Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or segment, from one parent and not the other. This abnormality has been observed in all chromosomes and generally does not result in a clinical phenotype. However, UPD can lead to the absence of essential copies of active genes that are regulated by genomic imprinting or result in expression of autosomal recessive mutations.  In these situations, clinical manifestations of UPD can result in symptoms such as delayed development, intellectual disability, or other health problems.

UPD occurs at a frequency of 1 in 2000 individuals worldwide (1). The most well-known conditions of UPD include Prader-Willi syndrome, characterized by binge eating and obesity, and Angelman syndrome, which causes intellectual disability and impaired speech (2). Techniques for detecting UPD include short tandem repeat analysis and next-generation sequencing (NGS), which is confirmed using segregation analysis of polymorphic alleles in the patient and parents (3).

One case study where UPD was observed was at the Hadassah Medical Center in Jerusalem, which analyzes thousands of rare genetic disorders annually. In this case study, prenatal testing was requested by the expecting parents and exome sequencing was performed on the fetus and parents. The fastq files were processed using the secondary pipeline integrated into Geneyx and the output VCF files were analyzed in a trio workflow using Geneyx Analysis.

UPD is automatically calculated in Geneyx Analysis when running trio exomes and genomes by comparing each variant of the proband to the parents. As shown in Figure 1, this feature shows the chromosome, significance (p-value), and category of inheritance, with the ability to further investigate maternal and paternal hetero- and isodisomy. In this case, the fetus was positive for a maternal UPD on chromosome 15 which was highly significant. This incidental finding of prenatal testing was then communicated to the expecting parents.

Figure 1: Geneyx Analysis displays UPD 15 inherited from the mother.

Although UPD is a rare disease, it is important to be able to detect it when using next-generation sequencing data. In this example, Geneyx Analysis was able to accurately identify an incidental finding of maternal UPD on chromosome 15, which could then be provided to the parents to make informed decisions. Without the integration of UPD analysis, this outcome would not have been possible. In summary, Geneyx Analysis is a leading variant analysis and interpretation platform that can handle complex cases, including the detection of UPD. For this reason, the Hadassah Medical Center in Jerusalem, and other hospitals worldwide, can continue to identify rare mutations using Geneyx Analysis and improve diagnostic yields and patient outcomes.

Works Cited:

1. Liehr, T. Uniparental disomy is a chromosomic disorder in the first place. Mol Cytogenet 15, 5 (2022). https://doi.org/10.1186/s13039-022-00585-2
2. https://medlineplus.gov/genetics/understanding/inheritance/updimprinting/
3. Yauy, K., de Leeuw, N., Yntema, H.G. et al. Accurate detection of clinically relevant uniparental disomy from exome sequencing data. Genet Med 22, 803–808 (2020). https://doi.org/10.1038/s41436-019-0704-x