Cracking the Code: Genetics and Pathology in SDS

Confirming a diagnosis of Shwachman-Diamond Syndrome (SDS) often requires a combination of clinical review, genetic detective work, and detailed bone marrow analysis when clinically indicated. Because SDS is so rare, the testing process can be technically challenging, sometimes requiring specialized laboratories to navigate the complexities of your child’s DNA ^[1][2].

The Genetics of SDS and SDS-Like Disorders

In most reported cohorts (approximately 90%), classic SDS is caused by pathogenic variants in the SBDS gene ^[1]. This gene provides the instructions for building the protein that helps “unlock” your child’s protein factories. However, there are other associated genes.

• Autosomal Recessive Inheritance: The genes SBDS, DNAJC21, and EFL1 generally follow an autosomal recessive pattern ^[1][3]. This means a child must inherit two pathogenic variants (previously called “broken copies”)—one from each parent—to have the condition. Parents are typically “carriers” who have one working copy and no symptoms ^[2]. For these genes, when both parents are carriers, there is a 25% chance in each pregnancy that a child will be affected.
• Autosomal Dominant / De Novo: An SDS-like disease can also be caused by the SRP54 gene. This is often “dominant,” meaning only one pathogenic variant is needed ^[4]. Frequently, these variants are de novo, meaning they happened for the first time in the child and were not inherited from either parent ^[4].

A genetic counselor is highly recommended to review sibling testing, recurrence risks, and future family planning.

The “Pseudogene” Complication

One of the biggest hurdles in diagnosing SBDS-related SDS is a “decoy” gene called SBDSP1, or a pseudogene ^[5]. This decoy sits right next to the real SBDS gene and is 97% identical to it, but it doesn’t function ^[5].

Standard genetic tests (like “whole exome sequencing”) can get confused by this decoy. They may “misalign” the DNA, looking at the decoy instead of the real gene, leading to false-negative results where a mutation is missed ^[6].

• Gene Conversion: Sometimes, the body accidentally copies pieces of the decoy’s broken code into the real SBDS gene ^[2]. This is called gene conversion. It requires highly specialized testing (like SBDS-specific PCR or RNA sequencing) to be seen accurately ^[2][6].

Reading a Bone Marrow Pathology Report

Because SDS affects the bone marrow’s ability to produce blood cells, bone marrow biopsies may be performed when there are cytopenias, dysplasia, or clonal evolution that need evaluation. These reports are dense, but you should look for several key data points:

Clones: Lower Risk vs. Needing Closer Review

It is common for children with SDS to develop “clones” in their bone marrow over time.

• Changes That May Be Lower Risk: Some clones (like del(20q) or those involving the EIF6 gene) might actually help the marrow work better by “rescuing” the cell’s ability to make proteins ^[10][11]. These “somatic rescue” changes are often considered lower-risk, but still require regular monitoring.
• Changes Needing Closer Review: Clones involving the TP53 gene are watched more closely ^[12][13]. TP53 normally prevents abnormal growth. However, finding a TP53 variant does not mean an automatic transplant is required. Interpretation depends heavily on whether the variant is somatic or germline, the clone’s size and trajectory, and the clinical setting.

Because MDS can develop even when blood counts look stable, your doctor uses the pathology report to see what is happening deep inside the “factory,” providing a more complete picture than a simple blood draw ^[14][15]. 🛡️ Individuals who undergo regular marrow surveillance have shown improved outcomes because changes can be caught early, though surveillance detects changes rather than guaranteeing prevention ^[15].