Compound heterozygosity
Encyclopedia
Compound heterozygosity in medical genetics is the condition of having two heterogeneous recessive
alleles at a particular locus that can cause genetic disease in a heterozygous state. That is, an organism is a compound heterozygote if it has two recessive alleles for the same gene, but with those two alleles being different from each other (for example, both alleles might be mutated but at different locations). Compound heterozygosity reflects the diversity of the mutation base for many autosomal recessive genetic disorders; mutations in most disease-causing genes have arisen many times. This means that many cases of disease arise in individuals who have two unrelated alleles, who technically are heterozygotes, but both the alleles are defective.
These disorders are often best known in some classic form, such as the homozygous recessive case of a particular mutation
that is widespread in some population. In its compound heterozygous forms, the disease may have lower penetrance
, because the mutations involved are often less deleterious in combination than for a homozygous individual with the classic symptoms of the disease. As a result, compound heterozygotes often become ill later in life, with less severe symptoms. Although compound heterozygosity as a cause of genetic disease had been suspected much earlier, widespread confirmation of the phenomenon was not feasible until the 1980s, when polymerase chain reaction
techniques for amplification of DNA made it cost-effective to sequence genes and identify polymorphic alleles.
and pathophysiology
before genetic diagnosis was available. Some genetic disorders are really a family of related disorders that occur in the same metabolic pathway
, or in related pathways. Naming conventions for the disease became established before precise molecular diagnosis was possible.
For example, hemochromatosis is the name given to several different heritable diseases with the same outcome, excess absorption of iron. These variants all reflect a failure in a metabolic pathway associated with iron
metabolism
, however mutations that cause hemochromatosis can occur at different gene loci. Mutations have occurred at each locus many times, and a few such mutations have become widespread in some population. The fact that multiple loci are involved is the primary cause for the variant forms of hemochromatosis and its outcome. This variation is caused not by compound heterozygosity, but rather by the fact that several different enzyme defects can cause the disease. Clinically, most cases of hemochromatosis are found in homozygotes for the most common mutation in the HFE gene. But at each gene locus associated with the disease, there is the possibility of compound heterozygosity, often caused by inheritance of two unrelated alleles, of which one is a common or classic mutation, while the other is a rare or even novel one.
For some genetic diseases, environmental cofactors are an important determinant of variation and outcome. In the case of hemochromatosis, penetrance
is incomplete, even for the classic HFE mutation, and is affected by gender, diet, and behaviors such as alcohol consumption. Compound heterozygotes are often observed only through subclinical symptoms such as excess iron. Disease is rarely observed in such compound heterozygotes unless other causal factors (such as alcoholism
) are present. As a result, compound heterozygosity for hemochromatosis may be more common than diagnosis based on pathology would suggest.
Some genetic diseases are named more precisely, and represent a single point of failure on a metabolic pathway. For example, Tay-Sachs disease
, GM2-gangliosidosis, AB variant
, and Sandhoff disease
might easily have been defined together as a single disease, because the three disorders are associated with failure of the same enzyme and have the same outcome. However, the three were discovered and named separately, and each represents a distinct molecular point of failure in a subunit that is required for activation of the enzyme. For all three disorders, compound heterozygosity is responsible for variant forms. For example, both TSD and Sandhoff disease have a more common infantile form and several late-onset variants. Post-infantile forms, which are rare, are generally caused by the inheritance of two unrelated alleles, of which one is usually a classic mutation, while the other is a rare or even novel one.
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
alleles at a particular locus that can cause genetic disease in a heterozygous state. That is, an organism is a compound heterozygote if it has two recessive alleles for the same gene, but with those two alleles being different from each other (for example, both alleles might be mutated but at different locations). Compound heterozygosity reflects the diversity of the mutation base for many autosomal recessive genetic disorders; mutations in most disease-causing genes have arisen many times. This means that many cases of disease arise in individuals who have two unrelated alleles, who technically are heterozygotes, but both the alleles are defective.
These disorders are often best known in some classic form, such as the homozygous recessive case of a particular mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
that is widespread in some population. In its compound heterozygous forms, the disease may have lower penetrance
Penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
, because the mutations involved are often less deleterious in combination than for a homozygous individual with the classic symptoms of the disease. As a result, compound heterozygotes often become ill later in life, with less severe symptoms. Although compound heterozygosity as a cause of genetic disease had been suspected much earlier, widespread confirmation of the phenomenon was not feasible until the 1980s, when polymerase chain reaction
Polymerase chain reaction
The polymerase chain reaction is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence....
techniques for amplification of DNA made it cost-effective to sequence genes and identify polymorphic alleles.
Etiology of genetic disease
Compound heterozygosity is one of the causes of variation in genetic disease. The diagnosis and nomenclature for such disorders sometimes reflects history, because most diseases were first observed and classified based on biochemistryBiochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
and pathophysiology
Pathophysiology
Pathophysiology is the study of the changes of normal mechanical, physical, and biochemical functions, either caused by a disease, or resulting from an abnormal syndrome...
before genetic diagnosis was available. Some genetic disorders are really a family of related disorders that occur in the same metabolic pathway
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...
