Angelman Syndrome Caused by a Paternal Uniparental Disomy (UPD) 15 in a 2-Year-Old Boy of a Mother with a Robertsonian Translocation 14;15

Background: Angelman syndrome is due to deficient expression or function of the maternally inherited UBE3A allele. Molecular genetic testing (methylation analysis and UBE3A sequence analysis) identifies alterations in ~90% of individuals: deletions, uniparental disomy, imprinting defects or UBE3A mutations. We report here on a boy with Angelman syndrome and a paternal UPD15 due to a Robertsonian translocation in the mother.

Case Report: The boy was born at term after a pregnancy complicated by gestational diabetes (weight 3,190 g (34th PCTL), length 50 cm (26th PCTL), head circumference 34.5 cm (33rd PCTL)) but suffered from hypoglycemia and aspiration pneumonia. At the age of 2, he was able to pull himself up and walk with support. Neurological examination showed divergent strabismus, truncal and gait ataxia, hypotonia, hypersalivation, lack of speech, and a secondary microcephaly (46 cm [<1st PCTL]); thus, Angelman syndrome was suspected. Accordingly, the awake EEG displayed intermittent 2–3/s waves with large amplitudes, especially after eye closure, the MRI scan revealed delayed myelination. The mother mentioned having been diagnosed with a Robertsonian translocation 14;15 after several miscarriages in the 1990s. Due to the combination of clinical signs and maternal findings, an MLPA analysis was performed showing an abnormal methylation pattern which confirmed the tentative diagnosis of Angelman syndrome in this boy. A microsatellite analysis validated our hypothesis of paternal uniparental disomy 15.

Conclusion: A maternal Robertsonian translocation is a rare predisposing factor for Angelman syndrome which can lead to a maternal gamete nullisomic for chromosome 15 with subsequent postzygotic correction to paternal disomy.