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PubMed This is a summary of 17 peer-reviewed journal articles Updated
Medical Genetics

The Path to Diagnosis: MRI and Genetics

At a Glance

Najm-type X-linked intellectual disability can be present even when a child's brain MRI is normal. Diagnosis depends on genetic testing that identifies a disease-causing CASK variant, often using sequencing plus copy-number analysis when needed.

The process of diagnosing a CASK-related disorder typically involves specialized brain imaging and detailed genetic testing. A definitive diagnosis requires finding a pathogenic or likely pathogenic variant in the CASK gene that fits the child’s clinical symptoms [1].

The Role of Brain Imaging (MRI)

For many families, an early clue comes from a brain MRI (Magnetic Resonance Imaging). Doctors may look for a pattern known as MICPCH (Microcephaly with Pontine and Cerebellar Hypoplasia) [2].

  • Microcephaly: This is measured clinically (with a tape measure), meaning the head circumference is significantly smaller than expected for the child’s age and sex [3]. (An MRI does not measure microcephaly, but it shows the brain structures inside).
  • Hypoplasia: In plain language, this means a part of the brain is smaller than it should be because it did not fully develop [4].
  • The “Target” Areas: In CASK-related disorders, the pons (part of the brainstem) and the cerebellum (which handles balance and movement) are often the structures that appear smaller than usual on the MRI [4][5].

Important Note: A normal MRI does not rule out a CASK-related disorder. Some children, particularly those presenting with the Najm-type XLID phenotype, may have brain structures that appear completely normal [6][7]. Repeat MRIs should be based strictly on clinical need, not an assumption that the imaging will eventually change.

Confirming with Genetic Testing

Because a CASK-related disorder cannot be diagnosed by MRI alone, genetic testing is required. Depending on the laboratory and the case, different tests may be used:

  1. Whole Exome Sequencing (WES): This test “reads” the coding regions of DNA to find spelling errors in genes like CASK [8]. While highly useful, exome sequencing can miss large missing/extra pieces of DNA (copy-number variants), deep-intronic variants, or low-level mosaicism.
  2. Gene Panels: These are targeted tests that look only at a specific group of genes known to cause developmental delays or brain malformations [1].
  3. Copy-Number Analysis (CMA): Some children are missing a large chunk of the CASK gene, or have an extra piece (duplication). A Chromosomal Microarray (CMA) or specialized deletion/duplication testing is often needed to find these [9][10].

Reading the Genetic Report

When you look at your child’s genetic results, there are a few key details to find:

  • Variant Classification: Look for the words Pathogenic or Likely Pathogenic. These mean the laboratory is confident the change is causing the disorder [11].
  • Variant of Uncertain Significance (VUS): This means a change was found, but it is not yet clear if it is harmful or just a natural, harmless variation [12][13]. Crucial Safety Rule: A VUS should NOT be used by itself to confirm the diagnosis, change major medical treatments, or make predictive testing decisions for family members. If you have a VUS, review it periodically with a genetics professional to see if new research has reclassified it.
  • HGVS Notation: This is the “address” of the variant, usually starting with a “c.” (DNA change) and a “p.” (protein change), such as p.Arg28Ter [14].

Overlapping Conditions

Because symptoms like small head size or motor delays happen in many different conditions, your doctor may consider other “differential diagnoses.” For example, Joubert Syndrome also affects the cerebellum but has a different look on MRI [15]. Other conditions, like MADD-related disease, require separate biochemical metabolic testing to rule out because MADD is a potentially treatable metabolic disorder—genetic testing alone does not exclude it [16][17]. Working closely with a geneticist ensures your child receives the right tests and the most accurate diagnosis.

Common questions in this guide

Can a normal brain MRI rule out Najm-type XLID?
No. Some children with Najm-type XLID have brain structures that look normal on MRI, so imaging alone cannot confirm or exclude the condition. Genetic testing is needed when the clinical findings suggest a CASK-related disorder.
Which genetic tests can find a CASK-related disorder?
Testing may include whole exome sequencing, a developmental-disorder gene panel, and copy-number analysis. Sequencing can miss larger deletions or duplications, deep-intronic variants, and low-level mosaicism, so additional testing may be needed.
What does a pathogenic CASK variant mean?
A pathogenic or likely pathogenic CASK variant is a genetic change that the laboratory considers capable of causing the disorder. The result should still be interpreted alongside the child's symptoms, examination, and other test findings by a genetics professional.
What is a VUS on my child's genetic report?
A variant of uncertain significance, or VUS, is a genetic change whose effect is not yet known. A VUS should not by itself confirm the diagnosis, change major treatment decisions, or guide predictive testing for relatives; ask a genetics professional whether it has been reclassified over time.
What do pons and cerebellar hypoplasia mean on an MRI report?
Hypoplasia means that a brain structure is smaller than expected because it did not fully develop. In CASK-related disorders, the pons and cerebellum may be affected; MRI shows these structures but does not measure head circumference or determine whether a child has microcephaly.
Could another treatable condition look similar to a CASK-related disorder?
Yes. Conditions such as MADD-related disease can overlap with developmental or neurologic findings and may require biochemical metabolic testing. Genetic testing alone does not exclude every treatable metabolic condition, so the care team may recommend additional tests.

