Paternal Transmission of Angelman Syndrome via a Mosaic sSMC(15): A Rare Case of Germline Epigenetic Reset Failure and Somatic Rescue.

Abstract

INTRODUCTION Angelman syndrome (AS) is an imprinting disorder that arises almost exclusively through maternal mechanisms; most commonly maternal 15q11.2-q13 deletion; less often, paternal uniparental disomy (UPD) of chromosome 15. Paternal transmission of a 15q11.2-q13 deletion typically results in Prader-Willi Syndrome, making familial paternal AS transmission exceptionally rare. Herein, we report a pedigree in which a neurotypical father transmitted AS to multiple offspring via a structural mechanism distinct from UPD. CASE PRESENTATION The progenitor exhibited 47,XY,+mar[24]/46,XY[6] mosaicism by G-banding karyotype, with three distinct cell lines identified by FISH analysis: a deleted lineage (SNRPN- ; 25%), a balanced lineage (SNRPN+ on sSMC; 45%), and a dosage-rich lineage (SNRPN++ on sSMC; 30%). The sSMC is proposed to have originated through a trisomic rescue event; in which an initial trisomy 15 conceptus underwent rescue with retention of deleted-region material on the marker, enabling somatic compensation in the progenitor. Notably, UPD was excluded as the pathogenic mechanism in affected offspring. Instead, the sSMC's mitotic instability likely facilitated transmission of the unbalanced deletion without the compensatory marker, whereas its structural interference with the imprinting center prevented the maternal-to-paternal epigenetic reset, resulting in an AS phenotype. CONCLUSION This report highlights the role of sSMCs in masking pathogenic deletions and underscores the diagnostic importance of high-resolution genomic mapping in cases of atypical imprinting transmission.