Uniparental Disomy: Shedding light on a rare genetic mystery

About Author: Dr. Aparna Ganapathy, Director – Population Genomics, Strand Life Sciences. Dr. Aparna has over 15 years of experience in the field of Molecular genetics and Genomics. She has overseen NGS based genetic testing of over 5000  cases primarily in the area of inherited Rare Disease Diagnostics. A CSIR-fellow and gold medallist, she has authored and co-authored >20 peer-reviewed  publications in international journals and participated in several national and  international conferences in the field of genomics.

Uniparental Disomy (UPD) is a rare genetic event that challenges both families and doctors with its complexity and its subtlety. Every person has 46 chromosomes, arranged in 23 pairs—one set from the mother, and one set from the father. This balanced contribution is essential for normal growth and development. 

But in UPD, for a particular chromosome pair, this balance is disturbed. 

What exactly is UPD?

UPD occurs when a person inherits both copies of a chromosome (or part of a chromosome) from one parent, instead of the usual one from each parent. But, UPD does not always lead to health problems. In many cases, UPDs are discovered by chance during genetic testing done for unrelated reasons, and researchers have found that they may occur in about 1 in 600–2,000 births. However, UPDs can sometimes cause two types of disorders.

One, imprinting disorders, where certain genes are normally active only on the maternal or paternal copy. When both copies come from the same parent, this normal pattern is disturbed. For example, UPDs in specific chromosomes can cause conditions such as Prader–Willi syndrome (paternal UPD 15), Angelman syndrome (maternal UPD 15), and Beckwith–Wiedemann syndrome (paternal UPD 11).

Two, recessive genetic conditions usually occur when both copies of a gene—one inherited from each parent—carry the same harmful mutation. In some rare cases, this can happen if UPD occurs, and a child inherits both copies of a chromosome (or part of it) from one parent instead of one from each. Some examples of such conditions are cystic fibrosis (caused by mutations in the CFTR gene if UPD 7 occurs), β-thalassemia (caused by mutations in the HBB gene if UPD 11 occurs), and Gaucher disease (caused by mutations in the GBA gene if UPD 1 occurs). However, such conditions are rare.

Not all chromosomes carry the same risk. Conditions linked to UPD most often involve chromosomes 6, 7, 11, 14, 15, and 20. 

How does UPD happen?

UPDs are usually random events that occur early in life—often before a person is even born. They are not caused by lifestyle, and in most cases, are not inherited. Two of the ways in which UPDs can arise are given below.

One, during errors in egg or sperm formation: A chromosome may fail to separate properly, creating an egg or sperm with an extra or missing chromosome.

Two, during “rescue” events in early embryos: If an embryo starts with an abnormal number of chromosomes (usually because one of the chromosomes has 3 copies instead of two), a “rescue” event can remove one of the copies; sometimes, this rescue leaves behind two identical copies of the chromosome from the same parent.

Why is diagnosing UPD so challenging?

Most people with UPDs have no symptoms at all, which makes them invisible conditions unless genetic testing is performed.

When UPDs do cause problems, the symptoms are often non-specific: growth delays, learning challenges, or unusual combinations of features that resemble other common conditions. As a result, UPD is rarely the first explanation considered.

Adding to the challenge, routine genetic tests do not always pick up UPD. Standard DNA sequencing might show a “homozygous” change (two identical copies of a gene) but cannot reveal whether both copies came from one parent. Detecting UPD usually requires several types of tests.

One type of test is single nucleotide polymorphism (SNP) microarray (chromosome microarray). This test detects long stretches of DNA with no genetic variation (called Regions Of Homozygosity or ROH), which is a hallmark of UPDs. Typically, ROH on a single chromosome can indicate UPD, but trio analysis (testing of both parents along with the child) is needed to confirm it. In addition, these tests can also reveal missing or extra pieces of chromosomes.

Another type of test is a methylation test. This is used when certain imprinting disorders are suspected. These tests check if certain key genes are active or silenced as expected in UPDs.

In complex or unexplained cases, whole genome sequencing (WGS) can uncover UPD while also screening for other genetic changes. However, WGS can detect UPD only if parental data or allele balance is also analyzed. Allele balance looks into the data on genetic variations at many genetic positions. Abnormal allele balance patterns across a chromosome can suggest that both chromosome copies were inherited from one parent, helping confirm UPD.

In most cases, SNP microarrays and methylation tests are the first step when UPD is suspected.

Why does an accurate diagnosis matter?

A UPD diagnosis can provide a clear explanation for otherwise puzzling medical findings. In some cases, a diagnosis can provide better care plans, as some UPDs are linked to specific syndromes with well-defined management guidelines. Finally, a confirmed diagnosis can provide peace of mind for families, who can learn whether a finding is likely to affect future children.

Looking forward: Better awareness, better answers

With the growing availability of advanced genetic testing, especially WGS services offered by companies such as Strand Life Sciences, UPDs are being detected more often than ever. However, the path to diagnosis can still be long, especially when symptoms are subtle or do not match classic syndromes. Awareness among doctors, genetic counselors, and families is key to ensuring that UPD is considered when other causes remain unexplained.

The good news? For many people, a UPD finding is simply part of their unique genetic story—not a cause for alarm. And for those where UPD does have an impact, early detection can guide treatment, improve outcomes, and support informed family planning.

*The views shared by the author are her own.