Spotting Rare UBE3A Mutations Can Require Comprehensive Gene Testing
A comprehensive genetic test called whole-exome sequencing (WES) can identify potential rare and disease-causing mutations that would be missed by standard tests for Angelman syndrome, a case report on a 2-year-old girl in Indonesia highlights.
The case study, “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.
Angelman syndrome is “marked by characteristic facial features, significant developmental delays with motor dysfunction, speech difficulty, a high incidence of epilepsy, and sleep and eating difficulties,” the researchers wrote.
Most cases are caused by a deletion of a region of the maternally inherited chromosome 15 containing the UBE3A gene, but 10% are associated with mutations in the maternal UBE3A gene.
Since the maternally inherited copy of UBE3A is the only active copy in specific regions of the brain, mutations in this copy result in a complete UBE3A deficiency in nerve cells and the neurodevelopmental symptoms seen in patients.
Given their rarity, UBE3A mutations — which are associated with a milder disease — are typically not covered by most commonly used, standard genetic tests for Angelman syndrome.
A research team at Gadjah Mada University’s Dr. Sardjito Hospital, in Indonesia, reported the case of a 2-year-old girl in whom a rare disease-causing UBE3A mutation was detected through WES, allowing the diagnosis of Angelman.
WES looks at all of a person’s exons, the sections in DNA that provide instructions for making proteins, with genes being comprised of exons interspaced with non-coding regions called introns.
The girl, approaching 3 years old, was referred to the hospital due to developmental delays and impaired speech.
She 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. Absence seizures — characterized by brief, sudden lapses of consciousness — occurred frequently since she was 2.5 months old.
The girl had sucking difficulties since 3 months of age, but showed no feeding issues, and her parents reported sleeping problems.
On examination, she had microcephaly (a smaller head and brain size), typical Angelman’s facial features, walking and movement coordination difficulties, and low muscle tone in the trunk.
She tended to laugh easily, 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.
While the child was first thought to have epileptic encephalopathy, a condition characterized by seizures that contribute to severe cognitive and behavioral problems, 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.
Researchers noted that the girl’s features and symptoms were consistent with the previously reported association between UBE3A mutations and a milder Angelman syndrome.
The girl was given valproic acid for absent seizures and received “walking physiotherapy and speech therapy for three months but had not shown significant improvement,” the report noted.
“To our knowledge, this is the first documented case of [Angelman syndrome] in Indonesia,” the researchers wrote, adding that “this may happen because genetic testing tools are not routinely conducted in our country.”
Reasons for this, they added, are “a lack of funding support for genetic testing, shortage of competent health care staff to do the testing, and the national health insurance has not made genetic testing a standard diagnostic test.”
Given that WES “could detect a rare variant of [Angelman syndrome], identified as the point mutation of the UBE3A gene, which cannot be seen with other tests,” the researchers wrote, this case highlights “the importance of WES in diagnosing this rare neurodevelopmental syndrome.”
The team noted that WES also has its limitations, including a high cost, the need for a competent technician to do the testing, and the inability to analyze a person’s non-coding DNA regions that may also contain disease-causing mutations.
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