Angelman Syndrome and Genetic Counseling » Division of Genetics and Metabolism » College of Medicine

This diagram shows the recurrence risk (i.e., the risk for the same parents to have another AS child) for the different AS genetic mechanisms.

This diagram shows that Angelman syndrome can be caused by four different genetic mechanisms, each carrying a very different risk of recurrence in future pregnancies. When the cause is a spontaneous (non-inherited) chromosome deletion, UBE3A mutation, IC defect, or uniparental disomy — meaning it happened by chance and neither parent carries the defect — the risk of having another affected child is extremely low (much less than 1%). When genetic testing cannot identify any known cause, the recurrence risk is simply unknown, making accurate counseling impossible without a definitive diagnosis. However, when the cause is an inherited UBE3A mutation or imprinting center (IC) deletion passed down from a carrier mother, the risk jumps dramatically to 50% with every pregnancy, because a carrier mother — who is unaffected herself — has a one-in-two chance of passing her faulty maternal chromosome 15 to each child. This diagram powerfully illustrates why identifying the exact genetic mechanism behind each Angelman syndrome diagnosis is not just a scientific exercise but an essential step in giving families accurate and meaningful guidance about future pregnancies.

The following aspects must be considered in understanding AS genetic risk:

1. Common chromosome deletion:

More than 98% of the chromosome deletion instances occur by a spontaneous event and thus they are are not inherited; the recurrence risk is <<1% for these families. However, 1-2% of deletions occur because of an inherited abnormality in the maternal chromosome 15, such as a balanced chromosome translocation. Another very small group (e.g., only a few cases reported in the literature), can have AS due to a very small, maternally inherited chromosome deletion that involves a small area around and including the UBE3A gene. For these cases, the maternal recurrence risk is increased depending on the type of abnormality present. Chromosome study of the mother, including FISH, helps rule out inherited chromosome 15 abnormalities.

2. Paternal uniparental disomy (patUPD):

More than 99% of patUPD cases occur as an apparent spontaneous, non-inherited, event. If an individual has AS due to patUPD and has a normal karyotype, a chromosomal analysis of the mother should nevertheless be offered in order to exclude the rare possibility that a Robertsonian translocation or marker chromosome was a predisposing factor (e.g., via generation of maternal gamete that was nullisomic for chromosome 15, with subsequent post-zygotic “correction” to paternal disomy).

3. Imprinting Center (IC) Defect:

There are two types of IC defects: deletions and non-deletions. Non-deletion events do not appear to be inherited and have a <1% recurrence risk. Most deletions are not inherited but a significant proportion of them are (i.e., maternally inherited), and these confer a 50% risk for recurrence.

4. UBE3A mutations:

UBE3A mutation can either occur spontaneously (e.g., not inherited and with no increased recurrence risk) or be maternally inherited and have a 50% risk of recurrence (see below for imprinting inheritance).

5. Individuals with no known mechanism (all 4 above mechanisms have been eliminated):

For parents of AS individuals who have apparent normal genetic tests (no evidence for deletion, imprinting defect, UPD or UBE3A mutation), and thus their children are only clinically diagnosed, it is not known what the recurrence risk is. An increased risk seems likely but probably does not exceed 10%.

6. Germ cell mosaicism:

This term refers to a phenomenon in which a genetic defect is present in the cells of the gonad (ovary in the mother’s case) but not in other cells of the body. This occurrence can lead to errors in risk assessment because a genetic test, for example on a mother’s blood cells, will be normal when in fact a genetic defect is present in the germline cells of her ovary. Fortunately, germ cell mosaicism occurs very infrequently. Nevertheless, it has been observed in AS caused by the mechanisms of large chromosome deletion, Imprinting Center deletion and UBE3A mutation.

7. Imprinting inheritance:

UBE3A mutations and Imprinting Center deletions can exhibit imprinting inheritance wherein a carrier father can pass on the genetic defect to his children without it causing any problems, but whenever a female passes this same genetic defect on to her children, regardless of the sex of her child, that child will have AS. The pedigree diagram below illustrates imprinting inheritance.

This family tree diagram illustrates how an inherited UBE3A mutation can silently pass through generations before causing Angelman syndrome (AS), which is shown by the highlighted blue individuals at the bottom of each family branch. The key to understanding this diagram is that the UBE3A mutation only causes Angelman syndrome when it is inherited from the mother. So when a grandfather (top left) carries the mutation, he passes it to his children without causing AS in anyone because he is male and transmits it as a paternal copy. His carrier daughters then become the critical link — they are completely unaffected themselves, but when they pass the mutation to their own children as a maternal copy, those children develop Angelman syndrome, as seen in the three highlighted AS individuals across the bottom of the pedigree. This explains the seemingly puzzling pattern where a mutation can skip generations and affect only certain children, and it powerfully demonstrates why both males and females in a family should be tested for carrier status when an inherited UBE3A mutation is identified, even if they appear completely healthy.

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