Phenotypic spectrum of 11p15.5 duplications: parent-of-origin and copy number variant size shape outcomes from Silver-Russell to Beckwith-Wiedemann syndromes

Genomic imprinting at the 11p15.5 region is critically involved in fetal growth regulation. Disturbances in this region are primarily associated with two opposing growth disorders: Silver-Russell syndrome (SRS, growth restriction) and Beckwith-Wiedemann syndrome (BWS, overgrowth). While epigenetic alterations are well-characterized in SRS and BWS, copy number variants (CNVs) rearrangements remain incompletely understood, particularly in terms of how duplication size and parental origin shape the phenotypic spectrum. We present a case series of three prenatally identified fetuses with 11p15.5 duplications, characterized by chromosomal microarray analysis and Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA). Parental origin was determined by segregation analysis. Case A: A focal duplication of the maternally inherited allele encompassing only the ICR2/CDKN1C domain presented with severe isolated intrauterine growth restriction (IUGR), consistent with a SRS phenotype. Case B: A large duplication of the maternally inherited allele spanning both the ICR1/H19/IGF2 and ICR2/CDKN1C domains resulted in a complex phenotype of IUGR (SRS-like) with omphalocele (a BWS-associated anomaly), demonstrating a mixed and paradoxical presentation. Case C: A large duplication of the paternally inherited allele of the entire 11p15.5 region was associated with a BWS phenotype, presenting with macrosomia and other features, consistent with the predominant effect of paternal inheritance. Our findings support a model in which parental origin shows a strong tendency to determine the direction of growth dysregulation (maternal allele duplications predominantly associate with SRS-like restriction; paternal allele duplications with BWS-like overgrowth), while duplication size contributes to phenotypic complexity, with larger rearrangements involving both ICRs more frequently associated with severe or blended features. However, exceptions to this generalization exist in the literature, highlighting that 11p15.5 duplication disorders exhibit variable penetrance and expressivity.