Compound heterozygosity
Compound heterozygosity is the presence of two different mutated alleles at a particular gene locus, one inherited from each parent.[1] This genetic configuration represents a specific type of heterozygosity where both alleles carry pathogenic variants, but they differ in their molecular alterations, such as distinct point mutations or insertions/deletions within the same gene.[2] In autosomal recessive disorders, compound heterozygosity often leads to a loss of functional protein from the affected gene, resulting in disease phenotypes comparable to those caused by homozygous mutations.[3] For example, it has been implicated in conditions such as protein S deficiency, which increases the risk of life-threatening thrombotic events, and restrictive dermopathy due to mutations in the ZMPSTE24 gene.[4][5] This mechanism underlies the inheritance pattern in many Mendelian diseases, where carriers of a single mutant allele are typically asymptomatic, but offspring receiving two different mutants from heterozygous parents manifest the disorder.[6] The identification of compound heterozygosity is critical in clinical genetics, particularly with the advent of exome and genome sequencing, as it can explain unresolved cases of recessive traits and inform risk assessment for hereditary conditions like pediatric cancers.[7][2] Challenges in detection arise because sequencing data often requires phasing to confirm that the variants are in trans (on different chromosomes) rather than in cis, yet tools and algorithms are improving to infer this configuration from large-scale genomic datasets.[8] Overall, understanding compound heterozygosity enhances diagnostic precision and contributes to broader insights into genetic disease susceptibility across populations.[2]Fundamentals
Definition
Compound heterozygosity refers to the genetic condition in which an individual inherits two different pathogenic variants in the same gene, one from each parent, at a specific locus on a chromosome, resulting in both alleles being altered or non-functional.[1][2] This genotype is a form of heterozygosity where the two alleles differ from each other and from the wild-type sequence, often leading to a loss of normal gene function in recessive contexts.[9] In genetic terminology, a locus is the fixed position of a gene or DNA sequence on a chromosome.[10] An allele represents one of two or more versions of the DNA sequence at that locus.[10] A variant denotes any alteration in the DNA sequence, which may be pathogenic if it disrupts gene function, whereas a polymorphism is a common variant (typically with a population frequency of at least 1%) that generally does not cause disease.[11][12] This phenomenon occurs in diploid organisms, such as humans, where each cell contains two copies of each chromosome—one inherited from the mother and one from the father—allowing for two alleles per locus.[10] Inheritance follows Mendelian principles, with each parent contributing one allele to the offspring.[10] The concept of compound heterozygosity emerged in the study of recessive genetic disorders in the mid-20th century, with early descriptions in hemoglobinopathies reported in the 1950s and formal recognition through investigations of metabolic diseases during that era.[13]Comparison to Homozygosity and Simple Heterozygosity
Compound heterozygosity differs from homozygosity and simple heterozygosity in the nature of the alleles present at a gene locus and their implications for recessive genetic disorders. In homozygosity, an individual inherits two identical alleles for a given gene, which may both be normal (homozygous dominant) or both mutant (homozygous recessive), resulting in either no disease manifestation or full expression of a recessive disorder due to complete loss of gene function. In contrast, simple heterozygosity involves inheriting one normal allele and one mutant allele, typically conferring carrier status without phenotypic effects in autosomal recessive conditions, as the normal allele produces sufficient functional protein.[14] Compound heterozygosity, however, occurs when two different mutant alleles are inherited—one from each parent—leading to a biallelic loss of function akin to homozygous recessive states but with potential variations arising from the distinct impacts of each mutation.[1][15] Phenotypically, both homozygous recessive and compound heterozygous genotypes often produce similar disease outcomes in autosomal recessive disorders, as both result in insufficient functional protein product, manifesting the full disorder.[15] However, compound heterozygosity can lead to variable severity compared to homozygosity, depending on the specific functional deficits caused by the differing mutations; for instance, in cystic fibrosis, compound heterozygotes for certain allele combinations exhibit phenotypes indistinguishable from homozygous cases but with reduced risk for complications like meconium ileus.[16] Simple heterozygosity, by comparison, rarely causes disease, emphasizing its role as a benign carrier state rather than a disease trigger.[15] The following table summarizes key distinctions among these genotypes in the context of autosomal recessive traits:| Genotype Type | Alleles Inherited | Disease Risk in Recessive Disorders | Example (Hypothetical Gene) |
|---|---|---|---|
| Homozygous Normal | Two identical normal (e.g., AA) | None | Full gene function, no disorder |
| Simple Heterozygous | One normal, one mutant (e.g., Aa) | None (carrier status) | Normal phenotype, asymptomatic carrier |
| Homozygous Mutant | Two identical mutants (e.g., aa) | High (full disorder expression) | Cystic fibrosis with ΔF508/ΔF508 |
| Compound Heterozygous | Two different mutants (e.g., a1a2) | High (disorder, potentially variable severity) | Cystic fibrosis with ΔF508/G551D |