How to test for Prader-Willi syndrome?

Testing for Prader-Willi Syndrome

DNA methylation analysis should be the initial diagnostic test for Prader-Willi syndrome as it detects >99% of cases regardless of the genetic mechanism. 1 This test is the most efficient first-line approach for confirming or ruling out PWS in patients with clinical suspicion.

Clinical Suspicion: When to Test

Testing should be considered based on age-specific presentations:

Infants (0-2 years)

• Unexplained hypotonia with poor suck
• Failure to thrive requiring special feeding techniques
• Characteristic facial features (almond-shaped eyes, thin upper lip, narrow bifrontal diameter)
• Hypogonadism (genital hypoplasia)

Young Children (2-6 years)

• History of infantile hypotonia with poor suck
• Global developmental delay
• Short stature
• Onset of excessive weight gain

Older Children (6-12 years)

• History of hypotonia in infancy
• Developmental delay/cognitive impairment
• Excessive eating with central obesity
• Characteristic behavioral problems

Adolescents and Adults (13+ years)

• Cognitive impairment
• Hyperphagia with central obesity
• Hypogonadotropic hypogonadism
• Typical behavior problems (tantrums, obsessive-compulsive features)

Diagnostic Algorithm

1. First-line test: DNA methylation analysis

   • Uses Southern hybridization with methylation-sensitive SNRPN or PW71B probes 2
   • Results interpretation:
     • Only maternal alleles present → PWS confirmed
     • Biparental inheritance identified → PWS ruled out
     • Only paternal alleles present → Angelman syndrome (not PWS)

2. If methylation analysis confirms PWS, determine genetic subtype:

   • FISH analysis with SNRPN or other probe in the 15q11-q13 region

     • Detects deletions (65-75% of PWS cases)

   • If no deletion found by FISH:

     • Perform microsatellite analysis/PCR using markers from 15q11-13
     • Identifies maternal uniparental disomy (20-30% of cases)
     • Biparental inheritance with abnormal methylation suggests imprinting defect (1-3% of cases)

3. If clinical suspicion remains high despite normal testing:

   • Consult with a geneticist experienced with PWS
   • Consider evaluation for other conditions with overlapping features:
     • High-resolution chromosome analysis
     • Testing for fragile X syndrome
     • Metabolic studies

Important Considerations

• The purpose of clinical criteria has shifted from making the diagnosis to identifying appropriate candidates for genetic testing 3

• PWS is caused by absence of paternally expressed imprinted genes at 15q11.2-q13 through:

  • Paternal deletion (65-75%)
  • Maternal uniparental disomy (20-30%)
  • Imprinting defect (1-3%)

• Early diagnosis is critical for:

  • Anticipatory guidance
  • Early intervention services
  • Growth hormone therapy consideration
  • Prevention of obesity through dietary management
  • Improved quality of life and mortality outcomes

Prenatal Testing

Prenatal testing is possible in specific circumstances:

• When cytogenetic deletion is suspected on CVS or amniocentesis
• When trisomy 15 mosaicism is detected
• In cases with familial or de novo translocation involving chromosome 15
• For families with previous PWS child (though recurrence risk is generally low at ~1%)

Common Pitfalls

• Relying solely on clinical features without confirmatory genetic testing
• Missing the diagnosis in infants who present only with hypotonia and feeding problems
• Failing to recognize that clinical features evolve with age (hypotonia and feeding problems in infancy, hyperphagia and obesity in childhood)
• Not considering PWS in obese children with developmental delay and behavioral issues
• Delaying diagnosis, which postpones critical interventions that could improve outcomes

Early diagnosis and intervention are essential for improving quality of life and reducing morbidity and mortality associated with complications of PWS, particularly obesity-related conditions 4.