Genomic Imprinting, Epigenetic Dysregulation, and Neuropsychiatric Mechanisms in Prader–Willi Syndrome: A Multi-Level Integrative Review

TL;DR

This review explores how genetic and epigenetic changes in Prader–Willi syndrome affect brain development and psychiatric outcomes, offering insights into broader neuropsychiatric mechanisms.

Contribution

The paper integrates multi-level evidence to clarify distinct and overlapping pathways in PWS subtypes, emphasizing their translational value for psychiatric research.

Findings

Deletion-type PWS is linked to impaired neuronal maturation and altered serotonergic signaling.

mUPD in PWS involves genome-wide epigenetic changes and increased psychosis risk via disrupted prefrontal-limbic connectivity.

PWS subtypes share mechanistic overlap, suggesting a continuum from genetic defects to behavioral outcomes.

Abstract

What are the main findings?
Genomic imprinting defects at the chromosome region 15q11-q13 are responsible for epigenetic and transcriptional abnormalities that contribute to neurodevelopmental vulnerability in individuals with Prader–Willi syndrome.Deletion-type and maternal uniparental disomy (mUPD) forms of Prader–Willi syndrome involve distinct molecular pathways that partially overlap in their downstream effects on neurotransmitter systems and neural circuitry.

Genomic imprinting defects at the chromosome region 15q11-q13 are responsible for epigenetic and transcriptional abnormalities that contribute to neurodevelopmental vulnerability in individuals with Prader–Willi syndrome.

Deletion-type and maternal uniparental disomy (mUPD) forms of Prader–Willi syndrome involve distinct molecular pathways that partially overlap in their downstream effects on neurotransmitter systems and neural circuitry.

What is the implication of the main finding?
Prader–Willi syndrome is an example of a natural model that relates psychiatric phenotype to the regulation of genes by imprinting-dependent mechanisms.Understanding shared and subtype-specific pathways may inform biomarker development and mechanism-based stratification in neuropsychiatric research.

Prader–Willi syndrome is an example of a natural model that relates psychiatric phenotype to the regulation of genes by imprinting-dependent mechanisms.

Understanding shared and subtype-specific pathways may inform biomarker development and mechanism-based stratification in neuropsychiatric research.

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.

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