Compound heterozygous

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 when 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.

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 biochemistry 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.

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