As part of the family case analysis that includes both parents, Franklin now includes UPD detection.

UPD (Uniparental Disomy) refers to the inheritance of two copies of a chromosome, or part of a chromosome, from one parent, instead of one copy from each parent. UPD can occur as a result of errors during cell division, such as nondisjunction, which causes the failure of chromosomes to separate properly during meiosis. UPD can lead to genetic disorders if the chromosome that is inherited in duplicate contains genes that are imprinted, meaning they are normally expressed from only one of the two copies of the chromosome.

There are two types of UPD - Isodisomy and heterodisomy. Isodisomy occurs when an individual inherits two identical copies of a chromosome or a segment of a chromosome from one parent. This can happen if there is a mistake in meiosis, the process of cell division that produces eggs or sperm. Isodisomy can also occur if one copy of a chromosome is lost during early embryonic development and the remaining copy is duplicated.

In heterodisomy, the two copies of the chromosome that are inherited from one parent are not identical, meaning they have different genetic information. This condition can occur due to a variety of reasons, such as a failure of the chromosomes to separate properly during meiosis or an error in the fertilization process.

When a UPD is detected, it will be displayed on the WB. If it is curated to have a clinical impact it will be flagged in red, together with the related condition and the Omim link out.

When a UPD is not detected, the QC metric will show “UPD - Run Completed”, and below under the ‘additional information section’ it will show: “UPD: No UPD was detected”.

The detection algorithm is based on SNPs of both parents and the proband.

Initially, SNPs are filtered by restrictive confidence rules, to eliminate artifacts. Then, for each parent and chromosome, each variant is tagged as either supportive, contradictive, or uninformative regarding uniparental disomy of the relevant parent in the designated chromosome, according to the following table:

Clustering methodology is applied to aggregate supportive variants, allowing a minor ratio of contradictive variants of 0.035. Clusters are then split into ranges of Isodisomies and Heterodisomies, based on differentiative evidence inside the defined cluster. Isodisomy differentiators are variants that appear as heterozygous in the designated parent and either as homozygous alternate or as homozygous reference in the proband.

Finally, clusters of size larger than 4Mbps, containing at least 20 supportive variants are filtered. and their breakpoints are refined. Breakpoints are defined either by a supportive variant, or by a chromosome end, when no contradictive variants are blocking the UPD expansion.