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PubMed This is a summary of 18 peer-reviewed journal articles Updated
Medical Genetics

The Path to a Clear Answer: Testing and Genetics

At a Glance

Diagnosing a congenital disorder of glycosylation (CDG) requires a two-step process: an initial blood screening called Transferrin IEF to spot abnormal sugar chain patterns, followed by definitive genetic testing like Whole Exome Sequencing to identify the exact gene mutation.

Navigating the diagnostic process for a rare disease like CDG can feel like solving a high-stakes puzzle. Doctors typically use a two-step approach: a screening test to look for “red flags” in the blood, followed by genetic testing to find the specific instruction-manual error that caused the condition [1][2].

Step 1: The Initial Screen (Transferrin IEF)

The most common first step is a blood test called Transferrin Isoelectric Focusing (TIEF) [3].

  • What it measures: Transferrin is a protein in the blood that carries iron. In a healthy body, it has a specific number of sugar chains attached to it. The TIEF test separates these proteins based on their electrical charge, which changes depending on how many sugar chains are present [3][4].
  • The “Patterns”: Doctors look for two main abnormal patterns. Type I patterns usually mean the body failed to attach the sugar chains entirely. Type II patterns usually mean the body attached the chains but didn’t “finish” them correctly [5][6].
  • The Catch: While TIEF is a great starting point, it is not perfect. Some children with CDG (such as those with the ALG13-CDG or MOGS-CDG subtypes) will have a completely normal TIEF result [7][8]. Additionally, other factors like liver disease can cause “false positives,” making the blood look like CDG when it isn’t [9][10].

Step 2: The Definitive Answer (Genetic Testing)

To be 100% sure of a diagnosis and the specific subtype, doctors must use Next-Generation Sequencing (NGS), which includes Whole Exome Sequencing (WES) [11][12].

  • Why it’s critical: WES reads the actual “code” of the 20,000+ genes in your child’s body to find the exact mutation (variant) causing the glycosylation error [1][13].
  • Finding the “Exact” Variant: Knowing the specific gene (e.g., PMM2) and the exact mutation (e.g., p.Arg141His) is vital. It allows doctors to predict potential symptoms, connect you with specific research trials, and provide accurate information for family planning [14][15].

The CDG Diagnosis “Completeness Checklist”

When you receive your child’s medical records, ensure they contain these specific pieces of information. If any are missing, your diagnosis might not be fully confirmed:

Component Why it Matters
Gene Name Identifies the exact subtype (e.g., MPI, PMM2, ALG1). [14]
Variant Description The specific “address” of the mutation (e.g., c.422G>A). [14]
Zygosity Tells you if the child has one or two copies of the mutation. For the vast majority of CDGs (which are autosomal recessive), two copies (homozygous or compound heterozygous) are required to confirm the diagnosis. A single heterozygous result means the child is likely just a carrier, and the diagnosis is incomplete. [1]
Pathogenicity Confirms the lab believes this specific variant actually causes the disease (look for “Pathogenic” or “Likely Pathogenic”).
Biochemical Match Do the blood tests (like TIEF) match what the genetics suggest? If they don’t, your doctor may need “functional studies” to prove the gene is the cause. [1][16]

If your child has all the symptoms of CDG but the screening tests and WES are negative, some specialist centers use even more advanced tools like Whole Genome Sequencing (WGS) or Mass Spectrometry to find “hidden” mutations or unusual sugar patterns that standard tests miss [17][18].

Once you know the exact genetics, you can explore the Subtypes and Targeted Therapies.

Common questions in this guide

What is the first step in testing for a congenital disorder of glycosylation?
The most common initial screening is a blood test called Transferrin Isoelectric Focusing (TIEF). This test looks for abnormal patterns in how sugar chains are attached to a protein called transferrin in the blood.
Can my child have CDG if their transferrin IEF screening test is normal?
Yes. While the TIEF test is a reliable starting point, some specific CDG subtypes can present with completely normal results. Doctors use advanced genetic testing to confirm a diagnosis in these cases.
Why is genetic testing necessary if the blood screening shows CDG?
Genetic testing identifies the exact gene and mutation causing the condition. Knowing the specific subtype is essential for predicting potential symptoms, finding targeted treatments, and making informed family planning decisions.
What does zygosity mean on my child's CDG genetic report?
Zygosity tells you if your child has one or two copies of a genetic mutation. Since most CDGs require two mutated copies to cause the disease, a result showing only one copy means they are likely a carrier and the diagnosis may be incomplete.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Which specific CDG gene was identified in my child's report, and are the mutations listed as 'pathogenic' or 'likely pathogenic'?
  2. 2.Since some CDG screening tests can be normal, was my child's genetic testing comprehensive enough to catch rare subtypes?
  3. 3.Does my child's transferrin IEF pattern (Type I or Type II) match the genetic results we found?
  4. 4.Are there any other conditions, like liver issues, that could have affected the 'screening' portion of my child's diagnosis?
  5. 5.Should our family (parents and siblings) undergo 'carrier testing' to understand the inheritance pattern?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (18)
  1. 1

    Congenital disorders of glycosylation.

    Chang IJ, He M, Lam CT

    Annals of translational medicine 2018; (6(24)):477 doi:10.21037/atm.2018.10.45.

    PMID: 30740408
  2. 2

    CDG biochemical screening: Where do we stand?

    Bruneel A, Cholet S, Tran NT, et al.