, or in related pathways. Naming conventions for the disease became established before precise molecular diagnosis was possible.
For example, hemochromatosis is the name given to several different heritable diseases with the same outcome, excess absorption of iron. These variants all reflect a failure in a metabolic pathway associated with iron
Iron
Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...
metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
, however mutations that cause hemochromatosis can occur at different gene loci. Mutations have occurred at each locus many times, and a few such mutations have become widespread in some population. The fact that multiple loci are involved is the primary cause for the variant forms of hemochromatosis and its outcome. This variation is caused not by compound heterozygosity, but rather by the fact that several different enzyme defects can cause the disease. Clinically, most cases of hemochromatosis are found in homozygotes for the most common mutation in the HFE gene. But at each gene locus associated with the disease, there is the possibility of compound heterozygosity, often caused by inheritance of two unrelated alleles, of which one is a common or classic mutation, while the other is a rare or even novel one.
For some genetic diseases, environmental cofactors are an important determinant of variation and outcome. In the case of hemochromatosis, penetrance
Penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
is incomplete, even for the classic HFE mutation, and is affected by gender, diet, and behaviors such as alcohol consumption. Compound heterozygotes are often observed only through subclinical symptoms such as excess iron. Disease is rarely observed in such compound heterozygotes unless other causal factors (such as alcoholism
Alcoholism
Alcoholism is a broad term for problems with alcohol, and is generally used to mean compulsive and uncontrolled consumption of alcoholic beverages, usually to the detriment of the drinker's health, personal relationships, and social standing...
) are present. As a result, compound heterozygosity for hemochromatosis may be more common than diagnosis based on pathology would suggest.
Some genetic diseases are named more precisely, and represent a single point of failure on a metabolic pathway. For example, Tay-Sachs disease
Tay-Sachs disease
Tay–Sachs disease is an autosomal recessive genetic disorder...
, GM2-gangliosidosis, AB variant
GM2-gangliosidosis, AB variant
GM2-gangliosidosis, AB variant is a rare, autosomal recessive metabolic disorder that causes progressive destruction of nerve cells in the brain and spinal cord. It has a similar pathology to Sandhoff disease and Tay-Sachs disease...
, and Sandhoff disease
Sandhoff disease
Sandhoff disease, also known as Sandhoff-Jatzkewitz disease, variant 0 of GM2-Gangliosidosis or Hexosaminidase A and B deficiency, is a lysosomal genetic, lipid storage disorder caused by the inherited deficiency to create functional beta-hexosaminidases A and B...
might easily have been defined together as a single disease, because the three disorders are associated with failure of the same enzyme and have the same outcome. However, the three were discovered and named separately, and each represents a distinct molecular point of failure in a subunit that is required for activation of the enzyme. For all three disorders, compound heterozygosity is responsible for variant forms. For example, both TSD and Sandhoff disease have a more common infantile form and several late-onset variants. Post-infantile forms, which are rare, are generally caused by the inheritance of two unrelated alleles, of which one is usually a classic mutation, while the other is a rare or even novel one.
Examples
- PhenylketonuriaPhenylketonuriaPhenylketonuria is an autosomal recessive metabolic genetic disorder characterized by a mutation in the gene for the hepatic enzyme phenylalanine hydroxylase , rendering it nonfunctional. This enzyme is necessary to metabolize the amino acid phenylalanine to the amino acid tyrosine...
. Because phenylketonuria was the first genetic disorder for which mass post-natal genetic screening was available, beginning in the early 1960s, atypical cases were detected almost immediately. Molecular analysis of the genome was not yet possible, but protein sequencing revealed cases caused by compound heterozygosity. As molecular genomic techniques became available in the 1980s and 1990s, it became possible to explain a range of disorders in heterozygotes carrying one copy of one of the classic mutations for phenylketonuria.
- Tay-Sachs diseaseTay-Sachs diseaseTay–Sachs disease is an autosomal recessive genetic disorder...
. In addition to its classic infantile form, Tay Sachs disease may present in juvenile or adult onset forms, often as the result of compound heterozygosity between two alleles, one which would cause the classic infantile disease in homozygotes and another that allows some residual HEXA enzyme activity.
- Sickle cell syndromes. A variety of sickle cell disorders result from inheritance of the sickle cell gene in a compound heterozygous manner with other mutant beta globin genes. These disorders include sickle cell-beta thalassemia. In the case of sickle cell anemia, an individual with one allele for hemoglobinHemoglobinHemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
S and one alleleAlleleAn allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
for hemoglobin CHemoglobin CHemoglobin C is an abnormal hemoglobin with substitution of a lysine residue for a glutamic acid residue at the 6th position of the β-globin chain.-Clinical significance:...
would still develop the disease, despite being heterozygous for both genes.