What Does a VUS Result Mean in Morquio Syndrome Testing?

When a child’s genetic test results come back showing a Variant of Uncertain Significance (VUS), it can be incredibly confusing and anxiety-inducing for parents. Simply put, a VUS means that a change (mutation) was found in your child’s DNA, but there is not yet enough medical evidence to know if this specific change causes Morquio syndrome or if it is just a harmless variation ^[1][2]. Morquio syndrome (Mucopolysaccharidosis type IV) is an autosomal recessive condition, meaning a child must inherit two non-working copies of the gene to have the disease. Because Morquio syndrome is so rare, doctors frequently encounter genetic changes in the associated genes (GALNS for Morquio A and GLB1 for Morquio B) that have not been studied or documented enough to classify as clearly disease-causing (pathogenic) or harmless (benign) ^[3][4].

A VUS on a genetic test does not automatically mean your child has Morquio syndrome, nor does it rule it out. Instead, it signals to your medical team that they need to look beyond the DNA sequence to establish a definitive clinical diagnosis. Genetics are just one piece of the puzzle.

Moving Beyond Genetics: Secondary Testing

When a genetic test is ambiguous, geneticists and metabolic specialists rely heavily on biochemical testing to clarify the situation. These tests look at how the body is actually functioning, rather than just reading the genetic blueprint.

Enzyme Activity Assays
This is considered the gold standard for diagnosing Morquio syndrome. Morquio A is caused by a deficiency of the GALNS enzyme, and Morquio B is caused by a deficiency of the GLB1 enzyme ^[5][6]. Doctors can measure the activity of these enzymes in white blood cells (leukocytes) or skin cells (fibroblasts). If your child’s enzyme activity is significantly lower than normal, it provides strong evidence that the VUS is indeed causing the disease, allowing doctors to confirm the diagnosis even if the genetic test remains uncertain ^[3][7]. A confirmed clinical diagnosis based on these low enzyme levels and physical symptoms often allows doctors to proceed with treatment options, such as Enzyme Replacement Therapy (ERT) for Morquio A, without waiting for the VUS to be reclassified.

Urine GAG and Biomarker Levels
People with Morquio syndrome lack the enzymes needed to break down certain complex sugars called glycosaminoglycans (GAGs), specifically keratan sulfate (KS) and chondroitin-6-sulfate (C6S), leading to their buildup in the body and elimination in urine ^[5][8]. Your doctor may order a urine test to measure GAG levels. However, it is important to know that total urine GAG levels can sometimes appear normal in patients with Morquio syndrome, which means a normal result does not completely rule out the disease ^[9][4]. Because of this, doctors often prefer looking specifically at keratan sulfate levels or moving directly to enzyme activity testing ^[9][4].

What Happens Next?

If your child receives a VUS, the clinical care team will take an integrated approach to solve the diagnostic puzzle:

• Correlating Symptoms: They will closely evaluate whether your child’s physical symptoms and imaging match the expected signs of Morquio syndrome ^[8][3]. This includes looking for specific bone changes on X-rays (called dysostosis multiplex), which may show up as short stature, a prominent chest, or knock-knees.
• Family Testing: Doctors will often test both parents (a process called segregation analysis). Because Morquio is an autosomal recessive disease, a child must inherit one disease-causing genetic change from each parent. Finding the VUS in one parent and a different pathogenic variant in the other helps confirm the diagnosis, as healthy parents are typically carriers who have one working gene and one non-working gene ^[1][10].
• Re-evaluation over Time: As more children are genetically tested globally, databases grow. A variant that is a VUS today may be reclassified as pathogenic or benign in the future as more data is collected ^[1][10]. It is highly recommended that you proactively follow up with your genetic counselor or specialist every 1-2 years to ask if there are any updates, as clinics do not always notify families automatically.

While waiting for answers is difficult, these secondary evaluations give your medical team concrete ways to piece together a definitive diagnosis and begin building a comprehensive care plan.