Case Study Details a Rare Gene Defect that Causes Angelman Syndrome

Janet Stewart, MSc avatar

by Janet Stewart, MSc |

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Based on the case study of a boy who has a rare defect in the UBE3A gene that went undetected using the usual genetic tests for Angelman Syndrome, a team of London researchers has recommended special analyses to detect the mutation.

The study, “Angelman Syndrome due to a Maternally Inherited Intragenic Deletion Encompassing Exons 7 and 8 of the UBE3A Gene,” was published in the journal Cytogenetic and Genome Research.

AS is caused by a variety of mutations (defects) in a gene called UBE3A, which usually are detected using genetic tests. But small deletions of the gene have been rarely described, and may be missed by conventional tests.

The authors report the case of a 4-year-old boy suspected of having AS, but not confirmed by standard tests that seek to identify gene mutations.

The boy had developmental delay with severe speech impairment, microcephaly (a small-sized brain), and happy disposition, but was able to walk independently in his third year. He did not have seizures or sleep disturbance, or autistic traits by the age of 4.

Using a special, sophisticated genetic analysis called array comparative genomic hybridization (array-CGH), the team found an intragenic deletion in the UBE3A gene, confirming that the boy had AS.

When his family members were tested for the mutation, the patient’s mother was found to carry it, having inherited it from her father, as did her sister, although neither had AS.

The patient’s cousin had a form of AS that also was milder than the classical Angelman syndrome. The patient’s brother did not carry the mutation and was unaffected.

The particular mutation found in this patient has a high recurrence risk of 50 percent when passed down from the mother. This means that the risk of the disease occurring in other family members is 50 percent. The authors stress the importance of finding these rare mutations in cases of AS because more people are likely to be affected.

Also, with knowledge of the type of mutation causing the disease, families can better prepare for managing the illness, place the patient in an appropriate school, know how much the patient needs to be supervised, and learn what to expect.

“The importance of identifying the underlying genetic defect is underlined by the high recurrence risk of 50% for maternally inherited intragenic deletions, compared to 1% or less for most other mechanisms. Other reasons, such as appropriate management, school placement, surveillance, and prognosis, are equally important,” the team wrote.

“In conclusion, a patient with a mild AS phenotype and a maternally inherited intragenic UBE3A deletion is described. The deletion was identified in his affected first cousin, and a recurrence risk of 50% was given to the [boy’s] mother and aunt. Identifying the genetic defect in AS patients is of utmost importance, given the large discrepancies in recurrence risk among different underlying mechanisms. Alternative methods, such as MLPA or array-CGH, may be appropriate when conventional testing fails to delineate the genotype,” they concluded.