SDS & Science Snapshots (2022-03-06)

In this issue: Genes involved in SDS, autosomal recessive inheritance, and what is a mutation vs. a VUS?

Welcome to our weekly updates on all things SDS and Science. 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 connect@SDSAlliance.org or message us on Facebook! This is all for you!

What genes are responsible for SDS?

Our genomes are organized into 23 pairs of chromosomes, made up of very long stretches of DNA. Genes are shorter sequences on the DNA, and each gene encodes one specific protein. Usually, the name of the gene corresponds to the name of the protein. The gene responsible for over 90% of SDS cases is called SBDS (for Shwachman-Bodian-Diamond-Syndrome), and the protein it encodes is called the SBDS protein. It was discovered by Dr. Johanna Rommens and her team, and published in 2003. Since then, several additional genes have been implicated in SDS, namely DNAJC21, EFL1, and SRP54. This GeneReviews article provides a comprehensive overview. Each of these newer genes account for less than 1% of SDS patients.

For about 10% of patients who meet the clinical definition of SDS, no genetic cause has been found thus far. This means that they don't have mutations in any of the genes mentioned above, or have only one mutation (which would only make them carriers). Research is ongoing in several labs around the world to look for additional genes that could be responsible for SDS; and to find additional hard-to-find mutations in the known genes. For example, traditional sequencing techniques are not able to identify large deletions that could have removed parts of the chromosome that contain the SBDS gene, and the patient could appear to have only one mutation. To find such large deletions, specialized testing is needed. Also note, that Analysis of SBDS is complicated by the presence of a highly homologous pseudogene, SBDSP.

Please reach out to an experienced SDS specialist or geneticist if these challenges could be relevant to you. We can help you connect with one (email us at connect@SDSAlliance.org).

What does it mean to be a carrier, not a patient?

SDS is inherited in an autosomal recessive pattern. This means that in order for SDS to happen, both copies of the gene have to lose (or significantly reduce) their function through mutations or deletions.

Note: This is actually quite a unique situation is SDS: complete loss of SBDS is not compatible with life. Therefore, all "SBDS" SDS patients have a mutation that greatly reduces the amount of functional SBDS protein, but doesn't completely eliminate it. The splice site mutation c.258+2T>C you may have heard about, or seen in your own genetic reports, is the most common SBDS mutation and can still produce a very small amount of functional SBDS protein.

If one copy of the gene is normal (functional), than the cell can make enough protein to make up for the mutated copy of the gene, and the cellular function can be maintained without issues. That is why carriers typically don't show any SDS symptoms.

What is a mutation vs. a VUS?

Both terms refer to a change in a gene, i.e. a change in the sequence of the 4 bases (A, C, T, G) that make up the genetic code. Our genomes are made up of billions and billions of base pairs of DNA. The majority of the sequence is the same across all humans, but a tiny amount differ (0.01%). That means, such a difference occurs once in every thousand letters of the genome on average. However, due to the negative connotation of the word “mutation,” the human genetics community has started to use a new term: “variant.” The term variant underlines the fact that not all variants are harmful.

Sometimes it can be difficult to tell whether a variant is harmful or harmless. The mass screening of genes is called Next Generation Sequencing (NGS). NGS genetic testing involves looking closely at the base sequence in our DNA code. When the DNA bases are changed, the gene may function differently.

Most variants are harmless and in fact make you unique. Some gene variants may even be beneficial, and can offer a benefit during evolution. For example, a variant could potentially increase our natural defense against some viruses. On the other hand, some gene variants can lead to genetic disorders, such as SDS. Based on their capabilities of causing disorders, variants are classified into five major categories:

Pathogenic
Likely pathogenic
Variants of uncertain significance (VUS)
Likely benign
Benign

When looking at a particular variant, it can be tricky to figure out into which category it belongs. The determination is usually made by testing laboratories based on various types of evidence. For example, if many patients with a particular disorder all have the same "variant" or "mutation", and the protein's function is well known, then researchers make the determination that is is pathogenic. This information is then available to the testing laboratories through specialized online databases, and scientific publications. If such information is not established for a particular variant, computer modeling and comparison of the sequence of the same gene in other organisms can provide good evidence. For example, if a change is detected in a region of the protein that is known to be critical for its function, then the variant may be "likely pathogenic". And/or if the change is in a region of the gene that is the same across multiple species, then that suggests that it is critical for the protein's function, and again is "likely pathogenic".

Unfortunately, more often then not, the above mentioned evidence is not present, and therefore scientist and clinicians don't have enough information to determine the significance of the variant. In those frequent cases, the variant would be called a VUS (variant of uncertain significance).

The best way to determine whether a variant is significant would be to develop a functional assay to determine whether the cellular process in which the protein is involved is disrupted; or whether some other key phenotype is affected. Another term for these measures are biomarkers, and as explained in a previous snapshots issue, they are incredibly important for therapy development as well. In the case of SDS, if there was an easy, validated assay to measure ribosome assembly or other markers, that would be a great way to tell whether a VUS in SBDS has any significance. We are currently working with our partners on develop biomarkers for this and other reasons.

Have you or your loved-one received VUSs in your genetic report? It’s important to work closely with an experienced SDS specialist or geneticist to help you understand what the VUS might mean for you or your family. Not all variants in SBDS or the other SDS genes means SDS. If a child is diagnosed with a VUS, it is helpful to have mom and dad tested as well to see if either of them have the same variant. If a parent shares a variant with their child, but the parent does not have symptoms that the child is experiencing, it is less likely that the VUS is pathogenic (or it would have likely affected the parent).

Every family with SDS as a potential diagnosis on their genetic report should reach out to an SDS specialist and enroll in a Registry and/or Natural History Study that covers your geographical area. Find a list, here: https://www.sdsalliance.org/sds-registries. Contact us at connect@SDSAlliance.org if you need additional guidance.

Why do I need to know whether I or my loved-one has "genetic" SDS?

As mentioned above, over 90% of SDS patients have mutations in both copies of their SBDS gene. This group of patients have been most thoroughly studies, as this is where most data is available. As most of us are keenly aware, SDS in these patients causes a high risk of MDS/AML (leukemia). However, this risk has NOT been established in SDS patients without a known genetic cause (often referred to as "clinical" SDS patients, or SDS-like). A recent example of some amazing research was published last year by Dr. Shimamura's group, where acquired / somatic mutations were measured and summarized. We can cover the article in more detail another time. The article is available for download, here: https://pubmed.ncbi.nlm.nih.gov/33637765/

As we learn more over time, it is very possible that different types of SDS patients will benefit from different types of monitoring and treatment options. Perhaps one group will need frequent monitoring for leukemic transformation and clonal hematopoiesis, while the others may not need monitoring that often. One group may benefit from some types of treatment options, while others may need other options. The natural history of the different groups may be different as well, and could have implications on how clinical trials and comparator arms are structured. Regardless of what category of SDS you or your loved-one falls into, please consider participating in research, be it in registries or clinical trials in the future. Find a list, here: https://www.sdsalliance.org/sds-registries.