Prader-Willi (PWS) and Angelman (AS) syndromes were the first examples in humans with errors in genomic imprinting, usually from de novo 15q11-q13 deletions of different parent origin (paternal in PWS and maternal in AS). Dozens of genes and transcripts are found in the 15q11-q13 region, and may play a role in PWS, specifically paternally expressed SNURF-SNRPN and MAGEL2 genes, while AS is due to the maternally expressed UBE3A gene. These three causative genes, including their encoding proteins, were targeted. This review article summarizes and illustrates the current understanding and cause of both PWS and AS using strategies to include the literature sources of key words and searchable web-based programs with databases for integrated gene and protein interactions, biological processes, and molecular mechanisms available for the two imprinting disorders. The SNURF-SNRPN gene is key in developing complex spliceosomal snRNP assemblies required for mRNA processing, cellular events, splicing, and binding required for detailed protein production and variation, neurodevelopment, immunodeficiency, and cell migration. The MAGEL2 gene is involved with the regulation of retrograde transport and promotion of endosomal assembly, oxytocin and reproduction, as well as circadian rhythm, transcriptional activity control, and appetite. The UBE3A gene encodes a key enzyme for the ubiquitin protein degradation system, apoptosis, tumor suppression, cell adhesion, and targeting proteins for degradation, autophagy, signaling pathways, and circadian rhythm. PWS is characterized early with infantile hypotonia, a poor suck, and failure to thrive with hypogenitalism/hypogonadism. Later, growth and other hormone deficiencies, developmental delays, and behavioral problems are noted with hyperphagia and morbid obesity, if not externally controlled. AS is characterized by seizures, lack of speech, severe learning disabilities, inappropriate laughter, and ataxia. This review captures the clinical presentation, natural history, causes with genetics, mechanisms, and description of established laboratory testing for genetic confirmation of each disorder. Three separate searchable web-based programs and databases that included information from the updated literature and other sources were used to identify and examine integrated genetic findings with predicted gene and protein interactions, molecular mechanisms and functions, biological processes, pathways, and gene-disease associations for candidate or causative genes per disorder. The natural history, review of pathophysiology, clinical presentation, genetics, and genetic-phenotypic findings were described along with computational biology, molecular mechanisms, genetic testing approaches, and status for each disorder, management and treatment options, clinical trial experiences, and future strategies. Conclusions and limitations were discussed to improve understanding, clinical care, genetics, diagnostic protocols, therapeutic agents, and genetic counseling for those with these genomic imprinting disorders.

Prader-Willi syndrome (PWS) is a rare imprinting-related neurodevelopmental disorder caused by loss of paternally expressed genes within the chromosome 15q11-q13 region, including SNORD116, MAGEL2, and NDN. It provides a natural model for examining how genomic imprinting disruptions shape neural development and psychiatric vulnerability. This review synthesizes current evidence to clarify the mechanistic pathways linking imprinting defects and epigenetic dysregulation to neuropsychiatric outcomes in PWS. Published studies-including patient-derived induced pluripotent stem cell (iPSC) models, animal knockout systems (e.g., Magel2-null models), transcriptomic and DNA methylation datasets, and human neuroimaging research-were identified through targeted searches of PubMed and Web of Science and integrated narratively rather than through systematic procedures. Across these data sources, deletion-type PWS is primarily associated with impaired neuronal maturation, altered serotonergic signaling, and locus-specific transcriptional dysregulation. Maternal uniparental disomy (mUPD) is characterized by broader epigenetic alterations within the imprinted domain, genome-wide transcriptional effects, dopaminergic pathway alterations, and disrupted prefrontal-limbic connectivity linked to increased psychosis risk. Importantly, available evidence supports substantial phenotypic and mechanistic overlap between PWS subtypes, with genotype-phenotype associations reflecting probabilistic tendencies rather than categorical distinctions. Collectively, convergent findings across molecular, neurochemical, and systems-level studies support a mechanistic continuum extending from imprinting defects to behavioral phenotypes. These insights position PWS as a translational model for understanding how epigenetic dysregulation contributes to psychiatric risk and highlight the need for genotype-informed, mechanistically grounded research to advance biomarker development and targeted therapeutic strategies.

