Uniparental disomy (UPD) describes a rare genetic event where an individual receives both copies of a specific chromosome pair, or a segment of a chromosome, from only one parent instead of receiving one copy from each parent. While the total number of chromosomes remains the correct two copies, the origin of these copies is skewed, leading to an inheritance anomaly. This deviation from the typical biparental inheritance pattern can have significant consequences for health, depending on which chromosome is involved and which parent contributed the copies. The distinction between Heterodisomy and Isodisomy classifies the specific type of inheritance error, which in turn predicts the potential clinical outcome.
The Foundation: What is Uniparental Disomy?
Uniparental Disomy (UPD) is the general phenomenon where both homologous chromosomes, or parts of them, come from the same parent. This is a relatively rare occurrence, estimated to happen in approximately 1 in 2,000 live births across all chromosomes. Normally, every person inherits one chromosome from their mother and the homologous chromosome from their father, ensuring a balanced genetic contribution.
UPD arises when this normal segregation process fails, often due to an error in the formation of the egg or sperm cell (a gamete). The most common mechanism involves a conceptus that initially has three copies of a chromosome (trisomy) or only one copy (monosomy). The early embryo then “rescues” itself by losing one of the three chromosomes or duplicating the single one to restore the correct two-copy state. If both remaining copies happen to be from the same parent, UPD results. The clinical consequences depend entirely on whether the two inherited chromosomes are genetically different or genetically identical.
Heterodisomy: Originating from Meiosis I Errors
Heterodisomy (UPhD) occurs when the two chromosomes inherited from the single parent are non-identical copies. This means the child received both homologous chromosomes from only one parent. If the parent had two different versions (alleles) of a gene, the child receives both of those different versions from that parent, resulting in the individual being heterozygous for the genetic markers on that chromosome.
The mechanism that typically leads to Heterodisomy is a nondisjunction error during Meiosis I, the first stage of cell division in gamete formation. Meiosis I is the stage where homologous chromosomes separate from each other. A failure of these homologous chromosomes to separate correctly results in a gamete that contains two different copies of that chromosome. Subsequent “trisomy rescue” eliminates the chromosome copy from the other parent, leaving the individual with two non-identical, homologous chromosomes from the single contributing parent. This type of UPD is more frequently observed when the error occurs in the maternal line.
Isodisomy: Originating from Meiosis II Errors
Isodisomy (UPiD) is defined by the inheritance of two identical copies of a single chromosome from one parent. Instead of receiving the two different homologous chromosomes, the child receives two exact duplicates of just one of the parent’s two chromosomes. If the parent had two different alleles, the child receives two copies of the same allele (e.g., two ‘A’ copies).
The typical mechanism leading to Isodisomy is a nondisjunction error during Meiosis II, the second stage of gamete formation. Meiosis II involves the separation of sister chromatids. The failure of these sister chromatids to separate results in a gamete that contains two identical copies of a chromosome. Isodisomy can also arise from a monosomy rescue event, which is the duplication of a single chromosome copy early in fetal development. The result is that the individual is homozygous for all genetic markers across the entire length of the affected chromosome segment.
Why the Difference Matters: Clinical Consequences
The distinction between Heterodisomy and Isodisomy is clinically significant because the two forms carry different risks for genetic disorders.
Heterodisomy and Imprinting Disorders
The primary concern with Heterodisomy is its link to disorders involving genomic imprinting. Genomic imprinting is a process where certain genes are expressed differently depending on whether they were inherited from the mother or the father. If a child inherits both copies of a chromosome containing imprinted genes from only one parent—a maternal Heterodisomy, for instance—the child will lack the necessary gene expression from the paternal copy. This absence of expression from one parental source can lead to imprinting disorders, such as Prader-Willi syndrome or Angelman syndrome, associated with UPD of chromosome 15. In these cases, the genetic information is present, but the parental “tag” for proper gene regulation is missing.
Isodisomy and Recessive Disorders
Isodisomy is most relevant for its potential to “uncover” recessive genetic disorders. Since Isodisomy results in the child having two identical copies of a chromosome segment, the child is homozygous for every gene in that region. If the single parent who contributed both copies was a heterozygous carrier for a recessive disease-causing mutation, the child will inherit two copies of that mutated gene. This homozygosity means the child will be affected by the recessive disorder, even though only one parent was a carrier. For example, if a parent carries a mutation for cystic fibrosis, and the child receives two copies of the chromosome segment containing that mutation via Isodisomy, the child will develop cystic fibrosis.