SNRPN – Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder caused by absence of expression of paternally imprinted genes in the 15q11-q13 region. SNRPN, encoding the small nuclear ribonucleoprotein-associated polypeptide N, resides within the Prader-Willi critical region and is subject to parent-of-origin-specific DNA methylation. Loss of the active paternal SNRPN allele—through deletions, uniparental disomy, or imprinting center defects—results in the hallmark PWS phenotype of neonatal hypotonia, feeding difficulties progressing to hyperphagia, central obesity, and hypogonadism.

Genetic Evidence

Genetic studies over >25 years have documented absence of paternal SNRPN expression in >1,000 unrelated PWS probands (PMID:8911606, PMID:9311744). Variant classes include: large 15q11-q13 deletions (~4 Mb), smaller submicroscopic deletions (100–209 kb), paternal uniparental disomy 15, imprinting center microdeletions, and the first de novo point mutation c.73C>T (p.Arg25Ter) detected in mosaic form (PMID:34099539).

Segregation and Familial Cases

Familial imprinting center microdeletions have been reported in three adult siblings, with two additional unaffected carriers in the paternal lineage (PMID:29437285). Submicroscopic deletions in two cousins demonstrated grandmatrilineal inheritance and segregation through unaffected carriers, consistent with imprinting transmission (PMID:10797418).

Variant Spectrum and Phenotypic Correlation

SNRPN variant spectrum spans: large deletions (Type 1/Type 2), atypical small deletions (100–847 kb), UPD cases, imprinting-center microdeletions (78 kb), and single-nucleotide changes (c.73C>T (p.Arg25Ter)). The clinical phenotype is consistent: neonatal hypotonia (HP:0001319), early feeding difficulties, later-onset hyperphagia (HP:0002591), central obesity (HP:0001513), hypogonadism (HP:0000135), developmental delay, and cognitive impairment.

Functional and Experimental Evidence

Methylation analyses at the SNRPN CpG island reliably detect all PWS genetic classes across tissues, including prenatal samples (PMID:9004133). Fluorescence in situ hybridization and MLPA confirm deletion boundaries. Mouse models of imprinting-center mutations recapitulate epigenetic imprinting defects, establishing a mechanism of loss of paternal allele expression.

Conflicting Evidence

Rare cases of "relaxed imprinting" in maternal uniparental disomy individuals exhibit milder or atypical features without hyperphagia, but retain absence of paternal SNRPN expression, underscoring variability in imprint maintenance.

Conclusion

Extensive genetic, segregation, and functional data over decades establish SNRPN as definitively implicated in PWS pathogenesis. Diagnostic testing via methylation analysis and targeted sequencing of SNRPN and its imprinting center is clinically essential for early and accurate PWS diagnosis.

Key Take-home: Absence of active paternal SNRPN expression is a definitive biomarker for Prader-Willi syndrome; integration of methylation testing and gene sequencing optimizes diagnostic yield and informs genetic counseling.

References

• American journal of medical genetics • 1996 • A 5-year-old white girl with Prader-Willi syndrome and a submicroscopic deletion of chromosome 15q11q13. PMID:8911606
• American journal of human genetics • 1997 • Balanced translocation 46,XY,t(2;15)(q37.2;q11.2) associated with atypical Prader-Willi syndrome. PMID:9311744
• American journal of medical genetics • 2000 • Submicroscopic deletion in cousins with Prader-Willi syndrome causes a grandmatrilineal inheritance pattern: effects of imprinting. PMID:10797418
• Journal of medical genetics • 2022 • Mosaic de novo SNRPN gene variant associated with Prader-Willi syndrome. PMID:34099539
• Journal of medical genetics • 1996 • Analysis of parent of origin specific DNA methylation at SNRPN and PW71 in tissues: implication for prenatal diagnosis. PMID:9004133

Evidence Based Scoring (AI generated)

Gene–Disease Association Definitive Extensive molecular evidence across >1,000 probands and decades of replication Genetic Evidence Strong Over 1,000 unrelated probands across multiple variant classes including deletions, UPD, and imprinting mutations ([PMID:8911606]) Functional Evidence Moderate Consistent methylation and expression analyses across tissues and reliable animal models of imprinting defects ([PMID:9004133])