Identifying Infrequent UBE3A Variants Demands Extensive Genetic Examinations
In a pioneering development, a 2-year-old girl from Indonesia has been diagnosed with Angelman syndrome, marking the first documented mycase in the country. The diagnosis was made through whole-exome sequencing (WES), a comprehensive genetic test that identifies potential rare and disease-causing mutations.
The case study, titled "The role of whole exome sequencing in the UBE3A point mutation of Angelman Syndrome: A case report," was published in the journal Annals of Medicine & Surgery. The research group led by Dr. Kalscheuer conducted the diagnosis, identifying a rare disease-causing mutation in exon 9 of one UBE3A gene copy.
The mutation identified, c.1513C > T (p.Arg505Ter), is a modification in a single nucleotide in the UBE3A sequence. This mutation is associated with a milder form of Angelman syndrome, as the girl's features and symptoms were consistent with previously reported associations.
Angelman syndrome is a condition marked by characteristic facial features, significant developmental delays with motor dysfunction, speech difficulty, a high incidence of epilepsy, and sleep and eating difficulties. The girl in question displayed hyperactive behavior, attention deficits, significant intellectual impairment, and superior non-verbal than verbal communication skills. She also had microcephaly, typical Angelman's facial features, and low muscle tone in the trunk.
The girl showed mild motor developmental delays in her first year of life, and at her current age could only walk two to three steps and tended to fall backward. She also had sucking difficulties since 3 months of age, but showed no feeding issues, and her parents reported sleeping problems. Absence seizures, characterized by brief, sudden lapses of consciousness, occurred frequently since she was 2.5 months old.
Despite treatment with valproic acid for absent seizures and three months of walking physiotherapy and speech therapy, the girl showed no significant improvement. An electroencephalogram showed abnormal brain activity suggestive of Angelman syndrome.
Whole-exome sequencing (WES) looks at all of a person's exons, the sections in DNA that provide instructions for making proteins. This makes it an important tool in diagnosing rare neurodevelopmental syndromes like Angelman syndrome, but it has limitations. These include a high cost, the need for a competent technician, and the inability to analyze a person's non-coding DNA regions.
Given the rarity of UBE3A mutations, which are associated with a milder disease, they are typically not covered by most commonly used, standard genetic tests for Angelman syndrome. 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 may be reasons for the rarity of genetic testing in Indonesia.
This case serves as a reminder of the importance of continued research and investment in genetic testing to improve early diagnosis and treatment of rare genetic disorders like Angelman syndrome.
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