Normally a child gets one copy of each chromosome from each parent. Sometimes both copies of a chromosome come from the same parent, which is called uniparental disomy, or UPD. Heterodisomy and isodisomy are the two forms of UPD, and the difference is whether the two copies from that parent are different from each other or identical. That distinction can change which health problems a child is at risk for and which test is able to find it.
What Each Term Means
Every parent carries two versions of each chromosome, one inherited from each of their own parents, and the two versions usually differ in small ways. Heterodisomy means a child inherits both of one parent’s two different versions.1PubMed Central. Case Report: Paternal Uniparental Isodisomy and Heterodisomy of Chromosome 16 With a Normal Phenotype Isodisomy means the child inherits two identical copies of just one of that parent’s versions.2PubMed Central. Case Report: Paternal Uniparental Isodisomy and Heterodisomy of Chromosome 16 With a Normal Phenotype Which of the parent’s two versions gets doubled in isodisomy is down to chance, one reason children with isodisomy can differ from each other.
Real cases are often mixed. Chromosomes swap pieces while eggs and sperm form, so a single UPD chromosome can show identical stretches among different ones.3PubMed Central. Case Report: Paternal Uniparental Isodisomy and Heterodisomy of Chromosome 16 With a Normal Phenotype A report may therefore call a chromosome partly heterodisomic and partly isodisomic. The identical stretches often sit near the ends of the chromosome while the middle still shows two different versions, though the pattern varies from case to case. One child with mixed paternal heterodisomy and isodisomy of chromosome 16 developed normally.4PubMed Central. Case Report: Paternal Uniparental Isodisomy and Heterodisomy of Chromosome 16 With a Normal Phenotype
On a report, you may see UPD written with a chromosome number and “mat” or “pat,” as in upd(15)mat. “Mat” means both copies came from the mother, and “pat” means from the father. Words like “iso” or “hetero” tell you which form the lab found. UPD can also affect only part of a chromosome, which reports call segmental UPD.5OBM Genetics. Uniparental Disomy and Imprinting Disorders
How Each Type Happens
The timing of the original error decides the type. Egg and sperm cells are made by a division process with two stages, and each stage separates a different thing. In the first stage, the two different versions of a chromosome pair are pulled apart. If they fail to separate, one cell gets both different versions, which leads to heterodisomy.6PubMed Central. Case Report: Paternal Uniparental Isodisomy and Heterodisomy of Chromosome 16 With a Normal Phenotype In the second stage, the two identical halves of each chromosome are pulled apart. If they fail to separate, one cell gets two identical copies, which leads to isodisomy.7PubMed Central. Case Report: Paternal Uniparental Isodisomy and Heterodisomy of Chromosome 16 With a Normal Phenotype
The parent matters too. Over 82% of mother-derived UPD of chromosome 15 traces to a first-stage error.8PubMed Central. Nondisjunction of chromosome 15: origin and recombination. Most father-derived UPD 15, though, seems to arise after conception instead.9PubMed Central. Nondisjunction of chromosome 15: origin and recombination.
“After conception” means the UPD begins in the embryo itself. A cell that started with a single copy of a chromosome can duplicate it to get back to two, and the duplicate is identical to the original. That route gives isodisomy, since both copies are the same one copied twice.
The most common route to UPD starts with an embryo that has three copies of a chromosome and then loses one, called trisomy rescue.10PubMed Central. Trisomy rescue mechanism: the case of concomitant mosaic trisomy 14 and maternal uniparental disomy 14 in a 15‐year‐old girl An egg or sperm carries an extra chromosome, so the embryo starts with three copies, and some cells then drop one copy to restore two. If the dropped copy is the other parent’s, the remaining two both come from one parent.11PubMed Central. Trisomy rescue mechanism: the case of concomitant mosaic trisomy 14 and maternal uniparental disomy 14 in a 15‐year‐old girl Rescue after a first-stage error tends to give heterodisomy.12PubMed. Advanced parental age in maternal uniparental disomy (UPD): implications for the mechanism of formation Rescue can be incomplete, leaving some cells with three copies. UPD can also arise when an egg missing a chromosome meets a sperm carrying two.13PubMed Central. Trisomy rescue mechanism: the case of concomitant mosaic trisomy 14 and maternal uniparental disomy 14 in a 15‐year‐old girl
Parental age links to one type more than the other. Older maternal age raises the chance of egg-formation errors that can lead to UPD.14PubMed Central. Incomplete Trisomy Rescue Reveals the Mechanism Underlying Discordance Between Noninvasive Prenatal Screening and Prenatal Diagnosis Mothers of children with heterodisomy tend to be older than those of children with isodisomy.15PubMed. Advanced parental age in maternal uniparental disomy (UPD): implications for the mechanism of formation In chromosome 15 cases from first-stage errors, mothers averaged about 36 when mixed iso/hetero stretches appeared versus about 33 when they didn’t.16PubMed. Maternal meiosis I non-disjunction of chromosome 15: dependence of the maternal age effect on level of recombination
These are random errors in cell division, and nothing parents did causes them.
