Kagami-Ogata syndrome: comprehensive clinical study in 67 molecularly diagnosed patients

Kagami-Ogata syndrome (KOS14) is a rare 14q32-related imprinting disorder. Since existing clinical data have mostly been limited to infancy and early childhood, long-term growth, maturation patterns, and neurodevelopmental outcomes remain poorly understood. In this study, we aimed to characterize the comprehensive clinical spectrum of KOS14. We obtained detailed clinical findings in 67 Japanese patients with molecularly confirmed KOS14 (37 with paternal uniparental disomy for chromosome 14 [UPD(14)pat], 17 with epimutation, 12 with deletions, and one with UPD(14)pat or epimutation). Polyhydramnios, placentomegaly, characteristic facial features with depressed nasal bridge, full cheeks, and protruding philtrum, and bell-shaped small thorax with coat-hanger appearance of the ribs were identified in nearly all patients. The characteristic face and coat-hanger appearance of the ribs remained diagnostic from infancy through adulthood. Respiratory distress was present in all patients at birth. The median duration of respiratory support was approximately 6 months, although support persisted beyond school age in around 5% of patients. Large for gestational age was detected in ~50% of patients, whereas postnatal growth was compromised, especially in patients with severe feeding difficulty. Two females with 2× of predicted DLK1 expression dosage had pubertal failure and amenorrhea. Omphalocele and diastasis recti were observed in ~30% and ~80% of patients, respectively, and severe constipation requiring treatment was observed in about two-thirds of patients as a long-term complication. Developmental delay was invariably observed, and substantial fraction of patients showed delay in communication skills, personal traits, and/or social behaviors. Joint contracture in infancy and scoliosis from childhood were relatively common, and most affected patients with scoliosis required orthopedic management. Overall clinical features were grossly similar among patients with UPD(14)pat, epimutation, and deletion, between patients with ~2.5× and ~5× of predicted RTL1 expression dosage, between patients with 1× and 2× of predicted DLK1 expression dosage, and between deletion subtypes with a difference in either predicted RTL1 or DLK1 expression dosage. These results clarify the detailed long-term clinical characteristics in KOS14, providing useful diagnostic and therapeutic implications in KOS14.