Identifying Uncommon UBE3A Mutations Demands Advanced Gene Analysis
First Documented Case of Angelman Syndrome in Indonesia Diagnosed through Whole-Exome Sequencing
In a groundbreaking development, a team of researchers from the Institut für Humangenetik, Universitätsklinikum Essen in Essen, Germany, have successfully diagnosed Angelman syndrome in a 2-year-old girl from Indonesia using a comprehensive genetic test called whole-exome sequencing (WES). This case marks the first documented instance of Angelman syndrome in Indonesia.
The girl, who is approaching 3 years old, was referred to the hospital due to developmental delays and impaired speech. From a young age, she showed mild motor developmental delays, and by her current age, she could only walk two to three steps and tended to fall backward. Additionally, she had sucking difficulties since 3 months of age, but showed no feeding issues, and her parents reported sleeping problems. Absence seizures occurred frequently since she was 2.5 months old.
During examination, the girl was found to have microcephaly, typical Angelman's facial features, walking and movement coordination difficulties, low muscle tone in the trunk, and showed hyperactive behavior, attention deficits, significant intellectual impairment, and superior non-verbal than verbal communication skills. An electroencephalogram showed abnormal brain activity suggestive of Angelman syndrome.
Despite receiving valproic acid for absent seizures and three months of walking physiotherapy and speech therapy, the girl had not shown significant improvement. The team noted that the girl's features and symptoms were consistent with the previously reported association between UBE3A mutations and a milder Angelman syndrome.
WES identified a rare disease-causing mutation in exon 9 of one UBE3A gene copy, confirming an Angelman diagnosis. The mutation - c.1513C > T (p.Arg505Ter) - comprised a modification in a single nucleotide, DNA's building blocks, in the UBE3A sequence.
Most cases of Angelman syndrome are caused by a deletion of a region of the maternally inherited chromosome 15 containing the UBE3A gene. However, 10% are associated with mutations in the maternal UBE3A gene, as was the case with the Indonesian girl. The maternally inherited copy of UBE3A is the only active copy in specific regions of the brain, and mutations in this copy result in a complete UBE3A deficiency in nerve cells.
The researchers wrote that this case highlights "the importance of WES in diagnosing this rare neurodevelopmental syndrome." While WES has limitations such as a high cost, the need for a competent technician, and the inability to analyze a person's non-coding DNA regions, it can detect rare variants of Angelman syndrome, as in this case, that cannot be seen with other tests.
Unfortunately, the lack of funding support for genetic testing, shortage of competent health care staff, and the national health insurance not making genetic testing a standard diagnostic test are reasons why such tests are not routinely conducted in Indonesia. This case underscores the need for increased investment in genetic testing and healthcare infrastructure to ensure early and accurate diagnosis of rare diseases like Angelman syndrome.
The case study was published in the journal Annals of Medicine & Surgery.
