Variants in the Imprinted IGF2 Gene: A Review and Phasing of De Novo Variants Using Long-Read Sequencing

Pathogenic variants on the paternal allele of IGF2 are linked to Silver-Russell syndrome (SRS). This report describes two unrelated individuals-a 5-year-old girl and an adult female-with de novo IGF2 missense variants, both diagnosed with SRS. While one exhibited normal development, the other had intellectual disability, highlighting phenotypic variability. A review of 20 individuals with IGF2 variants revealed that SRS features, as defined by the Netchine-Harbison Clinical Scoring System, were most common. Additional recurrent traits included delayed speech and motor development, under-masculinized male genitalia, hand/foot anomalies, and congenital heart defects. Growth faltering patterns varied, and intellectual disability was seen in some. We also demonstrated that long-read sequencing can determine the allelic origin of de novo IGF2 variants using differentially methylated regions, eliminating the need for parental samples. This approach confirms long-read sequencing as a powerful tool for identifying de novo variant origins in imprinted genes like IGF2.