Sisters’ Angelman syndrome tied to new UBE3A mutation

Previously unreported mutation identified after genetic sequencing

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A previously unreported mutation in the UBE3A gene was found to be the cause of Angelman syndrome for two sisters.

The sisters’ journey to obtaining a correct diagnosis was detailed in a paper, “Undiagnosed rare disease clinic identifies a novel UBE3A variant in two sisters with Angelman syndrome: The end of a diagnostic odyssey,” published in the journal Congenital Anomalies Clinical and Laboratory Research.

Angelman is caused by deficiency of the copy of the UBE3A gene that’s inherited from an individual’s biological mother. In most cases, the gene is either missing, or it’s inactivated due to a biochemical process called methylation. In a small number of cases — about 1 in 20) — Angelman syndrome is caused by changes in the genetic sequence of the maternal UBE3A gene.

That’s what turned out to be the case for the two sisters at the center of the report. Both girls had a lifelong history of symptoms indicative of genetic disease, including irregularities in development, absent speech, and seizures, but diagnostic tests — including tests to look for UBE3A deletion or abnormal UBE3A methylation — had not been able to pinpoint a cause for their symptoms.

The girls were 9 and 13 when they underwent more detailed genetic sequencing at Indiana University. The tests didn’t reveal anything definitive, but they did identify a mutation in the UBE3A gene in both sisters.

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The mutation, dubbed c.2443C>T p.(Pro815Ser), was initially classified as a variant of uncertain significance, meaning that, while the mutation did have a difference in the genetic code compared with the general population, it wasn’t clear if the mutation actually affected the UBE3A gene’s function to cause disease.

The sisters were brought to the university’s Undiagnosed Rare Disease Clinic for further evaluation. Analyses of their parents and grandparents showed their mother carried the mutation, and so did her father (the girls’ grandfather), which is consistent with maternally inherited mutations that cause Angelman.

Further computer-based analyses indicated the mutation interfered with the gene’s function, and ultimately these tests confirmed that the mutation was indeed disease-causing, cementing a diagnosis of Angelman syndrome in both girls.

“The novel heterozygous variant c.2443C>T p.(Pro815Ser) of the UBE3A gene found in this family was considered the cause of the phenotype of these two sisters with” Angelman syndrome, the researchers wrote.