Why the Type Matters for Health
Many people silently carry one faulty copy of a gene for a recessive disease like cystic fibrosis. With isodisomy, that one faulty copy can appear twice, causing the disease.17Best Practice & Research Clinical Endocrinology & Metabolism. Uniparental disomies 7 and 14 Children have been found with cystic fibrosis when only one parent was a carrier, explained by isodisomy.18Best Practice & Research Clinical Endocrinology & Metabolism. Uniparental disomies 7 and 14 So a disease appearing with only one carrier parent does not necessarily point to a paternity question.19Best Practice & Research Clinical Endocrinology & Metabolism. Uniparental disomies 7 and 14
Heterodisomy rarely does this. The child has both of the parent’s different versions, so a single faulty copy is paired with that parent’s other, usually working, copy. There are exceptions: if both of a parent’s versions happen to carry a fault, or in mixed cases where the identical stretch holds the gene, so the location on the chromosome matters.
The second kind of risk affects both types. Some genes work only from the mother’s copy or only from the father’s, a pattern called imprinting. Getting both copies from one parent can switch those genes off or double them, whatever the UPD type. Among 19 Prader-Willi syndrome patients with maternal UPD 15, 11 had heterodisomy and 8 isodisomy.20PubMed Central. Genetic subtypes and phenotypic characteristics of 110 patients with Prader-Willi syndrome Maternal isodisomy of part of chromosome 11 has been found in Silver-Russell syndrome, a growth disorder.21PubMed Central. Mosaic Segmental and Whole-Chromosome Upd(11)mat in Silver-Russell Syndrome Segmental isodisomy of chromosome 11 is a main cause of Beckwith-Wiedemann syndrome, an overgrowth disorder.22OBM Genetics. Uniparental Disomy and Imprinting Disorders
Transient neonatal diabetes is a clear paternal example. It affects about 1 in 400,000 newborns, who are usually small at birth.23PubMed. Paternal uniparental disomy of chromosome 6 and transient neonatal diabetes mellitus About one fifth of cases come from paternal UPD of chromosome 6.24PubMed. Paternal uniparental disomy of chromosome 6 and transient neonatal diabetes mellitus Two father’s copies of a gene on chromosome 6 appear to disrupt insulin release.25PubMed. Transient but not permanent neonatal diabetes mellitus is associated with paternal uniparental isodisomy of chromosome 6 It has been reported with paternal isodisomy of chromosome 6, with varying features between children.26European Journal of Human Genetics. Variable features of transient neonatal diabetes mellitus with paternal isodisomy of chromosome 6
The imprinting risk depends on which chromosome and which parent are involved, while the recessive risk depends on whether the copies are identical. Isodisomy can carry both, while heterodisomy mainly carries the first. Many UPDs on chromosomes without imprinted genes cause no problem at all.
After a UPD result, useful questions for the doctor include which chromosome is involved and from which parent, whether it is whole or segmental, and whether it is iso or hetero. You can also ask whether there is a known syndrome for that chromosome, and whether anyone should be tested as a recessive gene carrier.
How Tests Tell Them Apart
A routine chromosome count looks normal in UPD because the number of chromosomes is correct.27Mayo Clinic Laboratories. Uniparental Disomy, Varies It says nothing about where each copy came from. Finding it takes DNA testing with many markers along the chromosome.28Mayo Clinic Laboratories. Uniparental Disomy, Varies
The classic test compares markers in the child and both parents.29Mayo Clinic Laboratories. Uniparental Disomy, Varies The lab reads many known variable spots along a chromosome in all three people. If the child’s pair matches only one parent at those spots and nothing from the other, that is UPD. A child carrying both of that parent’s different versions has heterodisomy, and one carrying a single version twice has isodisomy. That is why labs usually ask for samples from both parents as well as the child or fetus.30The University of Chicago Genetic Services. UPD14 testing Cheek swabs or blood are typical, and testing a parent is about tracing inheritance, not finding fault.
