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PubMed This is a summary of 12 peer-reviewed journal articles Updated
Genetics

Diagnosing PWS and Understanding the Genetic Report

At a Glance

Prader-Willi syndrome is definitively diagnosed using a genetic test called DNA Methylation Analysis, which checks gene activity on chromosome 15. Additional testing like MS-MLPA reveals the exact cause, such as a paternal deletion or mUPD, which is essential for determining future recurrence risks.

Diagnosing Prader-Willi Syndrome (PWS) has evolved from looking at a checklist of physical symptoms to using precise genetic tests. While symptoms like low muscle tone and feeding issues in an infant may raise suspicion, clinical criteria alone are no longer enough for a final diagnosis because they can miss some cases or overlap with other disorders [1][2].

The Diagnostic Gold Standard

The “gold standard” for confirming PWS is DNA Methylation Analysis [3]. This test looks at the SNRPN locus on chromosome 15 to see if the paternal (father’s) genes are active [4]. In a typical person, the paternal genes are “on” and the maternal genes are “off.” In a child with PWS, the test will show only the maternal “off” pattern [4].

MS-MLPA: Determining the “Why”

Once a diagnosis is confirmed by methylation, doctors need to find out how it happened. MS-MLPA (Methylation-Specific Multiplex Ligation-dependent Probe Amplification) is a powerful tool because it can do two things at once:

  1. Check Methylation: It confirms the PWS diagnosis by looking at the “switches” on the genes [5].
  2. Check Copy Number: It counts the pieces of DNA to see if a deletion is present [6].

If the MS-MLPA shows a deletion, the diagnosis and the mechanism are both solved. If it shows the abnormal PWS pattern but a normal amount of DNA, the child likely has mUPD (two copies from the mother) or an imprinting defect [7].

Decoding Your Genetic Report

A genetic report can be difficult to read. Below is a checklist of key items that should be present for a comprehensive PWS diagnosis:

Genetic Report Checklist

  • Test Performed: Look for “DNA Methylation Analysis” or “MS-MLPA” [8].
  • Locus/Region: The report should mention the 15q11-q13 region or the SNRPN gene [9].
  • Results Statement: The report should indicate an abnormal methylation pattern or note that only the maternal genes are active [4]. (Note: Labs use different phrasing, such as ‘absence of paternal allele’ or ‘abnormal methylation at the SNRPN locus’).
  • Molecular Mechanism: The report should identify the specific subtype:
    • Paternal Deletion: A missing piece of DNA from the father [10].
    • mUPD: Two copies of chromosome 15 from the mother [11].
    • Imprinting Center Defect: The genes are present but incorrectly turned “off” [10].
  • Clinical Interpretation: A summary in plain language explaining what the findings mean for your child [12].

Understanding the specific genetic mechanism is essential for genetic counseling, as the risk of PWS occurring in a future pregnancy is very low for deletions (less than 1%) but can be significantly higher (up to 50%) for certain imprinting defects [12].

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Common questions in this guide

How is Prader-Willi syndrome diagnosed?
The gold standard for confirming PWS is a genetic test called DNA Methylation Analysis. It examines the SNRPN locus on chromosome 15 to determine if the paternal genes are active.
What is the MS-MLPA test for PWS?
MS-MLPA is a powerful genetic test that performs two functions at once. It confirms the PWS diagnosis by checking gene methylation and counts DNA copies to identify if a genetic deletion is present.
What are the specific molecular subtypes of PWS?
The three main genetic mechanisms are a paternal deletion (a missing piece of DNA from the father), maternal uniparental disomy or mUPD (two copies of chromosome 15 from the mother), and an imprinting center defect.
Does having a child with PWS increase the risk for future pregnancies?
The risk varies significantly based on the specific genetic cause of your child's PWS. Deletions have a very low recurrence risk of less than 1%, whereas certain imprinting defects can have a recurrence risk of up to 50%.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Does this report definitively confirm my child's PWS diagnosis through DNA methylation analysis?
  2. 2.Which specific molecular subtype (paternal deletion, mUPD, or imprinting defect) was identified?
  3. 3.Was the MS-MLPA test used, or do we need additional testing to determine the exact genetic mechanism?
  4. 4.How does the identified subtype affect the recurrence risk for our future pregnancies?
  5. 5.Is there any information in this report about the specific size of the deletion, and does that matter for my child's care?

