Blended phenotype of AP4E1 deficiency and Angelman syndrome caused by paternal isodisomy of chromosome 15

Abstract Atypical phenotype of an imprinting disease can develop with a recessive homozygous variant due to uniparental isodisomy. We present a girl with severe intellectual disability, developmental delay, distinctive facial features, and other neuropsychiatric features. Trio whole exome sequencing revealed a novel homozygous frameshift variant in AP4E1 [NM_007347.5:c.2412dupT:p.(Gly805Trpfs*8)] and uniparental isodisomy of chromosome 15 [iUPD(15)]. Single nucleotide polymorphism mapping analysis of exome data showed that the homozygous AP4E1 variant was derived from her heterozygous carrier father and unmasked by paternal iUPD(15). Brain magnetic resonance imaging confirmed the brain abnormalities characteristic of AP4 deficiency including the dilated ventricles and hypointensity in the globus pallidus in susceptibility-weighted imaging. This is the first case report of a combination of AP4E1 deficiency and Angelman syndrome. Our patient indicates that whole exome sequencing could uncover an atypical phenotype caused by multiple genetic factors including the uniparental isodisomy.