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SDS & Science Snapshots (2023-11-04)

In this issue: What is a pseudogene and why does it matter? Important genetic testing considerations for SDS.

Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email or message us on Facebook! This is all for you!

SBDS pseudogene complicates receiving an accurate genetic diagnosis for SDS

Long diagnostic journeys, otherwise known as the diagnostic odyssey, are not uncommon across rare diseases, specifically SDS. The barriers to diagnosis often vary but can include limited access to providers knowledgeable about SDS, nonspecific initial SDS symptoms that can overlap with other conditions (e.g., pancreatic insufficiency can also be seen in patients with cystic fibrosis), and difficulties accessing genetic testing (see our Science Snapshot from 2023-02-05). However, even once genetic testing has been completed, some individuals with SDS face additional barriers to receiving a genetic diagnosis due to false-negative or false-positive results, again prolonging the diagnostic odyssey.

In the article we are highlighting this week, inaccuracies in data analysis and special considerations for genetic testing for SDS, and the SBDS gene more specifically, are discussed. The authors describe a 3-month-old female in Korea with suspected SDS due to typical SDS symptoms (neutropenia, anemia, failure to thrive, decreased pancreatic enzymes, and elevated liver enzymes) who participated in genetic testing for SDS. Genetic testing revealed increased levels of one variant (i.e., mutation) commonly seen in individuals with SDS, but the proportion of this variant in comparison to other genetic changes was still lower than expected. This prompted the authors to complete a different type of genetic testing, called Sanger sequencing, which analyzes the SBDS gene one genetic position at a time. Sanger sequencing not only identified the previously detected variant, but it also detected a second genetic variant which is another variant commonly seen in individuals with SDS. Identification of this second variant in SBDS confirmed this individual’s diagnosis of SDS. But why was this second genetic variant not identified using the first method of genetic testing?

Our genetic information, or DNA, collectively known as the genome, is a collection of over three billion letters (i.e., bases, A, T, G, or C) in a very specific sequence to form genes. However, less than 1% of these genes are used as instructions for building proteins (i.e., protein-coding genes). The bases in the remaining 99% of our genome contain important regulatory regions, protective DNA regions, and pseudogenes which can be compared to a “genomic fossil.” As a result of evolution, these pseudogenes were once considered to be functional protein-coding genes but are now inactive and obsolete genes in our genomic information today. These pseudogenes are highly similar in their sequence to that of their functional, protein-coding genes’ counterparts, and depending on the level of similarity (i.e., homology), can be difficult to differentiate between when performing genetic sequencing and data analysis. Some of the defects in pseudogenes that result in their inactivation are outlined in the image below.

Examples of defects that are responsible for the non-functionality of pseudogenes. Source:

The SBDS gene, the gene mutated in most individuals with SDS, has a pseudogene, or genomic fossil, in another part of the genome. Depending on the sequencing method, protein-coding gene sequences can be switched with pseudogenes, such as SBDS, resulting in a false-positive or false-negative result.

This YouTube video, published by PBS, explores pseudogenes through a historical lens and shares other real-life examples of pseudogenes and the important role they used to play.

Compared to NGS methods, Sanger sequencing reads/identifies one genetic base at a time without fragmenting the original sequence. As a result, there is no re-alignment necessary, dramatically reducing the risk of inaccurate genetic testing results. Sanger sequencing is considered the gold standard of genetic testing for this reason, but is more time-consuming, labor intensive in its preparation, and expensive in comparison to NGS methods. In this week’s article, Sanger sequencing was performed as a second method of genetic testing and successfully identified two variants in the SBDS gene, confirming an SDS diagnosis for the 3-month-old female.

The authors from this week’s article encourage readers to acknowledge “the risk of erroneous diagnosis of disease-causing genes with pseudogenes when performing short-read NGS.” Another report from April 2020, written by Yamada et al. (PMID: 32412173), discusses a similar experience with short-read NGS in multiple individuals with SDS and advocates for the use of other genetic testing methods (e.g., Sanger sequencing or long-read sequencing) to identify and/or confirm SBDS variants.

Accurate genetic diagnoses of SDS are important for implementing appropriate screening protocols and treatment regimens. For those with negative genetic testing or one SBDS variant detected using short-read NGS and a clinical presentation suspicious for SDS, follow-up genetic testing could be considered using Sanger sequencing, long-read NGS sequencing, deletion analyses, and/or RNA sequencing to confirm the presence (or absence) of another variant in SBDS.


For more information regarding pseudogenes, you can refer to the Talking Glossary of Genomic and Genetic Terms on the National Human Genome Research Institute’s website or to this article published by Blueprint Genetics, a genetic testing company.

Variant Allele Frequency of Pseudogene-Related Variants in Short-read Next-Generation Sequencing Data May Mislead Genetic Diagnosis: A Case of Shwachman-Diamond Syndrome.

Lee H, Lee JA, Lee H, Lee JS, Ko JM, Kim MJ, Seong MW.

Ann Lab Med. 2023 Nov 1;43(6):638-641.

doi: 10.3343/alm.2023.43.6.638.

PMID: 37387500

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