Blended phenotype of combination of HERC2 and AP3B2 deficiency and Angelman syndrome caused by paternal isodisomy of chromosome 15

• Published in: American journal of medical genetics. Part A 2021-10, Vol.185 (10), p.3092-3098
• Main Authors: Ueda, Kimiko, Ogawa, Satoru, Matsuda, Keiko, Hasegawa, Yuiko, Nishi, Eriko, Yanagi, Kumiko, Kaname, Tadashi, Yamamoto, Toshiyuki, Okamoto, Nobuhiko
• Format: Article
• Language: English
• Subjects: Adaptor Protein Complex 3 - genetics; Adaptor Protein Complex beta Subunits - genetics; Angelman Syndrome - diagnosis; Angelman Syndrome - genetics; Angelman Syndrome - pathology; Angelman syndromeAP3B2 gene; Atrophy; Child, Preschool; Chromosome 15; Chromosomes; Chromosomes, Human, Pair 15 - genetics; Encephalopathy; Epilepsy; Gait; Genetic Predisposition to Disease; HERC2 gene; Homozygote; Humans; Intellectual disabilities; Intellectual Disability - genetics; Intellectual Disability - pathology; Magnetic resonance imaging; Male; Microencephaly; Myelination; Neurodevelopmental disorders; Neuroimaging; Phenotype; Phenotypes; Pigmentation; Strabismus; Ubiquitin-Protein Ligases - genetics; Uniparental Disomy - genetics; uniparental isodisomy of chromosome 15; Whole Exome Sequencing
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.62371

Angelman syndrome is a neurodevelopmental disorder characterized by intellectual disability (ID), a distinctive gait pattern, abnormal behaviors, severe impairment in language development, and characteristic facial features. Most cases are caused by the absence of a maternal contribution to the imprinted region on chromosome 15q11‐q13. Here, we present the first reported case of a 3‐year‐old boy with an atypical phenotype of Angelman syndrome due to uniparental isodisomy with two recessive homozygous pathogenic variants: in HERC2 and AP3B2. Known phenotypes related to HERC2 and AP3B2 include ID and early infantile epileptic encephalopathy, respectively. The patient had severe global developmental delay and profound ID and showed a happy demeanor, stereotypic laughter, and hand‐flapping movements, but also irritability. Craniofacial dysmorphic features, including brachycephaly, strabismus, wide ala nasi, short philtrum, wide open mouth, and slight hypopigmentation were seen. Progressive microcephaly was noted. Magnetic resonance imaging of the brain showed delayed myelination and cerebral atrophy. Trio whole exome sequencing and CGH‐SNP array analysis revealed paternal uniparental isodisomy of chromosome 15 and two coexisting recessive diseases resulting from homozygous HERC2 and AP3B2 pathogenic variants. The pathogenic variant in HERC2 was inherited from his heterozygous‐carrier father, and the variant in AP3B2 was de novo. We suppose that these unusual features were the combination of the effect of three concomitant disorders.