Some tests see only isodisomy. Isodisomy shows up as long stretches where both copies match, which a chromosome microarray can spot.31PubMed. Uniparental disomy: can SNP array data be used for diagnosis? But those scans missed heterodisomy in three of four confirmed cases.32PubMed. Uniparental disomy: can SNP array data be used for diagnosis? In one series, 29% of UPD 15 cases confirmed by parent-comparison testing were missed by the array.33Genetics in Medicine. Uniparental disomy: can SNP array data be used for diagnosis? Exome sequencing of child and both parents can catch all UPD types by spotting inheritance that doesn’t fit, while child-only sequencing finds isodisomy only.34PubMed Central. Accurate detection of clinically relevant uniparental disomy from exome sequencing data
If a child’s symptoms fit a UPD syndrome, it is reasonable to ask about parent-comparison testing. Imprinting syndromes may also be checked with specific methylation tests.
UPD Found During Pregnancy
Sometimes a screening blood test or CVS shows an extra chromosome only in the placenta and not in the baby. The baby may then have reached two copies by trisomy rescue, which can leave UPD.35PubMed Central. Incomplete Trisomy Rescue Reveals the Mechanism Underlying Discordance Between Noninvasive Prenatal Screening and Prenatal Diagnosis In one large study, the baby had maternal UPD in 17 of 94 such placental cases, most involving chromosome 16.36PubMed Central. Meiotic origin of trisomy in confined placental mosaicism is correlated with presence of fetal uniparental disomy, high levels of trisomy in trophoblast, and increased risk of fetal intrauterine growth restriction All those UPD cases came from an egg-formation error, the kind linked to heterodisomy.37PubMed Central. Meiotic origin of trisomy in confined placental mosaicism is correlated with presence of fetal uniparental disomy, high levels of trisomy in trophoblast, and increased risk of fetal intrauterine growth restriction
An extra chromosome found only in the placenta is called confined placental mosaicism, and the baby’s own cells may be normal. Rescue may also be incomplete, which can explain a screening result that doesn’t match diagnostic testing.38PubMed Central. Incomplete Trisomy Rescue Reveals the Mechanism Underlying Discordance Between Noninvasive Prenatal Screening and Prenatal Diagnosis
A screening blood test estimates the chance of a chromosome problem and can be wrong, partly because it picks up DNA from the placenta. A positive result is a reason for further testing, not a conclusion about the baby, and many babies with such a result turn out to be unaffected. Amniocentesis may be offered to check the baby’s own cells. UPD testing matters most for chromosomes with imprinted genes, like 6, 7, 11, 14 and 15, and growth monitoring by ultrasound may be suggested.
UPD 16 often comes up because placental trisomy 16 is common. A genetic counselor can explain the specific chromosome’s risks.
Chances of It Happening Again
Most UPD results from a chance error in one egg, sperm or early embryo, not from something built into the parents’ DNA. A chance error is not expected to repeat in the same way, so for most families the chance of another child with UPD is low and not much higher than for other couples.
The exception involves chromosome rearrangements. Some trisomy 14 rescue cases trace to a parent’s Robertsonian translocation, a rearrangement where two chromosomes are joined.39PubMed Central. Trisomy rescue mechanism: the case of concomitant mosaic trisomy 14 and maternal uniparental disomy 14 in a 15‐year‐old girl A person with one often has no health problems, but their eggs or sperm can end up with too much or too little of the joined chromosomes, which makes trisomy and later rescue more likely. Parents of a child with UPD may therefore be offered their own chromosome test. For couples who do have a translocation, IVF with embryo testing can screen for unbalanced chromosomes, and a genetic counselor can lay out the actual numbers for that rearrangement. UPD itself is very rare in IVF embryos, found as isodisomy in only 2 of 3,401 tested.40PubMed. Uniparental disomy (UPD) exclusion in embryos following Preimplantation Genetic Testing for Structural Rearrangements (PGT-SR)
If isodisomy unmasked a recessive disease, one parent is a carrier, and that parent’s relatives may be carriers too. Siblings can ask about carrier testing before having children.