Diagnostic Approach for Prader-Willi Syndrome

Clinical Suspicion and Indications for Testing

DNA methylation analysis should be the first-line diagnostic test for Prader-Willi Syndrome (PWS), as it can detect approximately 99% of cases regardless of the underlying genetic mechanism, according to the American Academy of Pediatrics 1
Unexplained hypotonia with poor suck requires immediate PWS testing, as recommended by the American Academy of Pediatrics 1
Feeding difficulties requiring assisted feeding methods should prompt PWS testing, as suggested by the American Academy of Pediatrics 1

Conduct methylation analysis using Southern hybridization with methylation-sensitive SNRPN or PW71B probes, as recommended by the American Society of Human Genetics 2, 3
If only maternal methylation pattern is present, PWS is confirmed, according to the American Society of Human Genetics 3
If biparental inheritance is identified, PWS is ruled out, as stated by the American Society of Human Genetics 3
Deletion of 15q11-q13 accounts for >70% of PWS cases, as reported by the American Society of Human Genetics 2
Maternal uniparental disomy accounts for approximately 28% of cases, according to the American Society of Human Genetics 2

Chromosome analysis should be performed routinely to rule out other abnormalities or rare translocations, as recommended by the American Society of Human Genetics 2
Recurrence risk varies by genetic mechanism, with deletions and UPD having low recurrence risk (approximately 1%), and imprinting mutations having up to 50% recurrence risk, as reported by the American Academy of Pediatrics and the American Society of Human Genetics 1, 4

Prenatal testing is possible in specific circumstances, including when cytogenetic deletion is suspected on CVS or amniocentesis, when trisomy 15 mosaicism is detected, or when there is prenatal identification of a translocation involving chromosome 15, as recommended by the American Society of Human Genetics 4