SNP Shot: Genomic Insights

Shwachman-Diamond syndrome (SDS) is a genetic disorder affecting multiple body systems, primarily the bone marrow, pancreas, and skeleton.

Bone marrow's primary role is to generate new blood cells, including: red blood cells (carrying oxygen), white blood cells (fighting infection), and platelets (essential for blood clotting). In SDS, the bone marrow is impaired, leading to a deficiency in certain or all types of white blood cells. A low count of neutrophils, a common type of white blood cell, results in neutropenia. Most SDS patients experience neutropenia episodes, increasing susceptibility to infections like pneumonia (lungs), otitis media (ears), or skin infections. Less frequently, bone marrow issues can cause anemia (low red blood cells, leading to fatigue and weakness) or thrombocytopenia (low platelets, causing easy bruising and bleeding).

Due to their compromised bone marrow, individuals with SDS face an elevated risk of serious complications, including myelodysplastic syndrome (MDS) and aplastic anemia (both disorders involving abnormal blood stem cells), and acute myeloid leukemia (AML), a cancer of blood-forming tissue.

SDS also impacts the pancreas, an organ crucial for digestion. The pancreas produces enzymes necessary for breaking down and absorbing nutrients from food. Many infants with SDS have pancreatic insufficiency, meaning the pancreas doesn't produce enough of these enzymes. This leads to difficulty digesting food and absorbing vital nutrients, resulting in fatty, foul-smelling stools (steatorrhea), slow growth and weight gain (failure to thrive), and malnutrition. Pancreatic insufficiency often improves with age in SDS patients.

Skeletal abnormalities are another hallmark of SDS. Many affected individuals experience issues with bone formation and growth, particularly in the hips and knees. Low bone density is also common. Some infants are born with a narrow rib cage and short ribs, which can cause life-threatening breathing problems. The combination of skeletal issues and slow growth often results in short stature.

Complications of SDS can extend to other areas, including the liver, heart, endocrine system (hormone production), eyes, teeth, and skin. Research also suggests a link between SDS and delayed speech and motor skill development (sitting, standing, walking).

Inheritance:

Most cases of SDS, including those linked to SBDS gene mutations, follow an autosomal recessive inheritance pattern. This means that both copies of the gene in each cell must have mutations for the condition to develop. Typically, both parents carry one copy of the mutated gene but do not exhibit symptoms of the condition themselves. In some instances, only one parent carries the mutated gene, and a new (de novo) mutation arises in the gene during the formation of reproductive cells (eggs or sperm) or during early embryonic development. Rarely, SDS is inherited in an autosomal dominant pattern, where only one copy of the altered gene is enough to cause the disorder. These cases usually result from de novo mutations in the gene and occur in individuals with no prior family history of the condition.