Confirming the Diagnosis and Genetics

Confirming a diagnosis of SLC35A2-CDG can be a complex journey because the standard screening tests used for most metabolic disorders often fail to detect it. Understanding why these tests “miss” the diagnosis—and how advanced genetic testing provides the answer—is an important step in managing your child’s care.

The Problem with Standard Screening

For most Congenital Disorders of Glycosylation (CDG), doctors use a blood test called serum transferrin glycosylation. This test looks at a protein made in the liver to see if its sugar chains are attached correctly ^[1].

In SLC35A2-CDG, however, this test is notoriously unreliable. In the largest study of patients with this condition, the vast majority had perfectly normal transferrin results ^[1]. There are several reasons for this:

• Brain-Specific Impact: The genetic defect in this condition often affects the brain much more severely than the liver. Since transferrin is made in the liver, it may look normal even when brain cells are struggling ^[1][2].
• Mosaicism: If the genetic change is only present in some cells (mosaicism), the “healthy” cells may produce enough normal transferrin to mask the problem in a standard blood test ^[3].
• Sugar Preferences: Research suggests this specific defect might affect fats (lipids) in the brain more than proteins in the blood, making a protein-based blood test like transferrin the wrong tool for the job ^[2].

Definitive Testing: WES and WGS

Because blood screening often fails, advanced genetic testing is used.

• Whole Exome Sequencing (WES): This test “spells out” all the protein-coding parts of your child’s DNA. It is a common way SLC35A2-CDG is diagnosed today ^[3][4].
• Whole Genome Sequencing (WGS): This is an even broader test that looks at the entire genetic code, including parts that don’t make proteins.
• However, even these tests have limitations. Routine blood-based sequencing can miss low-level or tissue-limited mosaicism regardless of the platform. A negative blood test does not end the evaluation when the phenotype remains convincing.

Understanding Somatic Mosaicism

One of the most unique aspects of SLC35A2-CDG is a phenomenon called somatic mosaicism. Unlike typical genetic conditions where every cell in the body carries the mutation, some children with this condition have a “patchwork” of cells.

In some cases, the genetic variant is brain-restricted. This means the mutation is found only in certain parts of the brain and is completely absent from the blood or saliva ^[5][6]. This is frequently seen in a specific brain malformation called MOGHE (Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia and Epilepsy) ^[6][7]. In these children, a standard blood-based genetic test will come back negative because the “broken” DNA isn’t in the blood; it’s only in the brain tissue ^[8]. Note that not every case of MOGHE is caused by SLC35A2, and invasive brain biopsies are not a routine diagnostic step unless neurosurgical tissue is obtained during a clinically indicated epilepsy surgery.

Reading the Genetic Report: VAF

When you look at a genetic lab report, you may see a term called Variant Allele Fraction (VAF).

• What it means: This is a percentage representing the fraction of sequence reads (the pieces of DNA measured by the machine) carrying a variant, not a direct count of the percentage of cells with the mutation.
• Typical numbers: Because SLC35A2 is X-linked, a variant present in all cells of a hemizygous male may approach 100%, while a heterozygous variant in a female may be near 50%.
• Mosaic numbers: In mosaic cases, the VAF can be much lower—sometimes as low as 1.4% to 7% ^[6][7]. A low VAF suggests possible mosaicism, but must be interpreted in context by a genetics laboratory.

Because of this, if a child has severe seizures and brain findings but normal blood tests, specialists may sometimes need to test other tissues or use “ultra-deep” sequencing to find these low-level mosaic variants ^[9][10].