**Background:** Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are imprinting disorders resulting from absent or reduced expression of paternally or maternally derived genes on chromosome 15q11q13, respectively. Genomic imprinting involves DNA methylation at CpG dinucleotides that silences genes without altering the nucleotide sequence. More than 100 imprinted genes have been identified, many arranged in clusters called imprinted domains. The main molecular mechanisms underlying these disorders include pathogenic sequence variants in imprinted genes, copy number variants, uniparental disomy (UPD), and epimutations. Approximately 70% of PWS/AS cases are caused by a 15q11q13 deletion on the paternal or maternal chromosome, respectively. PWS arises from loss of function of paternally expressed genes (SNURF-SNRPN, MKRN3, NDN, MAGEL2, NPAP1, PWRN1, SNORD116, IPW, SNORD115), while AS arises from loss of function of the maternally expressed UBE3A gene, which encodes a HECT domain E3 ubiquitin ligase. UPD accounts for about 25% of PWS cases (maternal UPD) and approximately 7% of AS cases (paternal UPD). Imprinting defects account for approximately 5% of PWS and 3–5% of AS. Intragenic pathogenic variants in maternally inherited UBE3A account for 10–25% of AS patients.
**Methods:** The paper reviews diagnostic approaches including methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), chromosomal microarrays (CMA), and UBE3A sequencing. MS-MLPA (kit ME028-D1) simultaneously detects copy number and methylation status using eight methylation-sensitive probes containing HhaI recognition sites. PWS patients show no digestion due to hypermethylation, while AS patients show complete digestion due to hypomethylation. CMA techniques include comparative genomic hybridization (CGH) for copy number changes and single nucleotide polymorphism (SNP) arrays that can detect UPD (isodisomy), long continuous stretches of homozygosity (LCSH), and mosaicism. UBE3A sequencing can detect small intragenic deletions/insertions, missense, nonsense, and splice site variants accounting for 90% of disease-causing pathogenic variants. Over 500 pathogenic or likely pathogenic variants of UBE3A are documented in ClinVar.
**Key Results:** PWS presents in neonates with severe hypotonia, decreased movement, lethargy, weak cry, and feeding/swallowing difficulties that may result in failure to thrive. Hyperphagia develops around 2 years of age. Approximately 10–20% of individuals with PWS have hip dysplasia. Most persons with PWS have mild intellectual disability. Central hypothyroidism may develop, requiring thyroid function evaluation in the first several months of life and screening every 2–3 years. Growth hormone replacement therapy can normalize height, increase lean body mass, and decrease fat. For AS, epilepsy occurs in up to 90% of individuals and is often refractory to anti-epileptic drugs. Sleep challenges are present in up to 80% of individuals with AS. The incidence of scoliosis in children with AS is up to 20% and up to 50% in adults. More than a quarter of children with AS exhibit hyperphagia. Clinical trials for PWS include intranasal oxytocin (inconclusive results), carbetocin (Phase III insufficient for FDA approval, NCT03649477), diazoxide choline (improvements in severe baseline hyperphagia and body composition), and cannabidiol oral solution (NCT05098509). For AS, trials of folate, betaine, metofalin, vitamin B12, creatine, and levodopa/carbidopa have not demonstrated significant clinical benefit. Gaboxadol (OV101) showed negative Phase 3 results (NCT04106557). Minocycline showed no significant improvements in a randomized placebo-controlled trial. Ongoing trials include antisense oligonucleotide therapies (NCT04428281, NCT04259281).
**Clinical Implications:** For suspected PWS/AS, methylation testing is recommended with MS-MLPA being the most sensitive method; CMA is an appropriate first-line test for individuals with developmental delay and/or hypotonia. Genetic counseling is essential throughout the diagnostic process. For parents of a child with PWS or AS, recurrence risk is most commonly <1%, though rare genetic subtypes have a 50% recurrence risk (inheritance of a pathogenic variant in an imprinted gene) and theoretically up to 100% (15/15 Robertsonian translocation). A female with PWS due to chromosome deletion or IC deletion has a 50% chance to have a child with AS. Management requires multidisciplinary care including genetics, endocrinology, neurology, feeding therapy, developmental interventions, and orthopedic monitoring. PWS individuals should be monitored for obesity-related complications including type II diabetes mellitus, sleep apnea, and osteoporosis. AS individuals require seizure management, sleep hygiene interventions, and screening for scoliosis and hip dysplasia. Ideally, individuals with PWS/AS should be followed in a multidisciplinary clinic to provide comprehensive medical, developmental, and behavioral management.