Hybrid-SNP Microarrays for Uniparental Disomy

Genetic Inheritance and Health Risks It Carries

Prenatal and postnatal genetic testing are increasingly common as researchers seek to learn more about genetic inheritance and health risks they carry.

Uniparental Disomy (UPD)

One genetic risk factor that is getting increased attention is uniparental disomy (UPD), in which a chromosomal duplication error results in having two copies of one parent’s chromosome and none from the other. Dr. Stuart Schwartz, Associate Vice President and Senior Director of Cytogenetics of the Laboratory Corporation of America at the Center for Molecular Biology and Pathology, explains the significance of UPD, the genetic conditions it can cause, and how hybrid-SNP chromosomal microarrays (CMAs) can help detect it.

UPD typically starts from a more common trisomy, from a duplicated chromosome from one parent. Chromosomal repair mechanisms can mistakenly destroy the corresponding chromosome from the other parent rather than the duplicate, resulting in a fetus that has a normal karyotype but a very high degree of homozygosity in the affected chromosome.

Copy Number Variation (CNV) Assays and SNPs in Hybrid-SNP Microarrays

Because of this pattern, Dr. Schwartz explains that conventional chromosomal microarrays can often make little sense of uniparental disomy. Since the overall number of copies of most genes remains normal in this situation, copy number variation (CNV) assays struggle to detect this condition, and it also appears normal on karyotypes. In combination with single-nucleotide polymorphisms (SNPs) in hybrid-SNP microarrays, however, copy number variations can provide the data needed to recognize UPD and detect the associated genetic conditions.

Solving Complex UPD Genetic Situations

Emphasis on the quality of the data produced may help solve particularly complex genetic situations, such as multiple simultaneous UPD events in different chromosomes or UPD combined with a homozygous deletion somewhere on the affected chromosome. With UPD implicated in as many as 40% of all cases of transient neonatal diabetes mellitus, it is more important than ever to bring this sea change in microarray technology into more research laboratories.

UPD poses a particular danger when it affects genes subject to chromosomal imprinting, in which only the maternal or paternal copy of a chromosome is expressed in some or all cells. When UPD occurs in these chromosomes, which include 6, 7, 11, 14, 15, and 20, that imprinting process must contend with either a double dose of those genes or their absence, resulting in some characteristic health conditions.

In some cases, UPD in a given chromosome can cause either of two separate pathologies depending on whether the duplicated copy is of maternal or paternal origin.  Dr Schwartz highlights that UPD in chromosome 15 causes Prader-Willi syndrome when the affected chromosome is maternal and Angelman syndrome when it is paternal. Uniparental disomy has other effects too; for example, UPD can both look like and have the same health effects as consanguinity, making it important to be able to distinguish the two situations.

As Dr. Schwartz puts it, “It’s hard to imagine coming from looking at chromosomes and now being able to see all these underlying changes that we never quite knew went on… now we’re getting insight into some of the mechanisms that we never could have imagined that went on with human chromosomes.”

Case Study Video Series – Watch Dr. Schwartz’s webinar and learn more on the detection of UPD with CMA. Other videos include case examples that highlight the unique position CMA and hybrid-SNP arrays hold in prenatal and postnatal testing, providing resolution to otherwise unsolved clinical research questions.

Related Resources

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» Choose the Right Chromosomal Microarray – Are all microarrays equal? Scientists share their journey – learn why GeneDx chose CytoScan chromosomal microarrays.