Two infants with mild, atypical clinical features of Kagami-Ogata syndrome caused by epimutation

Kagami-Ogata syndrome (KOS) is an imprinting disorder characterized by polyhydramnios, bell-shaped thorax with coat-hanger appearance (curved ribs), respiratory distress, abdominal wall defects, and distinct facial features, together with intellectual developmental delay with special needs. Abnormal expression of the imprinted genes on chromosome 14q32.2 causes KOS. Epimutation with aberrant hypermethylation of the MEG3/DLK1: intergenic differentially methylated region (MEG3/DLK1:IG-DMR) and the MEG3:TSS-DMR is one of the etiologies of KOS. We report two infants with KOS caused by epimutation presenting with some characteristic clinical features, mild clinical course, and almost normal motor and intellectual development. Methylation analysis for ten DMRs related to major imprinting disorders using pyrosequencing with genomic DNA (gDNA) extracted from leukocytes showed abnormally increased methylation levels of the MEG3/DLK1:IG-DMR and MEG3:TSS-DMR in both patients, but lower than those in patients with paternal uniparental disomy chromosome 14 (upd(14)pat). The methylation levels in the DMRs other than both DMRs were within normal range. We also conducted methylation analysis for the MEG3/DLK1:IG-DMR and MEG3:TSS-DMR with gDNA extracted from nails and buccal cells of both patients. Methylation levels in the MEG3:TSS-DMR, particularly in buccal cells, were closer to normal range compared to those in leukocytes. Microsatellite analysis for chromosome 14 and array comparative hybridization analysis showed no upd(14)pat or microdeletion involving the 14q32.2 imprinted region in either patient. A differential mosaic ratio of cells with aberrant methylation of DMRs at the 14q32.2 imprinted region among tissues (connective tissue, lung, and brain) might have led to their atypical clinical features. Further studies of patients with epimutation should further expand the phenotypic spectrum of KOS.