Uniparental disomy, or UPD, is a genetic condition where an individual inherits two copies of a chromosome from one parent and none from the other. This stands in contrast to the typical pattern of inheritance, where one chromosome of each pair is passed down from the mother and the other from the father. This rare event occurs in approximately 1 in 2,000 births and can happen randomly during the formation of egg and sperm cells or in the early stages of fetal development. The two main classifications of UPD are heterodisomy and isodisomy, which are distinguished by the specific origin and genetic similarity of the inherited chromosomes.
The Mechanisms of Formation
The formation of both heterodisomy and isodisomy is rooted in errors during meiosis, the cell division process that creates eggs and sperm. A primary cause is meiotic nondisjunction, the failure of chromosome pairs to separate correctly. These errors can lead to a gamete with an abnormal number of chromosomes. Fertilization involving such a gamete can result in an embryo that is either trisomic (three copies of a chromosome) or monosomic (one copy).
A common pathway for UPD is “trisomy rescue,” a corrective process in the early embryo. To resolve the lethal trisomic state, the embryo may eject one of the three chromosomes. If the chromosome from the parent who contributed only one copy is lost, the embryo is left with two chromosomes from the other parent. When this process follows a Meiosis I error, where different homologous chromosomes—the pairs of corresponding chromosomes from each parent—failed to separate, the outcome is heterodisomy.
Isodisomy can arise from a nondisjunction error during Meiosis II, where identical sister chromatids fail to part ways. This results in a gamete with two identical copies of a single chromosome. Another mechanism is “monosomy rescue,” where an embryo starts with only one chromosome for a particular pair and corrects this by duplicating the single chromosome it has. This duplication leads directly to isodisomy.
Distinguishing the Genetic Outcome
The fundamental difference between heterodisomy and isodisomy lies in the genetic makeup of the resulting chromosome pair. Heterodisomy is the inheritance of two different, or homologous, chromosomes from a single parent. The child receives both of the chromosomes that the parent inherited from their own two parents (the child’s grandparents). An easy way to visualize this is to think of a parent having two distinct volumes of a book series; in heterodisomy, the child inherits both unique volumes from that one parent.
Because the chromosomes are different, the individual is heterozygous for many of the genes on that chromosome pair. In contrast, isodisomy is the inheritance of two identical copies of a single chromosome from one parent. Following the book analogy, this is like receiving two exact photocopies of the same volume from a parent.
The two resulting chromosomes are genetically identical mirror images of each other. This duplication results in a state of complete homozygosity for that chromosome pair, where every gene is present in two identical copies. This lack of genetic variation on a whole chromosome is a significant marker that makes isodisomy more direct to identify in genetic tests.
Clinical and Phenotypic Consequences
The clinical relevance of uniparental disomy depends on which type is present and which chromosome is affected. Isodisomy carries a particular risk related to recessive genetic disorders. These conditions manifest when an individual inherits two copies of a mutated gene. With isodisomy, if the single inherited chromosome carries a recessive disease allele, its duplication means the individual will have two copies of the mutated gene and will express the disorder, even though only one parent was a carrier.
Both heterodisomy and isodisomy can cause problems through genomic imprinting. For a small number of human genes, expression is determined by parental origin; some genes are active only when inherited from the mother, while others are active only when from the father. UPD disrupts this parent-specific pattern by providing two maternal or two paternal copies of a chromosome, leading to an incorrect “dose” of these imprinted genes.
This disruption is the cause of well-known conditions like Prader-Willi syndrome and Angelman syndrome, which both involve imprinted genes on chromosome 15. Paternal UPD of chromosome 15 leads to Prader-Willi syndrome because active maternal gene copies are missing. Conversely, maternal UPD of chromosome 15 causes Angelman syndrome due to the absence of active paternal gene copies.
Apart from imprinted chromosomes, heterodisomy is frequently without direct clinical consequences. Because the individual possesses two different and functional chromosomes, genetic diversity is preserved. Unless imprinted genes are involved, heterodisomy often goes unnoticed.
Detection and Diagnosis
Identifying uniparental disomy requires specialized genetic testing, as it does not change the total number of chromosomes and can escape standard cytogenetic analysis. Historically, discovering UPD was often an incidental finding during investigations into other genetic issues, and early molecular techniques struggled to differentiate between the two types.
Modern diagnostic methods, particularly single nucleotide polymorphism (SNP) microarrays, have greatly improved the detection and classification of UPD. These arrays scan thousands of points across the genome, analyzing tiny variations in the DNA sequence known as SNPs. This detailed analysis allows clinicians to see the specific genetic makeup of each chromosome pair.
SNP microarrays clearly distinguish between heterodisomy and isodisomy. When analyzing a chromosome pair affected by isodisomy, the microarray reveals a long, continuous stretch of homozygosity—a clear absence of normal genetic variation. In heterodisomy, the array shows a pattern of heterozygosity, because the two inherited chromosomes are different. By comparing the child’s SNP profile with those of their parents, specialists can definitively confirm that both chromosomes originated from a single parent.