Clinically Distinct Epigenetic Subgroups in Silver-Russell Syndrome: The Degree of H19 Hypomethylation Associates with Phenotype Severity and Genital and Skeletal Anomalies

Context: The H19 imprinting control region (ICR), located on chromosome 11p15.5, has been reported hypomethylated in 20–65% of Silver-Russell syndrome (SRS) patients. Objective: We investigated the methylation status of 11p15.5 ICRs in SRS patients and children born small for gestational age (SGA) to clarify the relationship between phenotype and H19 methylation status. Methods: We performed methylation screens of the H19 and KCNQ1OT1 ICRs in 42 SRS patients, including seven maternal uniparental disomy of chromosome 7 patients, and 90 SGA children without SRS. Clinical data were evaluated from patient records, and seven hypomethylated patients were clinically and radiologically reexamined. Results: H19 ICR hypomethylation was found in 62% of SRS patients but in no SGA children. A clinical severity score demonstrated strong correlation between hypomethylation level and phenotype severity. Hypomethylation related to a more severe SRS phenotype, in which especially asymmetry and micrognathia were significant...