New Disease-causing UBE3A Variant Identified in 6 Members of Family

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by Steve Bryson PhD |

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A previously unreported variant in the UBE3A gene caused an inherited form of Angelman syndrome in six members of a Chinese family, a study reports.

The finding expands the genetic spectrum of Angelman syndrome and supports genetic counseling for those affected, its researchers said.

The study, “A novel variant in UBE3A in a family with multigenerational intellectual disability and developmental delay,” was published in the journal Molecular Genetics & Genomic Medicine.

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Angelman syndrome is caused by mutations, or variants, in the UBE3A gene, which leads to the absence or malfunction of the encoded enzyme called ubiquitin-protein ligase E3A in the nervous system. A deficiency in this enzyme results in developmental delays, intellectual disability, abnormal facial features, uncoordinated movements, or seizures, typically beginning in the first year of life.

To date, over 250 UBE3A variants are associated with Angelman, most of which occur sporadically during the early stages of fetal development. In rare cases, variants can be inherited within families.

Researchers at The First Affiliated Hospital of Zhengzhou University in China describe the discovery of a previously unknown UBE3A variant causing Angelman identified in six members of the same family.

It began when a 3-year-old girl was referred to the hospital due to developmental delays and intellectual disabilities. She was the second child of healthy parents, and medical records showed her birth was uneventful.

She started to walk at 15 months old and was prone to falls. She did not understand simple orders and only spoke two words: “BaBa” and “MaMa.”

Her non-verbal communication abilities were more advanced than her verbal skills, and she was hyperflexible in the lower legs and drooled often. She also showed attention deficits, irritability, and excessive laughter, but had no history of seizures or sleep disorders.

At the same time, her 8-year-old brother also had developmental delays with speech impairment. He needed help getting dressed and could only feed himself using a spoon. His right eye was crossed, and he was also hyperflexible but had a sleep disorder. Other symptoms were similar to his sister.

Based on these findings, researchers ordered genetic testing over three generations of the family. Here, they discovered a novel variant of the UBE3A gene within the family referred to as c.2029G>C, meaning that G (guanine) is changed to a C (cytosine), two building blocks of DNA within the gene.

Of the family members screened, four were unaffected carriers of this UBE3A variant, whereas five other members had the variant and were also diagnosed with Angelman syndrome. The 3-year-old girl and her 8-year-old brother received the variant from their unaffected mother. Among those affected, most showed symptoms similar to the girl.

Computer analysis predicted this genetic change would cause disease because it altered a critical and stable region of the encoded ubiquitin-protein ligase E3A enzyme.

“We identified a novel variant (c.2029G>C) in the UBE3A in a Chinese family with six [Angelman syndrome] patients,” the scientists concluded. “Our findings expanded the genotypic spectrum of [Angelman syndrome] and provided important information for genetic counseling.”