A recent study published by Nakka, et al.1 received media attention,2-5 reporting that about twice as many people as previously thought have a genetic finding called uniparental disomy (UPD). But what exactly does that mean?
What is uniparental disomy?
Chromosomes come in pairs, and we typically get one copy from each pair from each parent. Uniparental disomy (UPD) is when both copies of a chromosome pair are inherited from the same parent rather than one copy from mom and one copy from dad. This is generally a random event that occurs during early in the development of an embryo.6
Genetic testing such as chromosomal microarray (CMA) can identify a type of genetic change called absence of heterozygosity (AOH) which may suggest UPD. We usually think of CMA as a test that looks for deletions and duplications. CMA can also look at single letter DNA variants called polymorphisms. We expect the polymorphisms on the copy of the chromosome from mom and the copy of the chromosome from dad to have differences. But sometimes the polymorphisms will be the same across long stretches of a chromosome. This is called AOH. It can also be called long continuous stretches of homozygosity (LCSH) or a run of homozygosity (ROH).
What are the issues that can arise from UPD?
Most of the time UPD does not result in any symptoms. However, it can occasionally result in an imprinting disorder or autosomal recessive condition.
Imprinting is a normal process in which a gene from one parent is “turned off” while the same gene from the other parent is “turned on.” It only occurs in regions of some chromosomes. If a person has UPD of an imprinted chromosome, it could impact imprinting, leading to both gene copies being turned on or both being turned off.6 This can lead to a genetic condition.
An example of an imprinting condition is Angelman syndrome. This can be caused in a few ways; these are the two more common ways:
A deletion of a certain region on the copy of chromosome 15 from mom
UPD of chromosome 15 where a child has both copies from dad
Usually there should be a gene “turned on” from mom’s chromosome, but in the case of a maternal deletion or paternal UPD 15 there is no “on” signal resulting in Angelman syndrome.7
Autosomal recessive condition
An autosomal recessive condition is one that is caused by both gene copies not working as they should. A person with only one copy of a gene related to an autosomal recessive condition not working is called a carrier.8 If a child has UPD of a chromosome in which a parent carries a genetic change for an autosomal recessive condition, it can result in the child inheriting two copies of that genetic change and being affected with the condition.
Can UPD be linked to autism?
Angelman syndrome, used in the imprinting disorder example above, is associated with autism. Other symptoms of Angelman syndrome include developmental delay, intellectual disability, speech impairment, movement or balance difficulties, seizures, a small head, and a happy and excitable demeanor.7
The Nakka, et al. study found UPD of chromosome 22 (maternal or paternal) was significantly associated with a higher risk for autism.1 However, further studies are needed to determine the role of UPD22 in autism, if any.
Autism can be a feature of other genetic conditions that can result from UPD, such as Prader-Willi syndrome (UPD of the maternal copy of 15). Other childhood symptoms of Prader-Willi syndrome include developmental delays, learning disabilities, intellectual disability, behavior difficulties, unique facial features, short stature, and an insatiable appetite leading to obesity.9
Is UPD something my family should be tested for?
UPD often does not impact a person’s health and, in general, most people do not need to be tested for it. However, a healthcare provider may recommend testing for individuals who have symptoms of an imprinting disorder. Additionally, CMA is a recommended genetic test for individuals with autism, developmental delay, or intellectual disability. Occasionally UPD will be detected by this testing. Testing for UPD is not recommended for individuals who are asymptomatic.
UPD is more common that previously thought. Since it doesn’t impact most people’s health, it typically goes undetected.
UPD can be involved in symptoms for some people, particularly with imprinting or autosomal recessive conditions. UPD22 may increase the chance for autism.
Most people do not need to be tested for UPD. In individuals with certain symptoms, testing for a specific imprinting disorder or CMA may be recommended.