Uniparental disomy (UPD) occurs when both copies of a chromosome (or chromosomal region) are inherited from the same parent. It can cause disease through two mechanisms: disruption of imprinted gene expression and unmasking of autosomal recessive variants.
- Heterodisomy: Two different homologs from the same parent (both of mom's chromosome 15s, for example). Arises from meiosis I nondisjunction followed by trisomy rescue.
- Isodisomy: Two identical copies of the same homolog. Arises from meiosis II nondisjunction or post-zygotic mitotic error. Creates long runs of homozygosity (ROH).
- Trisomy rescue: The most common mechanism. A trisomic conceptus loses one of the three chromosomes. If the remaining two are from the same parent, UPD results. There is a 1/3 chance of UPD after trisomy rescue.
- Monosomy rescue: A monosomic cell duplicates its single chromosome, always producing isodisomy.
- Segmental UPD: Only part of a chromosome shows UPD, typically from a post-zygotic mitotic recombination event.
1. Imprinted chromosomes
UPD only causes clinical problems when it involves a chromosome with imprinted genes:
| UPD | Condition | Key features |
|---|---|---|
| Maternal UPD 15 | Prader-Willi syndrome | Paternal 15q11 genes silenced (missing) |
| Paternal UPD 15 | Angelman syndrome | Maternal UBE3A silenced (missing) |
| Paternal UPD 11p15 | Beckwith-Wiedemann syndrome | Overexpression of IGF2 |
| Maternal UPD 11p15 | Silver-Russell syndrome | Loss of IGF2 expression |
| Maternal UPD 7 | Silver-Russell syndrome | ~10% of cases |
| Maternal UPD 14 | Temple syndrome | (Paternal UPD 14 = Kagami-Ogata syndrome) |
| UPD 6, 20 | Transient neonatal diabetes (patUPD6); maternal UPD20q → pseudohypoparathyroidism type 1B (GNAS locus) |
2. Unmasking AR conditions (any chromosome)
Isodisomy makes the child homozygous for every variant on that chromosome. If the contributing parent is a carrier for an AR condition, the child becomes homozygous, even though only one parent carries the variant.
- Example: A child with CF whose mother is a carrier but father is not. Maternal isodisomy of chromosome 7 made the child homozygous for the maternal CFTR variant.
- Clue: An AR condition where only one parent is a carrier suggests UPD.
- SNP microarray: Detects long continuous stretches of homozygosity (ROH/LOH). Isodisomy shows as ROH spanning the entire chromosome. Heterodisomy is harder to detect and may require parental samples.
- Methylation studies: Detect imprinting abnormalities (e.g., methylation-specific MLPA for 15q11).
- Microsatellite analysis: Compares parental alleles to determine parent of origin. Gold standard for confirming UPD but requires parental samples.
- Imprinting disorder with normal copy number (no deletion)
- AR condition with only one carrier parent
- Confined placental mosaicism on CVS (trisomy in placenta, normal karyotype in fetus, which may have undergone trisomy rescue)
- Long ROH on SNP array involving an entire chromosome
- History of consanguinity should be excluded first (consanguinity causes ROH on multiple chromosomes, UPD causes ROH on a single chromosome)
"1 in 3 after trisomy rescue": when a trisomic pregnancy undergoes trisomy rescue, there is a 1/3 chance that both remaining chromosomes came from the same parent (UPD). This is why UPD testing is recommended after CVS shows confined placental mosaicism.
"Iso = Identical = homozygous everywhere": isodisomy creates complete homozygosity along the affected chromosome, which is why it can unmask AR conditions from a single carrier parent.