomes and two sex chromosomes (X,Y). The chromosomes contain the DNA which codes for the (up to) 40,000 human genes.

Each chromosome can be identified by light microscopy with staining techniques which give a specific pattern of light and dark bands. The short arm of a chromosome is designated p and the long arm q, each arm being subdivided numerically according to the number of bands. This allows a precise description of a structural abnormality (such as the breakpoints of translocations).
Classification of chromosomal abnormalities
As a chromosome contains thousands of genes, aberrations will affect multiple organ systems causing congenital malformations and mental retardation.

a) Numerical abnormalities

i) Excess
Additional copies of whole chromosomes (either an autosome or sex chromosome).

Examples:

Down syndrome (trisomy 21)

Patau syndrome (trisomy 13)

Edwards syndrome (trisomy 18)

Klinefelter syndrome (47XXY).

ii) Deficiency
The only viable condition where a whole chromosome is missing is Turner syndrome (a missing X chromosome - 45X).

b) Structural abnormalities

i) Translocation:
A translocation results from the transfer of material between chromosomes, requiring breakage of both chromosomes with repair in an abnormal arrangement.

If the exchange results in no loss or gain of DNA, the individual is clinically normal and is said to have a balanced translocation and is a translocation carrier. He/she is, however, at risk of having a chromosomally abnormal baby (an unbalanced translocation.)

Abnormalities resulting from an unbalanced translocation depend on the particular chromosome fragments present in monosomic or trisomic form. Sometimes spontaneous abortion is inevitable; in other cases a child with multiple abnormalities may be born alive. The risk of an unbalanced karyotype in a child depends on the individual translocation.

Once a translocation has been identified it is important to investigate relatives to identify carriers of the balanced translocation so that genetic information and prenatal diagnosis can be offered.

ii) Deletions (and inversions or duplications) of chromosomal material
Duplications and deletions of even apparently small segments of chromosomes can result in severe phenotypic effects. High resolution cytogenetic techniques have recognised small deletions in syndromes of previously unknown origin (for example some patients with Prader-Willi syndrome). DNA techniques are being used to identify some deletions of genetic material too small to be identified by conventional light microscopy.

c) Somatic mosaicism

In somatic mosaicism there are two cell lines present - usually one with a normal and one with an abnormal chromosomal complement. The proportion of each cell line can vary from tissue to tissue, and the number and distribution of cells with the abnormal karyotype will reflect the severity of the phenotype, physically and mentally. It can sometimes be very difficult to predict the effects on a child when mosaicism is found at prenatal diagnosis.

The abnormal cell line may not be present in the lymphocytes and so must be sought in another tissue: skin biopsy and culture may be required for diagnosis.

Recurrence risks:
The recurrence risk of having another chromosomally abnormal child is generally low if the previous child has a regular trisomy (usually 1 in 100) or other de novo structural abnormality. The parents may still wish to undertake prenatal diagnosis.

Carriers of translocations should be referred to the genetic clinic as the risk of a child with serious malformations may be high.

4. Mitochondrial Inheritance

The main store of DNA is in the cell nucleus, but mitochondria (which are found in the cell cytoplasm) also contain DNA which codes for a few mitochondrial enzymes. Mitochondrial DNA is maternally inherited as the egg (unlike sperm) contains cytoplasm as well as a nucleus. Males and females are affected but transmission is only by affected women. Certain muscle diseases and Leber's hereditary optic atrophy have been shown to be caused by mutations in mitochondrial DNA.

Abnormalities in mitochondria can be caused by autosomal dominant or recessive genes in the DNA in the cell nucleus or by genes of the mitochondrial DNA, and can result in severe disease.  However, many patients are affected by new mutations. Expert tests are required to determine which mechanism is operating.

5. Mutations in somatic Cells

Genetic conditions are usually considered to be due to mutations which have been inherited from a parent, or which have occurred during the production of the gametes. It has now been shown that mutations can occur in somatic cells as they grow and divide, and that these mutations can then be passed on to all the cells which are descendants of the cell with the mutation.

A mutation occurring in a gene which is involved in the control of cell division could be the first step in carcinogenesis - for instance, to remove the effects of a gene suppressing growth or to enhance the activity of a gene responsible for growth. However, it is usual for mutations to have to occur in several genes for a cancer to develop.

Affected members of families with certain types of dominantly inherited cancer are considered to have inherited from their affected parent a mutation which predisposes them to cancer. The cancer does not develop until mutations occur in other genes by somatic mutation (this is often called the "two hit" hypothesis). The gene in which the primary mutation occurs has been cloned for some of the dominantly inherited cancer syndromes (for instance, familial adenomatous polyposis coli).   

This page was last modified on Fri Feb 12 2010