    Biochimica et biophysica acta. General subjects 2020; (1864(10)):129652 doi:10.1016/j.bbagen.2020.129652.

    PMID: 32512173
  3. 3

    Transferrin isoform analysis from dried blood spots and serum samples by gel isoelectric focusing for screening congenital disorders of glycosylation.

    Bogdańska A, Kozłowski D, Pajdowska M, et al.

    Acta biochimica Polonica 2021; (68(1)):139-142 doi:10.18388/abp.2020_5576.

    PMID: 33667052
  4. 4

    Congenital Disorders of Glycosylation: What Clinicians Need to Know?

    Lipiński P, Tylki-Szymańska A

    Frontiers in pediatrics 2021; (9()):715151 doi:10.3389/fped.2021.715151.

    PMID: 34540767
  5. 5

    High-resolution capillary zone electrophoresis for transferrin glycoform analysis associated with congenital disorders of glycosylation.

    Tobler M, Caslavska J, Burda P, Thormann W

    Journal of separation science 2018; (41(13)):2808-2818 doi:10.1002/jssc.201800082.

    PMID: 29701302
  6. 6

    High-resolution mass spectrometry glycoprofiling of intact transferrin for diagnosis and subtype identification in the congenital disorders of glycosylation.

    van Scherpenzeel M, Steenbergen G, Morava E, et al.

    Translational research : the journal of laboratory and clinical medicine 2015; (166(6)):639-649.e1.

    PMID: 26307094
  7. 7

    Structural Analysis of the Effect of Asn107Ser Mutation on Alg13 Activity and Alg13-Alg14 Complex Formation and Expanding the Phenotypic Variability of ALG13-CDG.

    Mitusińska K, Góra A, Bogdańska A, et al.

    Biomolecules 2022; (12(3)) doi:10.3390/biom12030398.

    PMID: 35327592
  8. 8

    ALG13-CDG in a male with seizures, normal cognitive development, and normal transferrin isoelectric focusing.

    Gadomski TE, Bolton M, Alfadhel M, et al.

    American journal of medical genetics. Part A 2017; (173(10)):2772-2775 doi:10.1002/ajmg.a.38377.

    PMID: 28777499
  9. 9

    Assessing carnosinase 1 activity for diagnosing congenital disorders of glycosylation.

    Interdonato L, Himmelreich N, Garbade SF, et al.

    Molecular genetics and metabolism 2024; (143(1-2)):108571 doi:10.1016/j.ymgme.2024.108571.

    PMID: 39226631
  10. 10

    Screening for abnormal glycosylation in a cohort of adult liver disease patients.

    Jansen JC, van Hoek B, Metselaar HJ, et al.

    Journal of inherited metabolic disease 2020; (43(6)):1310-1320 doi:10.1002/jimd.12273.

    PMID: 32557671
  11. 11

    Diagnostic impact of whole exome sequencing in neurometabolic disorders in Syrian children: a single center experience.

    Al Khudari R, Baqla S, Al Asmar D

    Orphanet journal of rare diseases 2025; (20(1)):220 doi:10.1186/s13023-025-03732-1.

    PMID: 40336053
  12. 12

    [Exome diagnostics in neurology].

    Zech M, Wagner M, Schormair B, et al.

    Der Nervenarzt 2019; (90(2)):131-137 doi:10.1007/s00115-018-0667-1.

    PMID: 30645660
  13. 13

    A recurrent c.953A>C (p. Gln318Pro) variant in ALG11 causing congenital disorder of glycosylation in Turkish population.

    Kart PO, Demir O, Turkyilmaz A, et al.

    Neurogenetics 2025; (26(1)):46 doi:10.1007/s10048-025-00826-7.

    PMID: 40423864
  14. 14

    Frontiers in congenital disorders of glycosylation consortium, a cross-sectional study report at year 5 of 280 individuals in the natural history cohort.

    Lam C, Scaglia F, Berry GT, et al.

    Molecular genetics and metabolism 2024; (142(4)):108509 doi:10.1016/j.ymgme.2024.108509.

    PMID: 38959600
  15. 15

    DPAGT1-CDG: Recurrent fetal death.

    Tao H, Sun Y, Zhai J, Wu J

    Birth defects research 2023; (115(13)):1185-1191 doi:10.1002/bdr2.2219.

    PMID: 37421173
  16. 16

    Normal transferrin glycosylation does not rule out severe ALG1 deficiency.

    Bosnyak I, Sadek M, Ranatunga W, et al.

    JIMD reports 2024; (65(3)):135-143 doi:10.1002/jmd2.12415.

    PMID: 38736633
  17. 17

    Genome and RNA sequencing were essential to reveal cryptic intronic variants associated to defective ATP6AP1 mRNA processing.

    Morales-Romero B, Muñoz-Pujol G, Artuch R, et al.

    Molecular genetics and metabolism 2024; (142(3)):108511 doi:10.1016/j.ymgme.2024.108511.

    PMID: 38878498
  18. 18

    Advancement in Clinical Glycomics and Glycoproteomics for Congenital Disorders of Glycosylation: Progress and Challenges Ahead.

    Abu Bakar N, Hamzan NI

    Biomedicines 2025; (13(8)) doi:10.3390/biomedicines13081964.

    PMID: 40868218

This page explains CDG diagnostic testing and genetics for educational purposes. Always consult your child's metabolic geneticist or care team to interpret specific laboratory and genetic reports.

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