The clinical phenotype of mosaicism for genome-wide paternal uniparental disomy: two new reports

Abstract

Recently, mosaicism for genome-wide paternal uniparental disomy (patUPD), attributed to androgenetic/biparental mosaicism, has been shown to underlie placental mesenchymal dysplasia (PMD), a distinctive cystic placental phenotype. Manifestations of Beckwith-Wiedemann syndrome (BWS) have been observed in approximately one-third of fetuses or liveborn infants from pregnancies complicated by PMD. There are very few reports describing liveborn individuals with proven mosaicism for genome-wide patUPD in somatic tissues. We report two further children with complex phenotypes including some findings of BWS, congenital hyperinsulinemic hypoglycemia, prolonged feeding difficulty and failure to thrive in infancy. The first developed short stature, bilateral pheochromocytomas and progressive arterial stenoses, and the second had congenital adrenal cysts, and later developed hepatoblastoma and patchy hyperpigmentation. Leukocyte DNA methylation studies of KCNQ1OT1/LIT1 and H19 loci (11p15.5) showed almost complete loss of maternal methylation (LOM) in patient 1 and partial LOM in patient 2. Microsatellite marker panels showed whole chromosome 11 patUPD. SNP array studies in both were consistent with mosaic genome-wide patUPD in leukocytes, while fibroblast DNA in Patient 1 showed biparental inheritance. This report further illustrates the clinical consequences of mosaicism for genome-wide patUPD, which results in complex and variable phenotypes. Studies for genome-wide UPD should be considered in individuals with atypical UPD phenotypes.