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 (12)
  1. 1

    [Clinical screening and genetic diagnosis for Prader-Willi syndrome].

    Dong GQ, Su YY, Qiu XY, et al.

    Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 2020; (22(9)):1001-1006.

    PMID: 32933634
  2. 2

    Clinical and Molecular Characterization of Prader-Willi Syndrome.

    Sanjeeva GN, Maganthi M, Kodishala H, et al.

    Indian journal of pediatrics 2017; (84(11)):815-821 doi:10.1007/s12098-017-2386-1.

    PMID: 28660389
  3. 3

    A rapid and accurate methylation-sensitive high-resolution melting analysis assay for the diagnosis of Prader Willi and Angelman patients.

    Ribeiro Ferreira I, Darleans Dos Santos Cunha W, Henrique Ferreira Gomes L, et al.

    Molecular genetics & genomic medicine 2019; (7(6)):e637 doi:10.1002/mgg3.637.

    PMID: 31033246
  4. 4

    Diagnosis of Prader-Willi syndrome and Angelman syndrome by targeted nanopore long-read sequencing.

    Yamada M, Okuno H, Okamoto N, et al.

    European journal of medical genetics 2023; (66(2)):104690 doi:10.1016/j.ejmg.2022.104690.

    PMID: 36587803
  5. 5

    The Utilization of MS-MLPA as the First-Line Test for the Diagnosis of Prader-Willi Syndrome in Thai Patients.

    Prapasrat C, Onsod P, Korkiatsakul V, et al.

    Journal of pediatric genetics 2023; (12(4)):273-279 doi:10.1055/s-0041-1741008.

    PMID: 38162164
  6. 6

    Newborn screening for Prader-Willi syndrome is feasible: Early diagnosis for better outcomes.

    Mahmoud R, Singh P, Weiss L, et al.

    American journal of medical genetics. Part A 2019; (179(1)):29-36 doi:10.1002/ajmg.a.60681.

    PMID: 30556641
  7. 7

    Clinical Utility of Methylation-Specific Multiplex Ligation-Dependent Probe Amplification for the Diagnosis of Prader-Willi Syndrome and Angelman Syndrome.

    Kim B, Park Y, Cho SI, et al.

    Annals of laboratory medicine 2022; (42(1)):79-88 doi:10.3343/alm.2022.42.1.79.

    PMID: 34374352
  8. 8

    Beyond the usual suspects: neonatal presentation of Prader-Willi syndrome.

    Suresh Gowdar A, Padhi P, Akhila G

    BMJ case reports 2025; (18(9)) doi:10.1136/bcr-2025-267940.

    PMID: 40998537
  9. 9

    Expanding deep phenotypic spectrum associated with atypical pathogenic structural variations overlapping 15q11-q13 imprinting region.

    Mim RA, Soorajkumar A, Kosaji N, et al.

    Brain and behavior 2024; (14(4)):e3437 doi:10.1002/brb3.3437.

    PMID: 38616334
  10. 10

    Clinical Trials in Prader-Willi Syndrome: A Review.

    Mahmoud R, Kimonis V, Butler MG

    International journal of molecular sciences 2023; (24(3)) doi:10.3390/ijms24032150.

    PMID: 36768472
  11. 11

    Comparison of perinatal factors in deletion versus uniparental disomy in Prader-Willi syndrome.

    Gold JA, Mahmoud R, Cassidy SB, Kimonis V

    American journal of medical genetics. Part A 2018; (176(5)):1161-1165 doi:10.1002/ajmg.a.38679.

    PMID: 29681103
  12. 12

    Prader-Willi Syndrome - Clinical Genetics, Diagnosis and Treatment Approaches: An Update.

    Butler MG, Miller JL, Forster JL

    Current pediatric reviews 2019; (15(4)):207-244 doi:10.2174/1573396315666190716120925.

    PMID: 31333129

This page explains Prader-Willi syndrome genetic testing for educational purposes only. Always review diagnostic reports and recurrence risks with a qualified genetic counselor or pediatric specialist.

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