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Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Did my child's genetic testing include both 'sequencing' (to find spelling errors) and 'copy-number analysis' (to find missing or extra pieces)?
  2. 2.The MRI mentions 'hypoplasia' of the pons and cerebellum—can you show me on the scans what this looks like compared to a typical brain?
  3. 3.If the MRI was normal or only showed minor changes, does that rule out the Najm-type XLID diagnosis, or do we still need genetic confirmation?
  4. 4.Is this variant classified as 'Pathogenic' or a 'Variant of Uncertain Significance' (VUS), and what does that mean for my child's care?
  5. 5.Based on my child's symptoms, were other treatable conditions like MADD-related disease ruled out with biochemical testing?

References

References (17)
  1. 1

    Case Report: Identification of a novel CASK missense variant in a Chinese family with MICPCH.

    Zhang R, Jia P, Yao Y, Zhu F

    Frontiers in genetics 2022; (13()):933785 doi:10.3389/fgene.2022.933785.

    PMID: 36092876
  2. 2

    CASK related disorder: Epilepsy and developmental outcome.

    Giacomini T, Nuovo S, Zanni G, et al.

    European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 2021; (31()):61-69 doi:10.1016/j.ejpn.2021.02.006.

    PMID: 33640666
  3. 3

    Expanding the natural history of CASK-related disorders to the prenatal period.

    Gafner M, Boltshauser E, D'Abrusco F, et al.

    Developmental medicine and child neurology 2023; (65(4)):544-550 doi:10.1111/dmcn.15419.

    PMID: 36175354
  4. 4

    Pontocerebellar Hypoplasia: a Pattern Recognition Approach.

    Rüsch CT, Bölsterli BK, Kottke R, et al.

    Cerebellum (London, England) 2020; (19(4)):569-582 doi:10.1007/s12311-020-01135-5.

    PMID: 32410094
  5. 5

    Diagnostic Approach to Cerebellar Hypoplasia.

    Accogli A, Addour-Boudrahem N, Srour M

    Cerebellum (London, England) 2021; (20(4)):631-658 doi:10.1007/s12311-020-01224-5.

    PMID: 33534089
  6. 6

    Clinical heterogeneity and diagnostic challenges in CASK-related neurodevelopmental disorders: a longitudinal observational study.

    Pacheva IH, Timova E, Todorov T, et al.

    Frontiers in psychiatry 2026; (17()):1804756 doi:10.3389/fpsyt.2026.1804756.

    PMID: 42517139
  7. 7

    The eldest case of MICPCH with CASK mutation exhibiting gross motor regression.

    Nishio Y, Kidokoro H, Takeo T, et al.

    Brain & development 2021; (43(3)):459-463 doi:10.1016/j.braindev.2020.11.007.

    PMID: 33272775
  8. 8

    A novel missense variant in the CASK gene causes intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia.

    Wu S, Jiang C, Li J, et al.

    BMC medical genomics 2022; (15(1)):127 doi:10.1186/s12920-022-01275-z.

    PMID: 35668446
  9. 9

    Clinical and genetic spectrum of CASK-related disorders in Chinese patients.

    Chen Y, Cao J, Li J, et al.

    Journal of neurology 2026; (273(6)).

    PMID: 42133085
  10. 10

    Presynaptic dysfunction in CASK-related neurodevelopmental disorders.

    Becker M, Mastropasqua F, Reising JP, et al.

    Translational psychiatry 2020; (10(1)):312 doi:10.1038/s41398-020-00994-0.

    PMID: 32929080
  11. 11

    Gene Portals: A Framework for Integrating Clinical, Functional, and Structural Evidence into Rare Disease Variant Classification.

    Brünger T, Krey I, Kim S, et al.

    medRxiv : the preprint server for health sciences 2026; doi:10.64898/2026.03.05.26347086.

    PMID: 41822692
  12. 12

    Novel characterization of CASK variant c.1963 A>G (p.Asn655Asp) through whole-exome sequencing in a monochorionic diamniotic twin fetus with significant brain anomalies: A case report.

    Keller NA, Bracero LA, Kouba I, et al.

    Case reports in women's health 2024; (41()):e00583 doi:10.1016/j.crwh.2024.e00583.

    PMID: 38440102
  13. 13

    Clinical variants paired with phenotype: A rich resource for brain gene curation.

    Chopra M, Savatt JM, Bingaman TI, et al.

    Genetics in medicine : official journal of the American College of Medical Genetics 2024; (26(3)):101035 doi:10.1016/j.gim.2023.101035.

    PMID: 38059438
  14. 14

    Microcephaly, disproportionate pontine, and cerebellar hypoplasia syndrome: Two novel mutations in the CASK gene were discovered in Chinese females.

    Zhao J, Hou M, Wang H, et al.

    International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 2021; (81(3)):277-284 doi:10.1002/jdn.10100.

    PMID: 33629417
  15. 15

    Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.

    Bachmann-Gagescu R, Dempsey JC, Phelps IG, et al.

    Journal of medical genetics 2015; (52(8)):514-22 doi:10.1136/jmedgenet-2015-103087.

    PMID: 26092869
  16. 16

    New insights into the clinical and molecular spectrum of the MADD-related neurodevelopmental disorder.

    Abdel-Salam GMH, Abdel-Hamid MS

    Journal of human genetics 2024; (69(6)):263-270 doi:10.1038/s10038-024-01236-7.

    PMID: 38459224
  17. 17

    The neurodevelopmental spectrum of CASK-related disorder.

    Martin J, Mavrogalou-Foti A, Eck J, et al.

    Journal of neurodevelopmental disorders 2025; (17(1)):60 doi:10.1186/s11689-025-09643-3.

    PMID: 41039189

This page explains MRI and genetic testing for CASK-related disorders for informational purposes only and does not constitute medical advice. Your child's geneticist and care team should interpret the results and recommend next steps.