Angelman syndrome is a neurogenetic disorder marked by intellectual disability and epileptic seizures. It is primarily caused by dysfunction of the maternal UBE3A gene in the 15q11.2 region of chromosome 15. Its genetic causes are heterogeneous: a maternal deletion of 15q11-q13, paternal uniparental disomy of chromosome 15, a pathogenic variant on the maternal UBE3A copy, or an imprinting defect can each produce the syndrome.

The cohort consisted of clinically suspected Angelman syndrome patients whose clinical and genetic data were systematically analyzed. The team deployed multiple testing methods, including methylation-specific MLPA, trio-based whole-exome sequencing, whole-genome sequencing, SNP-array and copy number variation sequencing. For selected patients, they added long-range PCR, PacBio Sequel series Single Molecule Real-Time sequencing, and Blocker displacement amplification, the latter to detect very low-level mosaicism.

All 13 patients showed developmental delay, and six had epilepsy with characteristic EEG findings. Ataxia was observed in five cases, frequent smiling and laughter in four, microcephaly in two, and dysmorphic features in two.

Genetic analysis identified heterozygous UBE3A variants in eight cases, 15q11-q13 deletions in four cases, and paternal uniparental disomy in one case. Among the UBE3A variants, three were novel: c.409T>G causing p.(Cys137Gly), c.2038_2042del causing p.(Ser680fs), and c.2510C>T causing p.(Ser837Phe). None of these had been reported before, expanding the known variant spectrum of the gene.

The most striking finding came from two siblings who carried the same UBE3A variant, c.409T>C resulting in p.(Cys137Arg). This variant was undetectable in the blood of either parent, yet PacBio long-read sequencing confirmed that it was located on the maternally derived allele. This pattern points to germline mosaicism in the mother, meaning the variant is present in some of her eggs or germ cells even though it cannot be found in her blood.

A Blocker displacement amplification test on the mother was negative, suggesting that she either does not harbor the variant at all, or that the variant exists in the assessed somatic samples but at a level lower than 5 per thousand, below the detection limit of that method. For families affected by such hidden mosaicism, the recurrence risk is real even when parental blood testing appears normal, which is why the authors emphasize the need for prenatal counseling in similar situations.

According to the authors, the study summarizes the characteristics of 13 Chinese patients with Angelman syndrome and expands both the clinical and genetic spectrum of the condition. They conclude that the genetic heterogeneity of the syndrome necessitates multimodal testing for accurate diagnosis, that PacBio long-read sequencing enhances parental origin determination, and that germline mosaicism underscores the need for prenatal counseling. The work is an open-access research article published on 27 October 2026, and the published version notes it was shared early as a citable, peer-reviewed accepted manuscript subject to further edits.

For clinicians, the practical message is that a single genetic test may not be sufficient. Because deletions, uniparental disomy, imprinting defects and sequence variants all require different detection methods, a stepwise or combined approach is needed to reach a precise molecular diagnosis.

Subject of Research: Genetic and clinical characterization of Angelman syndrome in a Chinese pediatric cohort using multimodal genetic testing including long-read sequencing

Article Title: Clinical and genetic characterization of Angelman syndrome in a Chinese cohort: UBE3A variant spectrum expansion and utility of long-read sequencing

Article References: Zhang, M., Dai, W., Fan, Y., Wang, J., Zhang, Y., Yang, S., Jiao, A., Wu, Y., Jiang, Y., Yu, Y., Wang, J., & Yan, H. (2026). Clinical and genetic characterization of Angelman syndrome in a Chinese cohort: UBE3A variant spectrum expansion and utility of long-read sequencing. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07900-5

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07900-5

Keywords: Angelman syndrome, UBE3A, long-read sequencing, PacBio, genetic diagnosis, germline mosaicism, uniparental disomy, 15q11-q13 deletion, whole-exome sequencing, genetic counseling, pediatric neurogenetics, BMC Pediatrics