Prader-Willi Syndrome (PWS) is a complicated genetic disorder demonstrating a variety of clinical phenotypes. Using molecular cytogenetics approaches to detect the deletions of the paternal 15q11-q13 region and maternal uniparental disomy of chromosome 15 plays an important role in the prenatal diagnosis of PWS. A pregnant woman with advanced maternal age underwent amniocentesis. The amniotic fluid was subjected to karyotyping and chromosomal microarray analysis. A marker without autosomal material and loss of heterozygosity (LOH) of 15q14-q23 were found in the fetus. The LOH was consistent with maternal uniparental isodisomy (UPD) and the marker was inherited from the father. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) found increased methylation in the fetal 15q11.2-q13 region and fluorescence in situ hybridization confirmed the marker was not originated from chromosome 15. We presented a rare PWS case showing maternal UPD of chromosome 15 with concurrent paternal marker chromosome in the prenatal setting.

Angelman syndrome (AS) and Prader-Willi syndrome (PWS), two distinct neurodevelopmental disorders, result from loss of expression from imprinted genes in the chromosome 15q11-13 locus most commonly caused by a megabase-scale deletion on either the maternal or paternal allele, respectively. Each occurs at an approximate incidence of 1/15,000 to 1/30,000 live births and has a range of debilitating phenotypes. Patient-derived induced pluripotent stem cells (iPSCs) have been valuable tools to understand human-relevant gene regulation at this locus and have contributed to the development of therapeutic approaches for AS. Nonetheless, gaps remain in our understanding of how these deletions contribute to dysregulation and phenotypes of AS and PWS. Variability across cell lines due to donor differences, reprogramming methods, and genetic background make it challenging to fill these gaps in knowledge without substantially increasing the number of cell lines used in the analyses. Isogenic cell lines that differ only by the genetic mutation causing the disease can ease this burden without requiring such a large number of cell lines. Here, we describe the development of isogenic human embryonic stem cell (hESC) lines modeling the most common genetic subtypes of AS and PWS. These lines allow for a facile interrogation of allele-specific gene regulation at the chromosome 15q11-q13 locus. Additionally, these lines are an important resource to identify and test targeted therapeutic approaches for patients with AS and PWS.

The 15q11-q13 region is a genetic locus with genes subject to genomic imprinting, significantly influencing neurodevelopment. Genomic imprinting is an epigenetic phenomenon that causes differential gene expression based on the parent of origin. In most diploid organisms, gene expression typically involves an equal contribution from both maternal and paternal alleles, shaping the phenotype. Nevertheless, in mammals, including humans, mice, and marsupials, the functional equivalence of parental alleles is not universally maintained. Notably, during male and female gametogenesis, parental alleles may undergo differential marking or imprinting, thereby modifying gene expression without altering the underlying DNA sequence. Neurodevelopmental disorders, such as Prader-Willi syndrome (PWS) (resulting from the absence of paternally expressed genes in this region), Angelman syndrome (AS) (associated with the absence of the maternally expressed UBE3A gene), and 15q11-q13 duplication syndrome (resulting from the two common forms of duplications-either an extra isodicentric 15 chromosome or an interstitial 15 duplication), are the outcomes of genetic variations in this imprinting region. Conducted a genomic study to identify the frequency of pathogenic variants impacting the 15q11-q13 region in an ethnically homogenous population from Bangladesh. Screened all known disorders from the DECIPHER database and identified variant enrichment within this cohort. Using the Horizon analysis platform, performed enrichment analysis, requiring at least >60% overlap between a copy number variation and a disorder breakpoint. Deep clinical phenotyping was carried out through multiple examination sessions to evaluate a range of clinical symptoms. This study included eight individuals with clinically suspected PWS/AS, all previously confirmed through chromosomal microarray analysis, which revealed chromosomal breakpoints within the 15q11-q13 region. Among this cohort, six cases (75%) exhibited variable lengths of deletions, whereas two cases (25%) showed duplications. These included one type 2 duplication, one larger atypical duplication, one shorter type 2 deletion, one larger type 1 deletion, and four cases with atypical deletions. Furthermore, thorough clinical assessments led to the diagnosis of four PWS patients, two AS patients, and two individuals with 15q11-q13 duplication syndrome. Our deep phenotypic observations identified a spectrum of clinical features that overlap and are unique to PWS, AS, and Dup15q syndromes. Our findings establish genotype-phenotype correlation for patients impacted by variable structural variations within the 15q11-q13 region.